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Lecture 3 : Complications of chemotherapy in the dog and cat The primary target for most anticancer agents is DNA, preventing production of RNA and proteins coded by the DNA. The effect is decreased ability of tumor cells to replicate, and ideally, cell death. Unfortunately, rapidly proliferating normal cells such as bone marrow progenitor cells, gastrointestinal epithelial cells, hair follicles and germ cells can also be adversely affected by chemotherapy drugs. Toxicities to normal tissues limit the dose of drugs which can be given to patients. Therapeutic index is the dose of a drug required to produce a given level of damage to normal tissues divided by the dose of the drug required to produce anticancer effects. Optimizing the therapeutic index is the goal of modern clinical chemotherapy. Therapeutic Index = Dose of drug required to produce a given level of damage to normal tissues Dose of drug required to produce anti-cancer effects The main problems encountered in chemotherapy of lymphoma patients are adverse effects of therapy or emergence of resistance and relapse. Avoiding chemotherapy complications relies on predicting what might go wrong. As chemotherapy drugs affect dividing cells, many agents have adverse effects on the normal tissues where a high proportion of cells are dividing: the most important of these are the gastrointestinal tract (GI) and the bone marrow (BM) as described above. In addition to these commonly affected tissues, individual drugs have individual toxicities. Drugs in the same class, as defined by their mode of action, may have different toxicities. The toxicity profiles of agents differ in cats and dogs, and some breeds are at risk of increased toxicity from certain agents. The dosage of drugs given, the route of administration and the timing of dosages (relative to previous drug administration) may also affect toxicity. Poorly planned or executed chemotherapy can also result in treatment failure and early development of drug resistance, particularly in lymphoma. Established protocols provide the best basis for chemotherapy treatment, and should be followed whenever possible. Continuing to administer ineffective drugs after relapse and tumour progression places the patient at risk of toxicity with little potential benefit and should be avoided, especially when drugs with potentially cumulative toxicities are used. The consequences of dose alterations (increases or decreases) should also be carefully considered. Myelosuppressive potential of common anti-neoplastic agents (neutrophil count at nadir) Severe Moderate Mild-none (<1,000 neutrophils/L) (1-2,000 neutrophils/L) (>2,000 neutrophils/L) Carboplatin Actinomycin-D Chlorambucil (Leukeran) CCNU (Lomustine) Cisplatin Corticosteroids Cyclophosphamide Cytosine Arabinoside L-asparaginase Doxorubicin Hydroxyurea Vincristine Mitoxantrone Melphalan (Alkeran) Vinblastine Emetic potential of common anti-neoplastic agents High Medium Low Cisplatin Actinomycin Chlorambucil Streptozotocin Carboplatin Lomustine Vincristine L-asparaginase Vinblastine Cyclophosphamide Cytosine arabinoside Melphalan Methotrexate Mitoxantrone ADVERSE EFFECTS OF CHEMOTHERAPY Cytotoxic drugs have a lower therapeutic index than most other drugs used in veterinary medicine. As cytotoxic drugs kill dividing cells, the normal tissues which are affected by these drugs tend to be those which are rapidly dividing. Thus the normal tissues which are most affected by cytotoxics are the bone marrow and the gastrointestinal tract. Some agents have other adverse effects on specific organs. In addition to these specific toxic effects some drugs are associated with immediate adverse reactions which are a result of their biochemical nature rather than their action against tumours. Both you and the client must be aware of the potential side effects of the drugs you are using. The most commonly used drugs in lymphoma patients are vincristine, cyclophosphamide and prednisolone in COP regimens; and, in addition to these drugs, doxorubicin/epirubicin, (L-asparaginase) and antimetabolites in multidrug regimens like the Madison Wisconsin protocols. The drugs in the D-MAC and LMP protocols are also mentioned. Vincristine: vincristine is a severe perivascular irritant, and should be administered through a cleanly placed intravenous catheter which is flushed with saline prior to withdrawal. Strenuous efforts should be made to avoid extravasation. In the event of suspected extravasation, a hot compress should be applied immediately. Hyaluronidase (300units diluted in 6ml of 0.9% saline, administered circumferentially to extravasations site, immediately then weekly) may limit tissue necrosis and promote recovery. Topical DMSO may also then be applied by the