Chemotherapy does induce side effects. These can be very mild and self-limiting. They can also be severe and life-threatening. All persons involved in the care of chemotherapy patients and their owners have a duty to be conversant with the principal side effects associated with their use. In addition to guiding an owner through the decision-making process, we have to give them the knowledge to feel confident that if a problem happened, they would know exactly what to do about it.

Gastrointestinal Signs

Damage to the lining of the intestines can induce side effects ranging from mild inappetence lasting only a day or so to severe haemorrhagic gastroenteritis requiring hospitalisation. Mild signs should be managed in the same way that they would have been managed had they arisen under different circumstances. More severe gastrointestinal signs induce significant electrolyte and volume disturbances; the altered intestinal environment can also promote bacterial transfer from the intestine into the bloodstream. Patients with significant vomiting and diarrhoea will lose extracellular fluid volume and there will be significant electrolyte and acid-base disturbances. These cases require monitoring of plasma electrolyte concentrations and modifications to parenteral fluids to replace electrolyte losses. In many cases, simply providing adequate fluid support will allow the kidneys to resolve these disturbances themselves. For patients who can tolerate oral fluids, oral rehydration solutions are very effective.

Myelosuppression

Myelosuppression means damage to the rapidly growing elements of the bone marrow. It is standard chemotherapy practice to perform regular haematology analyses to define the red cell, white cell and platelet parameters to determine whether it is safe to administer chemotherapy or not.

Neutropenia

Neutropenia typically takes 7–10 days to develop following chemotherapy administration. It can happen sooner in some instances, but some drugs can induce neutropenia 2–3 weeks after treatment. Most chemotherapy protocols are structured so that the risk of chemotherapy-induced neutropenia is low. Typically chemotherapy treatments are only scheduled for administration once the bone marrow is expected to have recovered from the myelosuppressive effect of the previous chemotherapy dose. Some patients do demonstrate a delayed marrow recovery between doses; these cases need to be identified so that they are allowed a little longer between chemotherapy treatments.

If the lowest level that the neutrophils fall to is still more than 2.0 x 10⁹/l, it is not appropriate to postpone chemotherapy. If by contrast, neutrophil numbers are expected to fall further, it would be unwise to administer chemotherapy until the bone marrow has recovered.

Cases with neutrophil numbers below 1.0 x 10⁹/l or cases at risk of developing neutrophil numbers below 1.0 x 10⁹/l would be best managed with prophylactic antibiotic therapy. In dogs the antibiotic of choice for prophylaxis is potentiated sulphonamide. In cats, I advise potentiated amoxicillin. Treatment can be administered until neutrophil numbers are 2.0 x 10⁹/l or higher, or for 10–14 days, whichever is simpler.

Despite every effort 1–20% of cases will develop neutropenic septicaemia; the incidence varies with the choice of chemotherapy protocol. In normal veterinary practice, the risk with chemotherapy protocols in common use would be 1–5% only.

Septicaemia can be recognised by the sudden development of marked listlessness, weakness and inappetence, in association with marked pyrexia. Temperatures are expected to exceed 40°C. Prompt veterinary attention is required. These patients require intravenous antibiotics at first, followed by oral antibiotics for 3–5 days. These patients are expected to make a dramatic recovery to nearly normal within 48–72 hours. While it might be advisable for the patient to remain hospitalised for the first 24 hours, prolonged hospitalisation or intravenous fluids are contraindicated unless there are other complicating factors. Assuming they are well managed, a small proportion of these cases will still die of septicaemia. Prompt intervention is the secret to a good outcome. This requires good client education so they recognise the signs and take appropriate action.

Thrombocytopenia

Chemotherapy-induced thrombocytopenia is seen occasionally, in particular with carboplatin and melphalan administration. Since the platelet life span is longer than that of neutrophils, thrombocytopenia due to myelosuppression is not an unexpected acute phenomenon. If the platelet count is less than 100 x 10⁹/l, it should be regarded as unsafe to administer further chemotherapy. Treatment delay is indicated until such time as the platelet count has recovered. Wholesale treatment change may then be indicated.

Patients that are significantly thrombocytopenic should be handled with caution. Recovery can be prolonged (weeks). During this time patient handling must be gentle, exercise should be limited and venepuncture should only be performed out of necessity. Clinically relevant thrombocytopenia is associated with spontaneous haemorrhages, in particular large ecchymotic haemorrhages or epistaxis. Emergency management of a patient with a bleeding disorder involves administration of a fresh blood transfusion as platelets and clotting factors survive poorly in stored blood.

