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188 EQUINE VETERINARY EDUCATION / AE / JUNE 2006

Tutorial Article The use of cytotoxic drugs in equine practice T. S. M AIR* AND C. G. COUTO† Bell Equine Veterinary Clinic, Mereworth, Maidstone, Kent ME18 5GS, UK; †College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, Ohio 43210, USA. Keywords: horse; neoplasia; ; cytotoxic medicine; ageing

Introduction It is common to refer to a neoplastic cell as a transformed cell and the associated event as transformation. At this time, there Neoplastic diseases are a major cause of morbidity and is no single, unified concept of the biological mechanisms that mortality among domestic animals, just as they are in man. In underlie transformation and the development of neoplastic the horse, the skin is the organ most commonly affected by disease, and the reader is referred to more detailed texts that neoplasia and the sarcoid is the most common neoplasm describe the major theories about pathogenesis of neoplasia occurring at this site (Sundberg et al. 1977; Goodrich et al. (Ross 1998; Cockerell and Cooper 2002; Kelsey et al. 2002). It 1998). However, other neoplasms affecting all parts of the is generally believed that most neoplasms are monoclonal in body can and do occur, albeit at a lower frequency than origin, i.e. they arise from genetic mutations within a single tumours of the skin. With some exceptions, neoplasms tend to affected cell, although in certain tumours in some species be associated with ageing. Ageing per se is not generally (e.g. equine sarcoid and feline sarcoma) a polyclonal considered a direct factor in the induction of tumours, but mechanism may be involved. Over subsequent cell divisions in presumably allows increased opportunity to develop the neoplasm, heterogeneity can develop through the neoplasia, including cumulative exposure to environmental accumulation of further abnormalities (Kelsey et al. 2002). The carcinogens (Cockerall and Cooper 2002). This is probably one genes most commonly affected are those controlling reason why neoplasms are seen more commonly in dogs and check points, DNA repair and DNA damage recognition, cats than in other domestic animals, because these species are apoptosis, differentiation and growth signalling. Proliferation allowed to live out their natural life span. As geriatric may continue at the expense of differentiation, which together populations of equids increase, so it is likely that more cases of with the failure of apoptosis (apoptosis is also known as neoplasia will be encountered in the horse population (Savage ‘programmed cell death’) leads to tumour formation with the 1998a). However, not all cases of neoplasia occur in older accumulation of abnormal cells (Rudin and Thompson 1997). horses, and some specific tumours are commonly seen in In general, benign tumours grow slowly, and malignant young animals, including lymphoma (lymphosarcoma) tumours grow rapidly. The growth rate of an individual (Rebhun and Bertone 1984; Mair et al. 1985; Mair and Hillyer neoplasm is determined by such factors as the length of the 1992) and hepatocellular carcinoma (Roby et al. 1990; East mitotic cycle, proportion of cells in mitosis and rate of cell loss, and Savage 1998). amongst others. The spread of neoplastic cells by metastasis is the most Pathogenesis, cancer biology and clinical serious consequence of malignancy. More cancer treatment staging failures and deaths in man result from the effects of metastasis than of the primary tumour (Fidler 2000; Cockerall and Over the past 40 to 50 years there has been significant Cooper 2002). In many cases, metastatic dissemination of a progress in the basic understanding of the pathogenesis of malignant neoplasm will have occurred before it can be neoplasia (also known as oncogenesis or carcinogenesis). detected clinically. Microscopic spread, especially via blood Although details of the pathogenesis of neoplasia are beyond vessels and lymphatics, is the reason why surgical removal of the scope of this article, it is likely that future advances in the a primary malignant neoplasm is likely to fail to be curative in diagnosis, prognosis, and treatment of neoplasia in the horse approximately 50% of patients. and other species will be closely tied to advancements in the Grading and staging of neoplasms are commonly used in understanding of the pathogenesis and biology of neoplasia. many human as a means of quantifying the behaviour of the neoplasm in an individual patient. Grading represents an *Author to whom correspondence should be addressed. attempt to quantify the degree of malignancy at the 190 EQUINE VETERINARY EDUCATION / AE / JUNE 2006