owner at home. Vincristine is generally not very myelosuppressive, though dogs receiving the higher end of the dose range (0.7-0.75mg/m2) may occasionally become neutropenic 4-7 days after administration. Gastrointestinal side effects are generally uncommon, though some animals may not eat their food on the evening of drug administration. Vincristine has its effects against tubulin, and neuropathies (mainly sensory) are reported in people. In dogs, the autonomic nervous system may be affected and constipation or ileus is occasionally seen. Some Collies, Collie crosses and other individuals have mutations of the MDR1 (multidrug resistance 1) gene and may show toxicity with vincristine (and some other drugs) at lower than standard doses, and severe toxicity at standard doses, necessitating dose modification. It is sensible to start at the lower end of the dose range in Collies and establish the maximum tolerated dose on an individual basis. A screening test is available at Washington State University: however, other genes may also be involved in sensitivity so a normal result does not preclude toxicity. Cyclophosphamide can cause gastrointestinal side effects such as vomiting or diarrhoea 1-3 days after treatment, particularly after bolus dosing. It may cause myelosuppression (neutrophil nadir 5-7 days after bolus administration). Haematology must be checked immediately prior to every bolus dose of cyclophosphamide, and at appropriate intervals on low dose regimens. A particularly troublesome side effect of cyclophosphamide is haemorrhagic cystitis: in dogs, this affects 10-15% of patients. Acrolein, a metabolite of cyclophosphamide, causes haemorrhagic cystitis. Urinalysis (dipstick analysis of a voided sample for evidence of haemorrhage) should be carried out every 2-3 weeks on low dose regimes, and prior to every bolus on high dose COP/multidrug regimens. Detection of a subclinical problem and cessation of therapy can avoid clinical signs, so urine monitoring is mandatory. When bolus doses are used, risk may be reduced by administering furosemide or MESNA. On low dose regimes, give the drug in the morning and, where possible, pair this with corticosteroid administration. With either regime, patients should have access to ad lib water and be encouraged to drink and given frequent opportunities to urinate after drug administration. If blood is detected in the urine or the dog develops any signs of cystitis, cyclophosphamide should be stopped (and replaced with melphalan or chlorambucil). Haemorrhagic cystitis is debilitating for patients and frustrating for owners, and may take weeks to resolve. In slow to resolve cases, DMSO flush is of benefit: 10ml of medical grade 50% DMSO is diluted with 10ml of water for injection. The bladder is emptied and the diluted DMSO instilled. After 20 minutes, the DMSO is withdrawn. DMSO treatment can be repeated after a week. Anti-inflammatories are of benefit. The role of n-acetyl glucosamine in treatment of haemorrhagic cystitis is unproven. It is rare in cats. Prevention may be associated with treatment with furosemide at a dose of 2.2 mg/kg IV once, at the time of cyclophosphamide administration. This causes a forced diuresis and forced voiding of the toxic metabolites. The same effect may occur if an animal is already on a prednisolone containing protocol. Cyclophophosphamide can also be given early in morning and the pet allowed to drink and urinate often over 24h. In cats, cyclophosphamide can cause reduced appetite, thought to be due to altered taste and/or subclinical stomatitis. It is also associated with whisker loss, though this tends to occur gradually and patients adapt. Haemorrhagic cystitis is rare in cats and is not generally closely monitored for, but owners should be aware and monitor for clinical signs. Prednisolone has a number of problematic effects in lymphoma patients. Iatrogenic hyperadrenocorticism is potentially very problematic. Dogs with marked polyphagia may cause problems by raiding bins, stealing food from children and so on. In addition, obesity is a problem and must be counselled against overfeeding the patient. Polyuric dogs may get owners up during the night, which is intolerable long term. Owners must be warned about polyphagia and polyuria. Prednisolone can also cause gastrointestinal ulceration, and has rarely been associated with pancreatitis. Multidrug regimens tend to cease steroid therapy after the first few weeks. L-asparaginase is used inconsistently during induction in multidrug regimens. As an enzyme, it is a foreign protein. To reduce the risk of an anaphylactic reaction, the drug is given intramuscularly rather than intravenously. PEGylated L-asparaginase has reduced immunogenicity but the pharmacokinetics are also altered and it is not readily available. Repeated