Gerry Polton, MA, VetMB, MSc(Clinical Oncology), DECVIM-CA(Oncology), MRCVS, European Veterinary Specialist in Oncology, RCVS Recognised Specialist in Veterinary Oncology (Small Animals)
True oncologic emergencies are uncommon. They can be separated into cancer-derived and iatrogenic emergencies. The most frequently cited cancer-derived emergency is hypercalcaemia of malignancy. Others include pancytopenia and ruptured viscus. Iatrogenic emergencies include neutropenic sepsis, haemorrhagic gastroenteritis, and treatment-induced anaphylaxis.
Hypercalcaemia of Malignancy
Patients with hypercalcaemia are classically polydipsic and polyuric. Other clinical signs reported include dysuria, weakness, lethargy, altered behaviour, and tremors. Most probable causes of hypercalcaemia of malignancy include lymphoma, anal sac gland carcinoma, and parathyroid tumour in dogs and oral squamous cell carcinoma in cats. Dogs or cats with any of these complaints should have their serum calcium concentration assessed even without overt evidence of hypercalcaemia, as there can be significant damage to soft-tissue structures from persistent calcium aberrations.
The notion that hypercalcaemia is an emergency does misrepresent the majority of oncologic hypercalcaemic cases. The clinical status of hypercalcaemic cases correlates poorly with the degree of their calcium concentration abnormality. Regardless, treatment should be aimed at alleviating the clinical signs associated with hypercalcaemia and at reducing the risk of neuromuscular deficits arising due to the metabolic derangement. This is particularly pertinent if a patient is a candidate for anaesthesia.
One of the most important concepts when presented with a patient with hypercalcaemia is the avoidance of administration of agents which might later cloud diagnosis of the underlying cause. Since lymphoma is a potential differential diagnosis for a cat or a dog with hypercalcaemia, administration of corticosteroids should be avoided at all costs until diagnostic specimens have been obtained.
Hypercalcaemic patients are dehydrated, despite their increased thirst. This is because calcium interferes with reabsorption of water in the renal collecting ducts, so water is lost, which results in a drive to drink. Rehydration is critical to normalisation of haemodynamic parameters. Rehydration using 0.9% sodium chloride optimises calciuresis. Take care to ensure that the water load administered can be excreted. Hypercalcaemia may cause or may reflect renal failure. In renal failure, patients exhibit a reduced ability to excrete a water load.
Serial reassessment of blood calcium concentration permits modification of therapy. Additional treatments in the form of bisphosphonates or therapy directed at the cause of the hypercalcaemia are appropriate. Intravenous bisphosphonates can induce fatal cardiac arrhythmias if not administered appropriately. They must be given as a slow intravenous infusion. I prefer to use pamidronate 1–2 mg/kg over 1–2 hours is advised, or zoledronate 4 mg per dog over 10–15 minutes. Surgical removal of an enlarged anal sac tumour can lead to prompt normalisation of serum calcium concentration; however, hypercalcaemia of malignancy often reflects an increased burden of disease, so it is critical that the clinician in charge is aware of the full extent of the patient's neoplastic complaint before entertaining the idea of surgery with the intent of resolving hypercalcaemia. Removal of an anal sac tumour will not improve hypercalcaemia in a patient with widespread pulmonary metastases.
Persistent hypercalcaemia can be managed by oral bisphosphonate therapy. There are multiple agents available. I prefer to use etidronate at a dose of 20 mg/kg once daily. This almost never results in a restoration of normal serum calcium concentrations, but if the patient appears relatively well despite hypercalcaemia, they can survive for prolonged periods (6–9 months) with this therapy alone while their tumour progresses. Bisphosphonates do not appear to exert a direct antineoplastic effect in vivo in these cases.
Acute leukaemia, stage V lymphoma, and myelophthisis are all neoplastic proliferations affecting the bone marrow. Simple competition for resources results in a lack of space and nutrients available to the normal haematopoietic stem cells. A reduction in mature red cells, leucocytes, and platelets in the peripheral blood inevitably results. Patients do not always present with pancytopenia; in some cases a bi- or monocytopenia is present.