microscopic level. Staging represents an attempt to classify the TABLE 1: Categories and examples of commonly used neoplasm according to its progression or extent, with the size chemotherapeutic drugs in veterinary medicine of the primary lesion, the presence of lymph node Major mechanisms involvement, and the presence of metastasis being taken into Category of action Drug examples account (Cockerall and Cooper 2002). Such grading and staging systems are helpful not only in predicting outcome, Alkylating agents Damage DNA and but also for guiding treatment. For example, clinical staging of interfere with cell Chlorambucil replication canine lymphoma correlates with prognosis, and can be used to define the most effective chemotherapeutic regimen (Madewell 1999). In canine lymphoma, staging is based upon the results of a standard set of tests, including a physical Antitumour antibiotics Damage DNA and examination, complete blood count, biochemical profile, interfere with urinalysis, thoracic and abdominal radiographs, abdominal nucleic acid Actinomycin D ultrasound, lymph node and bone marrow aspiration cytology, synthesis and lymph nodebiopsy (Rosenthal 2001). Unfortunately such systems have not been described or Plant alkaloids Distrupt mitosis in the metaphase evaluated in the horse, mainly due to size of the patients, small numbers and difficulties in obtaining follow-up. The sheer size Hormones Immunosuppression Prednisolone of the equine patient makes clinical staging difficult to perform. and anti-tumour Prednisone The identification of abdominal tumours or metastases in the effects Dexamethasone horse can be especially difficult, and often the neoplasia will Interfere with L- have reached an advanced stage by the time clinical signs occur DNA and RNA and a diagnosis is achievable (East and Savage 1998). Similarly, synthesis by Cytosine arabinoside mediastinal tumours (primarily lymphoma) may be present for a interation with 5- enzymes considerable length of time before clinical signs become apparent, and their identification can be difficult using standard Interfere with Taxol techniques of ultrasonography and radiography because of cell division anatomical factors (Mair et al. 1985). Despite these problems, attempts to implement staging Miscellaneous Enzymatic Asparaginase destruction of systems should be encouraged in the most common equine amino acids neoplasms, and would probably aid in the development of chemotherapeutic and other approaches to treatment. For example, clinical staging of squamous cell carcinoma of the a logical approach. The major indication for systemic use of penis and prepuce of male horses has been suggested as being cytotoxic drugs in the horse is in the treatment of potentially valuable in defining prognosis and aiding treatment lymphoproliferative diseases such as lymphoma. Despite the choices (Mair et al. 2000). limitations of in horses, it is likely that as people become more knowledgeable about available treatments for Principles of chemotherapy cancer in man, they will demand more sophisticated treatment options for their animals, including horses. Provided they have an A variety of different treatment modalities are used for treating understanding of the treatment goals and costs, many owners neoplasia. Surgery (including traditional ‘sharp’ surgery, laser are appreciative of honest attempts to control neoplastic disease therapy and cryosurgery) remains the most effective form of (Chun 2001). treatment for most solid tumours of skin, soft tissues and bone, In general, chemotherapeutic agents damage DNA (and but early treatment and aggressive resection are necessary in RNA) and result in cellular death, apoptosis or inability to cases of malignant disease. The use of chemotherapy following undergo mitosis. Some may cause frank necrosis. For many of surgical management of a primary mass is frequently used in these drugs there is a fairly narrow therapeutic window between man as a way of managing malignant disease. effective systemic treatment and toxicity to normal tissues Despite the increasing use of chemotherapy in the treatment (therapeutic index). The drugs are not cancer-specific, but act on of cancer in man and small animals, the use of cytotoxic drugs in neoplastic cells preferentially because of their increased cellular horses has found only limited application. This is partly because proliferation rates. However, the proliferation rate in neoplastic of the high costs involved with treating horses with such drugs, tissues is usually not that much greater than normal tissues, and but also because of perceived problems with adverse drug toxic effects in normal tissues are therefore common in humans effects (see below). Local chemotherapy, including topical and receiving systemic chemotherapy. For this reason, the dose and intratumoral chemotherapy, has been used in cutaneous schedule of chemotherapy is limited by normal tissue tolerance, neoplasms as a way of maximising the exposure of the tumour especially in those tissues that proliferate rapidly such as the to the drug, while avoiding systemic toxicity. The high incidence bone marrow and gastrointestinal tract mucosa. Other tissues of cutaneous neoplasia in the horse makes topical/local therapy can also be affected depending on the individual tissue affinity of EQUINE VETERINARY EDUCATION / AE / JUNE 2006 191