administration of L-asparaginase is thought to be associated with a higher risk. L- asparaginase has also been associated with diverse effects on protein synthesis including coagulation disturbances in humans. It has rarely been associated with pancreatitis. Doxorubicin or epirubicin are used interchangeably in treatment of lymphoma. Epirubicin is a structural analogue of doxorubicin, but is much less cardiotoxic in dogs. Both are very severe perivascular irritants, and the complications of extravasation can be disastrous (limb amputation or euthanasia). Drugs should be administered through a cleanly placed, first stick catheter. Patients should be supervised throughout infusions, and injection/infusion stopped immediately if there is any local swelling, or if there are signs of discomfort, or changes in resistance to injection or rate of infusion. The catheter must be flushed through with saline prior to withdrawal to ensure no drug is dragged through the tissues on withdrawal. In the event of suspected extravasation, a cold compress should be applied immediately. Hyaluronidase may reduce the risk of severe tissue injury as above, and topical DMSO may then be applied by the owner at home. Dexrazoxane is used for anthracycline extravasations in humans under strict guidelines. Anaphylaxis/hypersensitivity is also occasionally seen after administration of doxorubicin and other anthracyclines, using within a few hours of administration. Premedication with chorpheniramine (0.5mg/kg i.m.) is recommended prior to doxorubicin (but not epirubicin). Hypersensitivity reactions have been rarely reported and it is recommended that patients receiving doxorubicin are premedicated with an antihistamine (usually chlorpheniramine). Another potential problem during drug administration is cardiac dysrythmias: pulse should be monitored throughout infusion and ECG must be available. The risk is reduced if the drug is infused over approximately 30 minutes. These agents are more emetic than the other commonly used drugs, and animals that have vomiting or are off their food post treatment should be treated with antiemetics (maropitant or metoclopramide: see below) ideally on the day of treatment and for three further days. Myelosuppression may occur and the nadir is generally 5-10 days after administration. Doxorubicin and epirubicin may cause an irreversible dose dependent chronic/cumulative cardiotoxicity in dogs. The cause is multifactorial but mostly related to free radical damage to myocardiocytes and high peak serum concentrations of drug. The maximum cumulative dose of doxorubicin for dogs is 240mg/m2 (8 standard doses) but many dogs will show changes in myocardial function at much lower doses. Echocardiographic evaluation prior to the first treatment and then at the third and each alternate treatment is recommended as a minimum. As a broad rule, avoid these drugs if the left ventricular fractional shortening is less than 27%, or the ejection fraction is <50%. Epirubicin is less cardiotoxic: patients are still monitored in the same stringent manner. Dogs that develop cardiomyopathy do not respond to traditional medical management and invariably die rapidly of irreversible cardiac failure. Cytosine arabinoside/methotrexate: as expected, the main adverse effects of these S phase specific agents are on the rapidly dividing cells in the gastrointestinal tract and bone marrow. Gastrointestinal side effects and/or myelosuppression are relatively common. Occasional animals develop severe GI toxicity after methotrexate administration. Cytosine arabinoside is rarely reported to cause anaphylaxis. COMMON SIDE EFFECTS 1. Gastrointestinal (GI) toxicity The mechanism of GI toxicity is multifactorial and includes direct damage to GI mucosal epithelial cells and stimulation of the chemoreceptor trigger zone (CRTZ - floor of 4th ventricle) via neurotransmitters. Stimulation of the medullary emetic center via neurotransmitters (especially neurokinins (NK1) can also occur. Abolishing vomiting at the level of the emetic center likely has a role in controlling emesis due to a variety of causes. Local GI tract irritation can also stimulate GI neurotransmitter receptors and subsequent activation of the vomiting center via vagus and sympathetic nerves. The neurotransmitters include serotonin, neurokinin 1 (substance P like), dopamine, histamine and noradrenaline. Serotonin released from enterochromaffin cells of the GI tract can lead to acute vomiting. Neurokinins (substance P) found in nuclei of vomiting center plays a central role as a neurotransmitter in sensory neurons and also in the afferent pathway of the vomiting reflex. Nausea and anorexia Some agents can cause nausea during or soon after administration, due to central effects on the chemoreceptor trigger