Learning Objectives

The veterinarian should recognise and have at least one management tool for the chief side effects of the commonly used chemotherapy agents vincristine, vinblastine, doxorubicin, cyclophosphamide, prednisolone, carboplatin, cisplatin, and understand the major contraindications and cautions of the less commonly used drugs toceranib, masitinib, capecitabine, fluorouracil, cytosine, methotrexate, paclitaxel, L-asparaginase, chlorambucil, melphalan, and lomustine.

Introduction

The first step in understanding and preventing the side effects of chemotherapy is to understand the common mistakes vets make when doing chemotherapy. This kind of vet:

1.  Doesn't have a tissue diagnosis (i.e., uses the incorrect drug for the tumour or even worse, treats noncancerous diseases with chemotherapy)

2.  Doesn't stage the disease, and therefore misunderstands the extent or limits of the disease, thereby over- or undertreats the disease

3.  Doesn't check the patient beforehand for comorbidities related to breed (e.g., DCM in a large-breed dog about to [potentially] receive doxorubicin; hepatic or renal insufficiency in a senior patient; and so forth)

4.  Doesn't get baseline values for the relevant tests of organ function (i.e., white cell count for myelosuppressive drugs; liver function for drugs metabolised by the liver)

5.  Doesn't keep checking these parameters at the correct intervals

6.  Doesn't react to changes in parameters

7.  Doesn't weigh the patient at each visit

8.  Doesn't read the package inserts and relevant veterinary literature on all and every drug being used, included supportive medications, for interactions, special precautions and contraindications

9.  Doesn't stick to established protocols, but rather just throws any old drug at any tumour, at any interval

10.  Doesn't take personal, staff, patient, and client safety into consideration when ordering, storing, formulating, administering, or dispensing chemotherapy

11.  Keeps doing the same thing even when it's patently not working

12.  Does something - like give a drug - when he/she doesn't know what to do

Understanding the Common Drugs

Contraindications, Special Precautions and Interactions Between Common Chemotherapy Agents

What Are the Main Problems Caused by Chemotherapy Agents?

1.  Myelosuppression

a.  The bone marrow is suppressed by most agents, reaching the minimum neutrophil count at a specific point called the nadir, which is dependent on the drug and sometimes the dose, concurrent illnesses or medications. In general practice, do not repeatedly allow patients to go below 4.0 x 10⁹ cells/L.

b.  A good strategy for managing this is the use of prophylactic antibiotics, such as trimethoprim-sulpha 10–15 mg/kg q 12 h for the duration of the chemotherapy induction and consolidation courses (not in Dobermann Pinschers or where there is renal or hepatic disease! Watch out for keratoconjunctivitis sicca by doing a baseline and repeated Schirmer tear test!)

c.  Prednisolone and low-dose (0.5 mg/m²) vincristine are not considered myelosuppressive. Vincristine at 0.7 mg/m² or when administered at the same time as L-asparagine can be myelosuppressive, or in the face of hepatic or renal disease. Monitor by means of a haematology and/or blood smear.

2.  Chemotherapy-induced nausea and vomiting (CINV)

a.  Many cytotoxic drugs have adverse effects on the gastrointestinal tract, either as a direct result of the action of the drug on the oral, gastric, and intestinal epithelium, or as a result of nonspecific myelosuppression. Death and desquamation of alimentary epithelium usually occurs 5–10 days following administration of the drug and leads to stomatitis, vomiting, and mucoid or haemorrhagic diarrhoea. In the majority of cases such problems are self-limiting and the animal recovers spontaneously as the normal alimentary epithelium regenerates. Some drugs induce nausea and vomiting by stimulation of the chemoreceptor trigger zone; these include cisplatin and doxorubicin.

b.  Treatment of CINV is symptomatic but a really good tool is prevention; give the patients Cerenia (maropitant) or metoclopramide from the morning of chemotherapy, before they arrive for treatment (i.e., at home) and for 3+ days thereafter.

i.  Antiemetics (e.g., maropitant, metoclopramide, prochlorperazine, Ondansetron, butorphanol [for platinum drugs], dexamethasone [for brain tumours or prior to radiation therapy]) are useful in the prevention or control of drug-induced vomiting.

c.  Antacids (sucralfate), anti-ulcer drugs (omeprazole, esomeprazole) and ulcer healing drugs (misoprostol) may be used to assist in the control of gastric ulceration.

d.  Intravenous fluid therapy should be given in cases where the vomiting/diarrhoea are severe or prolonged.

e.  Mucosal injury can also predispose to systemic infection and parenteral antibiotics may be indicated, as discussed above.

f.  Some patients may develop a severe colitis: Salazopyrin (= sulphadiazine), mesalazine, olsalazine may be a necessary adjunct here.

g.  Use diets such as i/d prior to the use of drugs known to cause diarrhoea, in an individual patient.

3.  Hypersensitivity/anaphylaxis

a.  Hypersensitivity reactions to cytotoxic drugs are rare, but have been reported in dogs following administration of L-asparaginase, doxorubicin, cisplatin, and cytarabine.

b.  Some cytotoxic drug hypersensitivities are immune-mediated reactions (e.g., L-asparaginase), although some drugs (e.g., doxorubicin) degranulate mast cells directly and others may activate the alternative complement pathway.

c.  The route of administration can affect the incidence of hypersensitivity reactions. L-asparaginase may produce anaphylaxis in up to 30% of dogs when administered intravenously; for this reason, it is recommended that the drug should always be given by the intramuscular or subcutaneous route. Patients sensitive to the E. coli-produced transgenic product may sometimes be safely given the original Erwinia product, if they can and must be found.

d.  Pre-treatment with mepyramine maleate at 2–4 mg/kg can reduce the frequency of some drug reactions and this is usually recommended prior to administration of doxorubicin.

e.  Treatment of allergic reactions

i.  Stop administration of the drug immediately

ii.  Treat with intravenous fluids, soluble corticosteroids, adrenaline, and antihistamines.