the particular chemotherapeutic agent. Although many of the Topical treatment with 5-FU has been used successfully for chemotherapeutic agents used in veterinary medicine are the the treatment of squamous cell carcinoma of the external same as those used in human medicine, veterinary applications genitalia (Fortier and MacHarg 1994) and other skin sites tend to use lower doses and less aggressive protocols, and so (Paterson 1997). The treatment involves the repeated application adverse effects are less of a problem. In veterinary patients of the drug to the tumour surface. In addition to having cytotoxic quality of life is generally as important as (or perhaps, more activity, 5-FU acts as a contact allergen and induces a delayed important than) disease control (Chun 2001). hypersensitivity reaction that causes the superficial cell layers to Many tumours will develop resistance to single-agent slough (Mansell et al. 1975). Although 5-FU destroys the chemotherapy. For this reason, intermittent combination superficial layers of the tumour, the precise depth of action is chemotherapy was developed. With such regimes, several drugs impossible to predict. Normal skin is less sensitive to the effects are combined together or sequentially, chosen on the basis of of the drug because of the lower proliferation rate of skin cells differing mechanisms of action and nonoverlapping toxicities and the barrier effect of keratin that prevents the drug from (Kelsey et al. 2002). The drug combination is given over a period penetrating to the deeper epithelial layers. Since the topically of a few days, followed by a rest period of a few weeks, during applied cream does not penetrate deeply, it is most useful for which time the normal tissues have the opportunity for superficial tumours (including squamous cell carcinoma) less regrowth. If the normal cells are more proficient at DNA repair than 2 mm thick, but not for the treatment of nodular or deeply than the cancer cells, then it may be possible to deplete the invasive tumours (Theon 1998). It can be used as an adjunct to tumour while allowing restoration of normal tissues between surgery for the treatment of squamous cell carcinoma after chemotherapy cycles. surgical debulking leaving a tumour bed less than 3 mm thick. Chemotherapeutic drugs Treatment should be started as soon as possible after surgery since the drug does not affect wound healing and will not penetrate through a healed skin wound. Treatment is generally Categories of commonly-used chemotherapeutic agents and applied daily for 3–4 months, or longer, until complete tumour examples of drugs are shown in Table 1. A number of the regression has occurred. Total regression of the lesion should be cytotoxic agents cause direct damage to DNA. Alkylating agents confirmed (preferably by biopsy) before treatment is such as cyclophosphamide act by covalently linking alkyl groups and their major effect is to cross-link DNA strands, thereby discontinued, because accelerated regrowth can occur if the interfering with DNA synthesis and causing strand breaks (Kelsey lesion is not completely eliminated (Theon 1998). The number of et al. 2002). These were among the earliest of the cytotoxic treatments required can be reduced if the area can be covered by drugs developed for use in man, but they are still widely used in a waterproof dressing. For the treatment of squamous cell cancer treatment. Platinum compounds, including cisplatin, carcinoma of the penis, the prepuce acts as a dressing and the cause interstrand cross-links of DNA and are often regarded as treatments can be reduced to applications at two week intervals non-classical alkylating agents. As with other heavy metal (Theon 1998). compounds, they can have toxic effects on the kidneys and Ocular (conjunctival and corneal) squamous cell carcinoma peripheral nerves. The antimetabolites, such as 5-fluorouracil can also be treated using topical 5-FU, either alone or in (5-FU), cytosine arabinoside and methotrexate, are structural combination with other treatments. Ophthalmic drops analogues of naturally occurring metabolites; they interfere with continaing 5-FU have been used in man (Yeatts et al. 2000; Foy the normal synthesis of nucleic acids by falsely substituting et al. 2002), but there is very limited information about the purines and pyrimidines in metabolic pathways. The most efficacy of this therapy in horses. This drug has also been used to commonly used drug of this class in the horse, 5-FU, consists of treat equine sarcoids (Figs 1a and b), often in combination with a uracil molecule with a substituted thymidylate synthetase other therapies such as surgical debulking. Sarcoids are which is essential for pyrimidine synthesis. common, locally invasive, non-metastatic, fibroblastic tumours The cytotoxic antibiotics, such as doxorubicin, act by that can affect any part of the body, but especially the ventral intercalating adjoining nucleotide pairs on the same strand of abdomen, limbs and head (Goodrich et al. 1998; Foy et al. DNA and by inhibiting DNA repair. The vinca alkaloids, including 2002). To aid the penetration of the 5-FU through the superficial vincristine and vinblastine, act by binding to tubulin and epidermis, the drug can be mixed with podophyllin, an irritant inhibiting mirotubule formation (part of the cytoskeleton of the cathartic (McConaghy et al. 1994; Piscopo 1999). Topical 5-FU cell), thus disrupting mitosis. The taxanes also bind to tubulin and needs to be applied daily for 30–90 days. Alternatively, it can be prevent their assembly into . applied less frequently under a bandage (Roberts 1970). It is most useful for single, small occult or verrucose sarcoids, or for Topical chemotherapy for cutaneous neoplasms larger areas of occult or verrucose sarcoids that are not amenable to any other form of treatment. The treated area can show a Topical and intralesional chemotherapy enable high marked inflammatory reaction, but scarring is usually minimal concentrations of cytotoxic drugs to be maintained within (Pascoe and Knottenbelt 1999). cutaneous and other superficial neoplasms over a long period Heavy metal compounds, including inorganic arsenic, while sparing adjacent normal skin (Theon 1998), thus antimony and mercury salts, cause tissue necrosis, and can be minimising toxicity. Immunotherapeutic agents can also be used topically to treat sarcoids (Pascoe and Knottenbelt 1999). successfully used by these application routes. A topical ointment (AW-3-LUDES)1 containing a variety of 192 EQUINE VETERINARY EDUCATION / AE / JUNE 2006