zone. Later nausea and vomiting may be due to direct GI tract toxicity. Nausea may be reduced/prevented by pre-treating patients with maropitant orally (2mg/kg p.o.) the night before or by injection prior to chemotherapy (1mg/kg s.c.), and by continuing with treatment orally once daily for up to 4 days if the patient is off his/her food or there is vomiting. (Metoclopramide is unlicensed in the UK, but has a prokinetic effect and useful as a constant rate infusion for animals with GI toxicity). In cats, cyproheptadine (Periactin®, 2-4mg/cat q12-24h) can be fairly effective to treat anorexia and mirtazapine (alpha-2 antagonist, nonselective serotonin antagonist – cats 1/8 to 1/4 of 15-mg tab q 3d) is a new treatment for which more information is needed before recommending its general use. Gastrointestinal Toxicity The direct effects of cytotoxic drugs on the dividing cells of the oral basal epithelium, gastric mucosa and intestinal crypt cells may cause clinical signs, usually 1-5d after treatment (uncommonly up to 10d after treatment). The pattern is most often anorexia on day 1 after treatment, then vomiting or diarrhoea at day 2-3. Symptomatic treatment is required: (intravenous fluids, electrolytes, antiemetics, gut protectants, acidity regulators and antibiotics) and should be aggressive. If GI toxicity results in epithelial damage then there is a greater risk of sepsis should neutropenia develop, as the gut mucosa is a less effective barrier to bacterial translocation. GI signs are also seen as a sequelum to myelosuppression. Vomiting – mild, self-limiting Withold food for 12-24h and perform water only trial; introduce bland foods/small meals. Diarrhoea – mild, self-limiting No food x 12h, introduce bland food Metronidazole (Flaygl®, 15 mg/kg q12h PO), effective for hemorrhagic colitis associated with doxorubicin, epirubicin Severe Vomiting or Diarrhoea Hospitalisation for fluid, antiemetic, prophylactic antibiotics and possibly nutritional support. GI symptoms assoc with a fever may be more serious and can be the first signs of sepsis. Fluid support Antiemetics o Metoclopramide – 1-2mg/kg IV as a CRI over 24h is preferable. o Maropitant (Cerenia®) 1 mg/kg SQ q 24h x 5d or 2.2 mg/kg PO q24h x 5d o Chlorpromazine (Thorazine®) – 0.5 mg/kg q6h SQ if persistent vomiting. o Serotonin antagonists (Ondansetron, Zofran®, 0.1 -1mg/kg q12-24 IV, PO; o Dolasetron, Anzemet®, 0.6-1 mg/kg q24h IV). o Butorphanol (Torbugesic®) – 0.4 mg/kg IM administered once H2-antagonists – ranitidine (2mg/kg BID IV, PO) has prokinetic activity and might have a role for ileus secondary to vinca alkaloids. Antidiarrhoeals o Loperamide (Imodium®, 0.08 mg/kg q6-8h) o Consider opportunistic infections secondary to altered GI flora in patients with prolonged diarrhea or diarrhea nonresponsive to therapy- colitis – metronidazole (Flaygl®, 15 mg/kg q12h PO), sulfasalazine Small bowel diarrhea – rarely r/o salmonella, campylobacter Pancreatitis is reported as an idiosyncratic toxicity with many drugs, including L-asparaginase and prednisone/prednisolone. 2. Myelosuppression Haematology should be carried out at appropriate intervals depending on any low dose regime and prior to every bolus dose of myelosuppressive agents. Bone Marrow Toxicity In healthy adults there are many myeloid stem cells in a quiescent state, which are protected from cytotoxic drugs, but they are triggered into active proliferation when there is any increased demand. Marrow transit time for neutrophil is about 4 days, and in marrow in healthy animals there is a storage pool with about 5 days worth of neutrophils. If neutrophil production ceases, the patient runs out in about 5 days. After a bolus dose of most drugs, the neutrophil nadir occurs 5-7 days later. Some drugs have a delayed effect (melphalan, lomustine) and this effect may also be cumulative. Patients that have problems with particular drugs after bolus doses sometimes cope better with low dose metronomic therapy (e.g. giving low dose cyclophosphamide every other day instead of using a bolus dose every 21 days) , though this may also impact on tumour cell kill and predispose to resistance. Neutropenia is usually the most important bone marrow toxicity, but thrombocytopenia is seen due to melphalan, actinomycin, and lomustine and cytosine arabinoside. BM toxicity will be worsened if there are inadequate recovery periods between myelosuppressive drugs (usually 21 days is allowed). For patients with delayed myelosuppression (e.g. after carboplatin administration) a 4 week dosing interval may be required to allow marrow recovery and prevent cumulative toxicity. Some considerations: The combination of vincristine and L- asparaginase when given within 24 hours of each other will often cause significant myelosuppression (reduction in neutrophil