4.  Phlebitis and tissue necrosis

a.  Many cytotoxic drugs are irritant or vesicant and may cause severe local tissue necrosis following perivascular injection or extravasation from the intravenous injection site.

b.  Vesicants include doxorubicin, vincristine, vinblastine.

c.  Irritants include cisplatin, carboplatin

d.  Prevention

i.  Adequate restraint of the patient.

ii.  First-prick technique - if the vein is damaged, blown or over-penetrated by the catheter, use another vein. I make a point of using the cephalic not the accessory cephalic vein; you can then "move up" the leg and the vessel is more visible; avoid using the jugular or saphenous if possible. Consider referral to a specialist oncologist who can place a "vascular access device" in patients with bad veins.

iii.  An intravenous catheter must be used for administration of the drug. This should be flushed with saline prior, during, and after administration of the agent. Use an "aspirate - flush - chemo aspirate - inject 1/3–¼ dose - saline aspirate - flush - repeat" cycle to continuously keep checking yourself.

e.  Treatment in the event of perivascular leakage

i.  Stop the infusion but do not remove the catheter.

ii.  Aspirate the extravasated drug from the affected area immediately; this may be assisted by subcutaneous injection of 0.9% sodium chloride to dilute any residual drug. Try to draw some blood/fluid back from the catheter. In the case of Vinca alkaloids and doxorubicin, make "fishnet stocking" cuts into the surrounding skin so that flushing actually expels the drug onto the surface, through the cuts, so as to permit mopping up (wear double gloves of course!)

f.  Remove catheter.

i.  Soluble corticosteroids (e.g., hydrocortisone) should be administered systemically IV, locally as subcutaneous injections, and topically (as cream) around the site of extravasation.

ii.  Cold compresses may also help reduce the inflammatory response, especially for doxorubicin.

g.  Specific recommendations for different agents can be found in medical texts. The agents are:

i.  Vinca alkaloids: Hyaluronidase, 100–400 IU subcutaneously; very expensive.

ii.  Anthracyclines: DHM-3, cold compresses, dexamethasone.

iii.  Platinum compounds: Sodium thiosulphate SC

h.  Prevention is better than trying to manage it.

5.  Specific drug-associated toxicity

a.  Cyclophosphamide (CPP): Sterile haemorrhagic cystitis (SHC)

i.  Metabolites of cyclophosphamide (in particular acrolein) are excreted in the urine and have an irritant action on the bladder mucosa, resulting in an acute inflammation, often accompanied by profuse bleeding. This sterile haemorrhagic cystitis can occur at any time during cyclophosphamide therapy, but is more common following administration of a high dose or after long-term, continuous low-dose therapy. It is not commonly seen with cyclophosphamide therapy. In some cases, the cystitis resolves following withdrawal of treatment, but in severe cases, resolution can take considerable time. There is no specific treatment for cyclophosphamide-induced haemorrhage cystitis, although instillation of aluminium hydroxide, formalin or dimethylsulphoxide (DMSO) into the bladder has been reported to assist its resolution. Because of the distressing nature of the problem, it is preferable to try and minimize the risk of haemorrhagic cystitis in patients receiving cyclophosphamide by:

a)  Administration of the drug in the early morning.

b)  Ensuring a good fluid intake.

c)  Encouraging frequent emptying of the bladder.

d)  Concurrent glucocorticoid or furosemide administration will assist diuresis.

e)  The urine of dogs receiving cyclophosphamide should be checked regularly for blood and protein to help detect the problem in its early stages.

f)  The preventative (not curative!) antidote, Mesna (Uromitexan) can be given IV, just prior to cyclophosphamide administration, or orally.

(1)  The dose administered is 40% of the dose of cyclophosphamide IV, or 80% of the dose per os, mixed with food; well tolerated (tasteless), affordable and recommended, given 0, 4 and 8 h after CPP administration

b.  Doxorubicin (& related drugs): Cardiotoxicity

i.  Doxorubicin can cause acute and chronic cardiac toxicity through a combination of (1) generation of large amounts of Fe³⁺ and Cu²⁺ free radicals, (2) "quenching" of endogenous antioxidant systems in the cells, and (3) the low level of these antioxidant systems in myocardial cells. The rate of infusion can influence this cardiac toxicity and it is recommended that the drug be administered as an infusion over at least 45 minutes.

a)  Acute cardiac toxicity: Tachycardia and arrhythmias may occur on administration of the drug. The pulse rate and character should be monitored throughout administration and immediately afterwards. If problems occur, the infusion should be stopped or slowed. Characteristic changes in the QRS complex and atrial fibrillations are the most common seen.

b)  Chronic changes are due to cumulative, dose-related damage to the myocardium that leads in some cases to an irreversible cardiomyopathy. All dogs should have thoracic radiographs, an ECG, and ultrasound assessment of ventricular fractional shortening prior to treatment. There is no absolute dose at which cardiomyopathy occurs in all dogs, and there is tremendous variation between patients. The total, lifetime, dose of the drug administered should be limited to 240–280 mg/m², as it is above this level at which cardiomyopathies usually occur in > 2–3% of patients. Some authors recommend a maximum of 180 mg/m² (i.e., 6 treatments at 30 mg/m² each).

The specific toxicities, myelosuppressive actions and effects of the less commonly used drugs will be mentioned in the lecture. These drugs are considered specialist medications and should not be used by general practitioners.

References

References are available upon request.