a) b) a) b)

Fig 1: Successful treatment of a superficial verrucose sarcoid on Fig 2: Treatment of a fibroblastic sarcoid on the cannon region the head with 5 fluorouracil ointment. a) Before treatment and with topical AW-3-LUDES cream. a) Before treatment and b) one year later. b) 2 months after treatment. heavy metals with 5-FU and thiouracil has been used in the UK a) b) for the treatment of sarcoids for several years (Knottenbelt and Walker 1994; Knottenbelt and Kelly 2000; Newton 2000). The ointment is applied on successive or alternate days for 3–5 treatments, depending on the size, number and nature of the sarcoids, and the strength of the ointment used. An inflammatory reaction is usually seen after one or more treatments. In some cases, a painful and marked oedematous reaction occurs, necessitating anti-inflammatory treatment. A full response is usually seen in 5–10 weeks, characterised by necrosis and sloughing of the sarcoid tissue. A granulated wound bed usually remains once the sarcoid tissue sloughs. A resolution rate of over 80% has been reported in cases where sarcoids are being treated with topical AW-3-LUDES for the first time (Knottenbelt and Walker 1994) (Figs 2a,b and 3a,b). Fig 3: Treatment of a fibroblastic sarcoid on the medial thigh The success rate decreases by 30–40% for each previous with topical AW-3-LUDES cream. a) Before treatment and 2 unsuccessful treatment. A topical paste (Xxterra) containing b) 2 months after treatment. zinc chloride and plant alkaloids derived from the bloodroot plant has recently become available in the USA, and there is there appear to be few published studies, and it is not possible anecdotal evidence that it can be successful in eliminating to compare the short- and long-term results of these small, localised sarcoids (Palmer 2002). A rapid response to the treatments with other therapies. extract is usually seen, with inflammation followed by pus accumulation under the tumour base and sloughing of the Intralesional chemotherapy for cutaneous lesion in 7–10 days; the surrounding healthy skin is left intact. neoplasms The reaction appears to be similar to that seen in graft rejection. There is anecdotal evidence of effect on sarcoids Intralesional injection of cytotoxic drugs into the tumour and remote from those being treated in some cases. Another tumour bed allows higher intratumoral drug concentrations to bloodroot extract (Animex)3 containing Sanguinaria be achieved and permits accurate placement of the drug canadensis, puccoon, gromwell, distilled water and trace within the tumour. The beneficial effects of this route of minerals has also recently been used to treat various skin administration are enhanced if drug carriers that prolong the lesions including sarcoids (Foy et al. 2002). The ointment is said persistence of the drug in the tissue are used. Viscous fluid to penetrate the lesion, killing the affected cells while leaving preparations such as sesame seed oil or almond oil are the surrounding healthy tissue intact. In the UK, a topical frequently used to achieve this effect (Theon et al. 1993). The ointment of undisclosed composition is available commercially viscosity of the drug mixture can be altered, and vasoactive (Camrosa)4. There is anecdotal evidence of efficacy of this agents included that will alter drug reabsorption, depending substance in the treatment of all types of sarcoid. on the individual characteristics of the tumour being treated. Unfortunately, the results of topical therapies using the Cisplatin is the drug most widely used in this manner, above mentioned drugs are difficult to quantify. Although although carboplatin, 5-FU and bleomycin are also suitable for there are many anecdotal reports indicating good efficacy, intralesional use. EQUINE VETERINARY EDUCATION / AE / JUNE 2006 193