count). Carboplatin: variable nadir (dogs, 7-28 days; cats, 14-21days). Lomustine (CCNU): cats, variable nadir (7-28 days). Prior therapy can influence neutrophil nadir and recovery Lomustine and Melphalan (especially when given sequentially), can also affect platelet production, sometimes leading to prolonged or permanent thrombocytopenia Carboplatin: dogs, severe thrombocytopenia can occur Life span of erythrocytes in circulation is 110-120 days (dog) and 70 days (cat) Mild anemia during chemotherapy is common – consider treatment associated gastrointestinal blood loss or anaemia of chronic disease Anemia is rarely severe and rarely of clinical significance Individual patient variation Regular haematological monitoring (at least prior to every bolus dose and strategically in metronomic therapy) and monitoring of trends is essential. The clinically significant effects of myelosuppression are: • Neutropenia (a neutrophil count of less than 3x109/l in a dog, 2.5x109/l in a cat) • Thrombocytopenia (a platelet count of less than 70x109/l) Anaemia is rarely clinically significant and is often indistinguishable from anaemia associated with the neoplasm itself (chronic disease). Chronic GI haemorrhage is a potential complication in patients on long term steroid therapy. Haematological monitoring is vital in all cases receiving potentially myelosuppressive drugs. Thrombocytopenic patients should be kept quiet until platelet count recovers. It is relatively unusual to see thrombocytopenia without neutropenia. Neutropenic Patients There is no need to panic, particularly if the neutropenia is picked up on haematological evaluation prior to the next scheduled treatment and the animal is well. Asymptomatic, Afebrile Neutropenic Animals If the neutrophil count is less than 1x109/l, the animal may be treated as follows: • Trimethoprim sulphonamide (TMPS) or another broad spectrum antibiotic • Sulphadiazine-trimethoprim (Tribrissen®, 15 mg/kg q12h PO x 5-7d) Clavulanate potentiated amoxicillin (Synulox® 13.75mg/kg PO BID) Discontinuation of the offending drug until neutrophil numbers recover • If possible, the owner should check the animal's temperature 2 or 3 times a day If the neutrophil count is 2 to 3x109/l then discontinuation of the drug until the count recovers will suffice. If it is 1 to 2x109/l then antibiotics may be given at the discretion of the clinician e.g. if there is a pre-existing focus of infection, but should not be given routinely. TMPS combinations are recommended for prophylaxis as although they affect the aerobic intestinal flora, the anaerobes remain, and these bacteria are involved in local defence in the intestines. TMPS combinations also have broad spectrum bactericidal activity, and do not have the resistance issues associated with enrofloxacin. Some oncologists prefer to use clavulanate-potentiated amoxicillin as their first line drug because of the potential toxicities associated with TMPS combinations. Pyrexic, Neutropenic Patients These patients are a medical emergency, but in most cases, pyrexia resolves within hours and circulating neutrophil numbers normalise within 24-48 hours. Patients must be supported aggressively as well as treated with antibiotics. Chemotherapy-induced mucosal damage allows invasion by opportunistic gram negative bacteria (Escherichia coli, Klebsiella, Pseudomonas). Infections with gram-positive cocci and anaerobes are less common but can occur e.g. associated with staphylococci. The clinical signs of neutropenic sepsis include fever, weakness, shaking/shivering, brick-red mucus membranes, tachycardia, tachypnoea, coughing, vomiting and diarrhea. Interestingly, the cardinal signs of inflammation may be absent due to insufficient numbers of neutrophils to participate in the inflammatory process; however it is most common for patients despite extremely low neutrophil numbers to be febrile at presentation. Neutropenic sepsis represents a medical emergency. The following steps should be taken: • All cytotoxic drugs except corticosteroids should be immediately discontinued ▪ The patient should be barrier nursed ideally in isolation, and all sampling, catheter placements etc carried out aseptically • Supportive therapy: intravenous fluids, electrolytes, glucose as indicated • Bactericidal antibiotics: TMPS, fluoroquinolones (enrofloxacin) (can alter later based on sensitivity). Enrofloxacin is preferable to gentamicin (historically recommended) due to the nephrotoxicity of gentamicin • 5-7 days of antibiotic therapy after clinical recovery and restoration of neutrophil numbers. What about the use of Granulocyte Colony-Stimulating Factor? G-CSF (Filgrastim, Neupogen®) regulates production, maturation and function of neutrophils. Its primary use in human chemotherapy patients is to administer