Anaemia

Anaemia is expected with cancer and with chemotherapy. Both constitute what we term 'chronic disease', which is a mechanism underlying a form of anaemia that is typically mild to moderate, non-regenerative and which is described as normocytic and normochromic. The red cells look normal, there are just fewer of them. Anaemia can also happen with haemolysis and haemorrhage. Differentiation between causes of anaemia is critical; haematology analyses must be regularly reviewed so that acute changes are noted.

Hair Loss

Many clients are concerned about the possibility of complete hair loss in their pet if they have not had direct experience of chemotherapy before in animals. Hair loss affects humans because the hair follicles in humans are constantly working; hair grows continuously. In dogs and cats, hair usually grows and then stops growing. The hair-coated breeds including poodles, Bichons Frises, Bologneses, Soft-Coated Wheaten Terriers and Bedlington Terriers can develop hair loss though it is typically patchy. These owners should be warned of this possibility but should also be informed that complete hair loss is not expected.

Specific Side Effects

There are many idiosyncratic side effects of the individual chemotherapy agents. Some are frequently seen and do require discussion.

Sterile Haemorrhagic Cystitis

Cyclophosphamide-induced cystitis is extremely debilitating. It affects approximately 25% of dogs receiving chronic cyclophosphamide therapy. Sadly many dogs have been euthanased due to intractable cystitis pain, sometimes when in complete remission from their cancer. Microscopic haematuria can be detected long before the patient is clinically affected and termination of the cyclophosphamide treatment at this stage can save them from a terrible clinical problem. Owners should be coached in the technique of urine collection, dipstick testing and interpretation so that samples can be performed regularly without incurring prohibitive costs or time commitments.

In patients receiving cyclophosphamide as part of a COP protocol for lymphoma, cyclophosphamide can be replaced by chlorambucil at a dose of 5mg/m² every other day should cystitis develop.

Assuming that a diagnosis of sterile haemorrhagic cystitis is made, these cases can respond partially to administration of anti-inflammatory therapies (care to avoid co-administration of non-steroidal anti-inflammatory drugs (NSAIDs) with corticosteroids) and low-dose furosemide (2 mg/kg twice daily). Ultimately, it will take 3–6 months for all clinical signs to resolve in cases that are severely affected before cyclophosphamide treatment is withdrawn.

Tissue Necrosis

All chemotherapy for intravenous administration must be given via an indwelling catheter. Failure to do so may result in extravasation of the chemotherapeutic agent. This will result in painful tissue necrosis and loss of skin, subcutaneous tissue, muscle and fibrous tissue over an area of 2 x 2 x 3–4 cm at best, loss of an entire limb at worst. If extravasation does occur, contact a veterinary oncologist immediately. There are antidotes to extravasation but prompt referral is critical.

Cardiotoxicity

Doxorubicin, epirubicin, mitoxantrone and daunorubicin are all related drugs which can induce myocardial cell death and therefore cardiotoxicity. This risk of toxicity is related to total dose given. It is impossible to explicitly define what a safe total treatment dose is. A total cumulative dose of 240 mg/m² of doxorubicin is a widely accepted upper safety limit. In reality, cases are more variable and toxicity is certainly seen in patients who have received less than this. Patients with myocardial insufficiency prior to chemotherapy administration are poor candidates for these chemotherapy agents. There is an antidote; to work, dexrazoxane must be administered prior to each chemotherapy treatment.

Nephrotoxicity

Cats develop nephrotoxicity with administration of doxorubicin and related drugs just as dogs can develop cardiotoxicity. Serial monitoring of renal biochemical parameters is critical to evaluating the safety of chemotherapy. Cisplatin and carboplatin induce nephrotoxicity in dogs. Cisplatin will cause renal failure from a single dose if aggressive saline diuresis is not applied. Carboplatin is occasionally associated with nephrotoxicity and care must be taken in cases with pre-existing renal disease or receiving concurrent carboplatin and NSAID drugs.

Hepatotoxicity and Thrombocytopenia

Lomustine is associated with fatal irreversible liver and platelet side effects. These must be avoided. Haematology and biochemistry analyses should be performed prior to every chemotherapy administration and if there is evidence of progressive changes in liver enzymes or platelet count, treatment may not be safe to give.