a) b) pushing the plunger of each syringe until a milky white suspension develops. The target volume of tissue to be injected should include all visible tumour plus a margin of normal tissue of 1–2 cm (Theon 1997). This formulation of cisplatin (3.3 mg of cisplatin/ml of emulsion) is relatively stable and will not separate into two phases over a 3 hour period (Theon et al. 1993). The tumour and surrounding tissue margin are infiltrated with the emulsion through a 20–23-gauge needle attached to a luer-lock syringe; the last step is important, since the high viscosity of the emulsion frequently causes for the needle to get detached from the syringe (spilling its contents on the patient or the operator) if a luer-lock mechanism is not used. To administer the drug, the needle is inserted into the tissue to the desired depth and the Fig 4: Squamous cell carcinoma of the vulva in an aged mare. drug is injected as the needle is withdrawn. The desired a) Before treatment and b) after 4 treatments with volume of emulsion is injected via multiple sites using a intralesional cisplatin (administered at approximately 3-week parallel-row technique or field-block technique. The rows of intervals). The tumour mass is significantly reduced in size, although complete resolution was not achieved in this mare following further treatments.

Fig 6a: Mare in the early stages of chemotherapy for multicentric lymphoma using the COP (cyclophosphamide, vincristine and prednisolone) protocol. At this time the mare Fig 5: Horse receiving intravenous chemotherapy for lymphoma was pregnant (second trimester), had been receiving (note vinyl gloves are being worn by the operators, but these chemotherapy for 7 weeks and was in complete remission. are now known to not be protective).

Intralesional cisplatin therapy has been found to be effective in the treatment of a variety of solid tumours including squamous cell carcinoma (Fig 4), sarcoid, soft tissue sarcomas, lymphoma, plasmacytoma and hamartoma (Theon 1998). For melanomas, it has been suggested that more effective treatment is achieved when a vasoactive agent such as adrenaline is added to the formulation (Theon 1997). Intralesional cisplatin can be effective as the sole treatment for tumours measuring up to 3–5 cm in diameter; for larger tumours (>20 cm3), the treatment should usually be combined with surgery (Theon et al. 1994). Emulsions made up from 1 ml of an aqueous solution of 10 mg cisplatin/ml and 2 ml sesame oil are frequently used at a dose rate of 1 mg cisplatin/cm3 of tumour (Goodrich and Semevolos 2000). The emulsion is created by attaching 2 luer-lock syringes (one with Fig 6b: Mare shown in Figure 6a with foal after successful the aqueous cisplatin solution and one with the sesame oil) to chemotherapy for multicentric lymphoma. Chemotherapy was a 3-way valve; the valve is closed towards the exit (i.e. needle initiated in the second trimester of and was not port) and the solution and oil are mixed by alternatively associated with adverse effects. 194 EQUINE VETERINARY EDUCATION / AE / JUNE 2006