G-CSF 24-48h after highly myelosuppressive chemotherapy to decrease the duration and depth of neutropenia. This allows dose intense chemotherapy of human patients, particularly if they are elderly by providing support to the bone marrow. The neutropenic state causes upregulation and production of endogenous G-CSF so serum concentrations are actually higher than before neutropenia, however, dogs with cancer will have lower G-CSF concentrations at their nadir than a healthy dog that was given chemotherapy. Evidence suggests that G-CSF can actually improve neutrophil function therefore giving G-CSF to neutropenic patients that are already febrile might speed neutrophil recovery and reduce hospitalization. Unfortunately data from the human literature does not show consistent clinical benefit and G-CSF is not always recommended as an adjunct to empirical antibiotic therapy. Also, currently only human GCSF is available and dogs and cats might develop neutralizing antibodies if prolonged courses are given (i.e. > 2-3 weeks). The dose for dogs and cats is 5 μg/kg SQ q24h for up to 5 days. What Happens the Next Time? When re-introducing a previously myelosuppressive drug a reduced dose rate is often required. Remember all drug dose reductions reduce tumour cell kill. A 20% reduction in drug dosage can result in a 50% reduction in tumour cell kill in some situations. Dose reduction should be discussed with the owner: approaches include trying a 10% reduction in the first instance, or reducing by 20% or 25% then increasing to 90% of initial dose if there is no toxicity. In some cases the original planned dose will be tolerated by the patient once in remission. When drugs associated with previous GI toxicity are given again, supportive therapy should be increased. Where there has been vomiting, should be treated with antiemetics (metoclopramide or maropitant) ideally on the day of treatment and for three further days. Where there has been severe GI upset, a dose reduction might be required. Some individual animals do not cope well with particular drugs or dosage regimens, and protocols should be tailored to suit. A dog on high dose COP that has problems after bolus doses of cyclophosphamide may do better on low dose oral treatment at home, and a cat that is inappetent after cyclophosphamide treatment may do better on chlorambucil or melphalan. 3. Hair loss Complete hair loss is very uncommon but can be seen in certain dog breeds. Typically affected breeds have continually growing coats and include Poodles, Old English Sheepdogs and some terrier breeds. More commonly slow hair regrowth and alteration in coat quality in cats and dogs and whisker loss in cats are seen. SPECIFIC TOXICITIES Cardiac toxicity Chronic cardiac toxicity has been associated with treatment with anthracycline drugs: doxorubicin and epirubicin. See above. Acute toxicity occurs during or shortly after treatment and is uncommon. It is non-dose dependent. It occurs due to histamine-mediated catecholamine release from mast cells during rapid drug infusion. The signs are acute arrhythmias, hypotension, collapse and other signs of hypersensitivity reaction. This acute toxicity is almost completely eliminated if drug is given slowly (1mg per min). In the event of an acute reaction occurring, discontinue the infusion, administer dexamethasone (0.2mg/kg IV) and chlorpheniramine (4-8mg per dog IM); wait 20 minutes and then restart the infusion at a slower rate. To prevent cardiotoxicity being a problem, avoid use of doxorubicin if there is underlying cardiac disease (myocardial disease, arrhythmias). A baseline echocardiogram is indicated and essential in at risk breeds (Doberman, Boxer, giant breeds). Limit the cumulative dose to 150-180 mg/m2.Cardiac monitoring during infusion can be carried out using a stethoscope and continuous ECG monitor. Cardiac troponin (cTnt) is a protein that mediates interaction between actin and myosin. Measurements of troponin may allow for early detection of myocardial injury caused by doxorubicin. More information is needed however based on clinical research. Dexrazoxane (Zinecard®) is an iron chelator (iron needs to be present for free radical generation to occur that results in myocardial damage). This drug effectively reduces the cardiotoxicity of doxorubicin however there is no benefit once cardiac damage has occurred and the drug is expensive. If a patient appears to have significant systolic dysfunction prior to commencing treatment with potentially cardiotoxic drugs, the owner must be counseled on the risk-benefit ratio of giving the medication and an alternative medication such as mitoxantrone or actinomycin D may be indicated in place of doxorubicin or epirubicin. Hepatic Toxicity Lomustine may cause hepatotoxicity and liver enzymes should be monitored. This toxicity may be idiosyncratic and can be fatal. Care should be taken with agents that undergo hepatic metabolism (e.g. vincristine, doxorubicin, epirubicin) in patients with significantly impaired liver function: these drugs will be metabolised less effectively and toxicity may be increased, rather than there being a direct hepatotoxicity. Nephrotoxicity Anthracyclines (doxorubicin, epirubicin etc) are potentially nephrotoxic. Hypersensitivity reactions There are a number of different mechanisms for development of hypersensitivity reactions due to chemotherapy administration. For L-asparaginase, a polypeptide of bacterial origin (E.coli), the mechanism is stimulated production of IgE and other immunoglobulins that mediate an acute type I anaphylactic reaction. Delayed reactions a few hours to several days can occur. As the mechanism of the hypersensitivity reaction usually requires prior exposure of the immune system to the protein, this rarely occurs on the first administration of the drug. Cases however have been reported and this may be due to previous gastrointestinal disease allowing translocation of small peptide sequences from E. coli in the gut. The risk of reaction increases on second and subsequent administrations of the drug. For doxorubicin/epirubicin, the reaction is not immunologically-mediated. Hypersensitivity reaction is related to direct mast cell degranulation and histamine release if the drug is given too quickly (see above). Clinical signs of hypersensitivity reactions include pruritis, urticaria, cutaneous erythema, agitation, head shaking, facial edema, vocalization, injection-site discomfort, vomiting, diarrhea, hypotension and collapse. Treatment is outlined above. Premedication with chlorpheniramine and dexamethasone 20minutes prior to drug administration may reduce the risk of anaphylactic reactions developing. RESISTANCE AND RELAPSE It is imperative that you check that the animal achieves and maintains remission. Complete remission (CR) means that there is no detectable disease. Lymph nodes should be normal or subnormal in size, and of normal texture. Extranodal disease should be undetectable. Even in complete remission many tumour cells remain. Partial remission (PR) refers to a reduction in tumour volume of more than 50%. In PR there is a huge population of resistant cells. IF YOUR PATIENT IS NOT IN CR YOU MUST DECIDE HOW TO DEAL WITH YOUR RESISTANT POPULATION OF CELLS: YOUR CHEMO IS NOT WORKING. When relapse occurs, it is often possible to achieve a second remission. However, this remission is invariably shorter than the first. Re-induction: for modern non-continuous regimens (e.g. Madison Wisconsin 24 week), simply starting at the beginning again is the usual approach. Re-induction plus additional drugs cytosine arabinoside, L-asparaginase (taking care to avoid additive toxicities) Alter regime completely using drugs which have not been used before e.g. doxorubicin/epirubicin instead of COP, D-MAC (dexamethasone, melphalan, actinomycin D), lomustine after other protocols etc. Radiation therapy Eventually, most dogs and cats develop multidrug resistance and will cease to respond to any drugs. OTHER PROBLEMS IN CHEMOTHERAPY OF LYMPHOMA Alimentary Lymphoma Lysis of GI tract tumours can result in perforation and peritonitis. Where there is a mass lesion that is amenable to surgery this should be resected. Where there is extensive intestinal infiltrate, chemotherapy should be initiated in a staggered manner to reduce the risk of tumour lysis resulting in intestinal perforation. One method of doing this with e.g. COP is to initiate vincristine therapy, then give cyclophosphamide on the third day and start prednisolone therapy on the fifth. Remember absorption of orally administered drugs may be poor. Cutaneous Lymphoma Standard chemotherapy regimens generally have poor response rates in cutaneous lymphoma, and recent studies suggest lomustine is more effective. The role of retinoids (isotretinoin/etretinate) in the treatment of cutaneous lymphoma remains controversial. These agents have significant side effects in some patients, and are very teratogenic and must not be handled by women of child bearing age. They may ameliorate clinical signs (pruritus) but do not seem to produce true remission. Alpha interferons show promise for cutaneous lymphomas, but only human recombinants are available. Tumour Lysis Syndrome Rarely, where there is a large tumour burden, sudden lysis of the neoplastic lymphoid cells produces a hyperkalaemia and hyperphosphataemia (with resultant hypocalcaemia) which can cause cardiac dysrythmias, or renal failure. Aggressive supportive care is required, with frequent monitoring of electrolytes. CNS/Renal lymphoma It may be beneficial to include cytosine arabinoside in induction.