injections should be kept 0.6–0.8 cm apart (Theon 1997). Systemic chemotherapy Injection into multiple tissue planes may be required (Goodrich and Semevolos 2000). Repeated injections every 2 weeks are Systemic chemotherapy has been used and reported relatively continued until all clinical evidence of neoplasia has infrequently in adult horses. There are, however, a limited disappeared. Local wound toxicosis is minimal and number of reports of chemotherapeutic treatment of equine perioperative cisplatin treatment does not appear to affect lymphoma (lymphosarcoma) (Fig 5). Lymphoma is the wound healing. Alternative formulations of cisplatin have commonest of the lymphoproliferative diseases in horses. It is been described. An emulsion of almond oil and cisplatin with also the commonest malignant neoplasm seen in this species a final concentration of 1 mg cisplatin/ml, injected every (Rebhun and Bertone 1984) and carries a grave prognosis. As 5–7 days, resulted in complete resolution in 6 of 18 cases of the disease is most commonly multicentric or generalised, periorbital sarcoid in one report, and improved but did not surgical resection of lymphomatous masses is unlikely to be resolve a further 10 of 18 cases (Knottenbelt and Kelly 2000). beneficial. However, in cases of solitary lymphoma with no A mixture of aqueous cisplatin (5 ml; 1 mg/ml) and 1 ml of spread, local surgical resection or radiotherapy can be epinephrine (adrenalin 1:1000) is described by Doyle (1998); beneficial or curative (Coumbe 1994). Small intestinal and the solution is administered weekly. large colon resection have proved curative in a limited Intralesional cisplatin treatment generally has good number of cases of solitary intestinal lymphoma masses cosmetic results, and can be used at sites such as the eyelid, (Dabareiner et al. 1996). pinna, muzzle, penis and base of tail (Theon 1998; Chemotherapeutic protocols have been used in cases of Knottenbelt and Kelly 2000). A 2-year local control rate of generalised lymphoma with some limited success (Couto approximately 90% has been reported for sarcoids and 1994; Savage 1998b; Johnson 1998). Most protocols have 70–90% for squamous cell carcinoma (Theon et al. 1993, included combinations of vincristine, cyclophosphamide, 1994; 1998; Goodrich and Semevolos 2000). cytosine arabinoside, chlorambucil, doxorubicin, Intralesional 5-FU has been used most commonly in the and prednisolone. The dosages are generally extrapolated treatment of squamous cell carcinoma. In one study from small animal and human oncology, and are calculated on 5-FU was found be ineffective as a single intralesional agent a square metre basis using the following formula (Couto for the treatment of squamous cell carcinoma (Orenberg et al. 1994; Doyle 1998): 1992), although it can be effective when combined with surgery or used as multiple treatments. A solution of 5-FU Body surface area (m2) = weight (g2/3) x 10.5 (500 mg in 10 ml) can be mixed with 3 ml of epinephrine 104 (1 mg/ml) and administered intralesionally (50–60 mg/cm3) (Doyle 1998). It may also be injected together with cisplatin. An approximately 50% remission is usually achieved and is At The Ohio State University we have used a 5-FU/ sesame oil seen within 2–4 Weeks (Figs 6a and b). Dosages for the emulsion for intralesional injection of squamous cell commonly used antineoplastic agents are summarised carcinomas with a high degree of success. We typically mix in Table 2. 250 mg of 5-FU (i.e. 5 ml) with 3–5 ml sesame oil in a 12 ml The Ohio State University currently uses the CAP protocol, luer-lock syringe and administer every 2 weeks for a combination of cytosine arabinoside at an average dose of 3–5 treatments as described above. Adverse effects are 1–1.2 g (total dose), subcut. or i.m., once every 1–2 weeks; minimal and over 75% of the tumors experience complete or cyclophosphamide at a dose of 1 g (total dose) i.v., every partial remission. 2 weeks (alternating with cytosine arabinoside); and A variety of other agents administered by intralesional prednisolone at a dose of 1 mg/kg, per os, every other day. injection have been used in the treatment of cutaneous Vincristine (2.5 mg, i.v.) is added on the weeks when the neoplasms in horses. These include chemicals such as cytosine arabinoside is administered if there is no response. formalin, calcium chloride, zinc chloride and copper sulphate. These are starting doses; the total doses can be increased by Although there are anecdotal reports of their efficacy, no 20–30% without expecting complications. With remission, published studies exist to support the use of such substances. the starting doses are maintained for 2–3 months and then

TABLE 2: Dosages of chemotherapeutic agents used systemically in equine neoplasia

Drug Dose rate Route Frequency Typical doses

Prednisolone 1 mg/kg per os Every other day Vincristine 0.5 mg/m2 i.v. Weekly 2.5–3.0 mg/horse/dose Cytosine arabinoside 200–300 mg/m2 subcut., i.m., i.v. Every 1–2 weeks 1–1.5 g/horse/dose Cyclophosphamide 200 mg/m2 i.v. Every 1–2 weeks 1 g/horse/dose Doxorubicin 20–30 mg/m2 i.v. Every 2–3 weeks 2.5–3.0 mg/horse/dose Dactinomycin 0.5–0.75 mg/m2 i.v. Every 3 weeks 2.5–3.0 mg/horse/dose Chlorambucil 20 mg/m2 per os Every 2 weeks 100 mg/horse/dose L-asparaginase 10,000–40,000 i.u./m2 i.m. Every 2–3 weeks 50,000–200,000 i.u./horse/dose EQUINE VETERINARY EDUCATION / AE / JUNE 2006 195

the horse is switched onto a maintenance protocol. The first References cycle of maintenance therapy increases the treatment interval for each antineoplastic agent by one week (except Carlson, G. (2002) Lymphoma (lymphosarcoma) in horses. In: Large prednisolone which is kept at the same frequency but with Animal Internal Medicine, 3rd edn., Ed: B.P. Smith, Mosby Inc., St Louis. pp 1072. a reducing dose). If the horse is still in remission after 2–3 months of the first cycle, the second cycle is begun by Chun, R. (2001) Theory of chemotherapy. In: Veterinary Oncology Secrets. Ed: R.C. Rosenthal, Hanley & Belfus, Philadelphia. pp 67-70. adding a further week to the treatment intervals of each Cockerall, G.L. and Cooper, B.J. (2002) Disorders of cell growth and drug. Most horses in remission are treated for a total of 6–8 cancer biology. In: Mechanisms of Disease. A Textbook of months (Schneider 1997). Approximately 50% of Comparative General Pathology, Eds: D. Slauson and B. Cooper, multicentric lymphoma patients can be brought into Mosby, St Louis. pp 299-377. remission for several months to a year using this protocol. Coumbe, C.M. (1994) Primary parotid lymphoma in a 10 year old Recurrence is likely following withdrawal of the treatment. Hanoverian gelding. Equine vet. Educ. 6, 91-94. Horses receiving systemic chemotherapy should be Couto, C.G. (1994) Lymphoma in the horse. In: Proceedings of the monitored for signs of gastrointestinal, renal or neurological 12th Annual Forum of the American College of Veterinary Internal Medicine, San Francisco. p 865. toxicity. Weekly haematological evaluations, as well as occasional serum biochemical profiles, are advised. Dabareiner, R.M., Sullins, K.E. and Goodrich, L.R. (1996) Large colon resection for treatment of lymphosarcoma in two horses. J. Am. Myelosuppression and gastrointestinal adverse effects are vet. med. Ass. 208, 895-897. extremely rare in horses receiving systemic multi-agent Doyle, P.S. (1998) Chemotherapeutic modulation of skin tumors. In: chemotherapy (unpublished observations). Current Techniques in Equine Surgery and Lameness, 2nd edn., Other chemotherapy protocols have included single Eds: N.A. White and J.N. Moore, W.B. Saunders Co., Philadelphia. agent L-asparaginase i.m. once every 2–3 weeks, single pp 93-97. agent cyclophosphamide i.v. once every 2–3 weeks and East, L.M. and Savage, C.J. (1998) Abdominal neoplasia (excluding combinations of either cytosine arabinoside or urogenital tract). Vet. Clin. N. Am.: Equine Pract. 14, 475-493. cyclophosphamide with prednisolone (Schneider 1997). Fidler, I.J. (2000) Angiogenesis and cancer metastasis. Cancer J. Sci. Am., Suppl. 6, 134-141. Corticosteroids, such as oral or parenteral dexamethasone, used alone have also proved helpful in reducing lymphoma Fortier, L.A. and MacHarg, M.A. (1994) Topical use of 5-fluorouracil for treatment of squamous cell carcinoma of the external genitalia of masses and controlling some clinical signs temporarily horses: 11 cases (1988-1992). J. Am. vet. med. Ass. 205, 1183-1185. (for up to 18 months) in some cases (Schneider 1997; Foy, J.M., Rashmir-Raven, A.M. and Brashier, M.K. (2002) Common McClure 2000; Carlson 2002; Gerber et al. 2002). equine skin tumours. Comp. cont. Educ. pract. Vet. 24, 242-253. Corticosteroids are also indicated to treat immune mediated Gerber, V., Schott, H.C., Mullaney, T.P., Marteniuk, J. and Kiupel, M. anaemia and that may occur in (2002) Glucocorticoid treatment for intestinal lymphomas of T-cell association with lymphoma. origin. In: Proceedings of the 7th International Equine Colic Symposium, Equine Veterinary Journal Ltd., Newmarket. p 125 Chemotherapy safety Goodrich, L.R. and Semevolos, S.A. (2000) How to prepare and inject cisplatin in oily emulsion to treat equine sarcoids and squamous Cytotoxic drugs have a very narrow margin of safety, and cell carcinomas. Proc. Am. Ass. equine Practnrs. 46, 173-175. use of proper personal protection equipment during Goodrich, L., Gerber, H., Marti, E. and Antczak, D.F. (1998) Equine preparation and chemotherapy administration is necessary sarcoids. Vet. Clin. N. Am.: Equine Pract. 14, 607-623. to minimise exposure of personnel to the drugs (Lucroy Johnson, P.J. (1998) Dermatologic tumors (excluding sarcoids) Vet. 2002). Disposal of materials used should also follow the Clin. N. Am.: Equine Pract. 14, 625-658. appropriate guidelines (Yodaiken and Bennett 1986). Drugs Kelsey, S.M., Gallagher, C.J. and Tate, T. (2002) Medical oncology including haematological malignancy. In: Clinical Medicine, 5th edn. such as 5-FU are commonly dispensed to owners for topical Eds: P. Kumar and M. Clark, W.B. Saunders, Edinburgh. pp 473-510. treatment over a prolonged time course. As the drug is Knottenbelt, D.C. and Kelly, D.F. (2000) The diagnosis and treatment mutagenic and carcinogenic, safety guidelines for handling of periorbital sarcoid in the horse: 445 cases from 1974-1999. Vet. the drug and for disposal of contaminated dressings must Ophthalmol. 3, 169-191. be followed by the owners. Knottenbelt, D.C. and Walker, J.A. (1994) Topical treatment of the equine sarcoid. Equine vet. Educ. 6, 72-75. Acknowledgements Lucroy, M.D. (2002) Chemotherapy safety in veterinary practice: hazardousdrug administration. Comp. cont. Educ. pract. Vet. The authors thank Dr Derek Knottenbelt for providing Figures 2 24, 140-146. and 3. Madewell, B.R. (1999) Diagnosis, assessment of prognosis, and treatment of dogs with lymphoma: The sentinel changes (1973- 1999). J. vet. int. Med. 13, 393-394. Manufacturers’ addresses Mair, T.S. and Hillyer, M.H. (1992) Clinical features of lymphosarcoma in the horse: 77 cases. Equine vet. Educ. 4, 108-113. 1D.C.Knottenbelt, University of Liverpool, Neston, South Wirral, UK. 2Larson Labs Inc., Vet Line, Fort Collins, Colorado, USA. Mair, T.S., Lane, J.G. and Lucke, V.M. (1985) Clinicopathological 3NIES Inc., Las Vegas, Nevada, USA. features of lymphosarcoma of the thoracic cavity in the horse. 4Camrosa Equestrian Ltd., Wadhurst, East Sussex, UK. Equine vet. J. 17, 428-433. 196 EQUINE VETERINARY EDUCATION / AE / JUNE 2006

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