Management is directed toward the marrow aberration present. Anaemia can be managed by serial crossmatched blood transfusions. Neutropenia results in an increased risk of sepsis; bactericidal antibiotics should be administered. Thrombocytopenia results in a risk of spontaneous haemorrhage; some patients may require a transfusion of blood products; thrombocytopenia cases are handled and managed carefully to minimize the risk of spontaneous haemorrhage. All of these interventions can be considered to be symptomatic treatments for the emergency patient. However, there is no future for these patients if the underlying cause cannot be addressed. That requires a diagnosis and a treatment plan. Many cases are nonresponsive to therapy. In one study, only 28% of cases diagnosed with acute lymphoblastic leukaemia lived as long as fourteen days after diagnosis.
The most common oncologic ruptured viscus emergency is splenic rupture due to haemangiosarcoma. These patients typically present with acute-onset lethargy and marked pallor. Emergency splenectomy can save life. Appropriate preoperative preparation includes restoration of circulating volume, ideally with whole blood. The prognosis for cases diagnosed with splenic haemangiosarcoma is poor: median survival times of approximately two months are reported for patients undergoing splenectomy alone; this increases to approximately six months if splenectomy is followed by a course of adjuvant chemotherapy. Other tumours can induce splenic rupture including metastatic carcinoma and histiocytic sarcoma. Complete physical examination and thoracic radiographs should be considered a mandatory aid to decision making in the management of these cases.
Chemotherapy can induce myelosuppression. Serial haematology analyses are a routine part of chemotherapy protocols to protect against this eventuality. Despite this, septic events still develop. Such cases typically present 7–10 days after chemotherapy administration with a peracute onset of listlessness and pyrexia (40°C). Owners must be educated to recognise the signs of sepsis, as prompt action is required. If there is doubt about the diagnosis, manual blood smear examination will reveal a stark absence of neutrophils. Some automated haematology analysers will consistently give error messages and can delay diagnosis. Intravenous antibiotics are recommended, followed by oral therapies. Other supportive care can be provided as indicated. Typically, these patients will recover as quickly as they deteriorated. Antibiotic choices vary between oncologists but a combination achieving broad-spectrum coverage such as potentiated amoxicillin and a fluoroquinolone would be appropriate. It is important to forewarn owners that there is a risk of antibiotic resistance in patients exposed to chronic antibiotic therapy or in animals belonging to healthcare workers. If sepsis arises due to the presence of an antibiotic-resistant bacteria, the patient would be dead before such information came to light.
Severe gastrointestinal complications of chemotherapy administration are rare. Typically, they arise due to mismanagement of chemotherapy or due to a preexisting susceptibility such as seen in cases expressing the mutated p-glycoprotein as seen in some Border collies and Australian shepherd dogs. Gastrointestinal signs induced by chemotherapy are expected to develop within the first 48–72 hours after treatment administration. Severe toxicity will require a number of days for recovery. To further complicate matters, those patients with poor drug metabolism are also more likely to suffer neutropenic sepsis. These patients must therefore also be monitored carefully for evidence of haematological disturbances. Management of severe gastroenteritis should be the same as it would be if the trigger was unrelated to chemotherapy. Patients require intravenous fluid support, antiemetic therapy, antidiarrhoeal treatment, antibiotic therapy to modulate intestinal flora, and good nursing care.
Acute hypersensitivity reactions are very unusual in routine veterinary chemotherapy. There are agents which are renowned for inducing hypersensitivity reactions. However, these agents trigger anaphylaxis due to an intolerance of the Cremophor carrier molecule utilised in certain human chemotherapy preparations which are insoluble in aqueous solution, such as paclitaxel. Taxanes (like paclitaxel) are not in use in regular veterinary oncology practice so this should not present a challenge to most practicing veterinary surgeons. Strategies are available to reduce the risk of anaphylaxis in these cases, requiring administration of intravenous corticosteroids and antihistamine treatments. Gastroprotectants are also advised.
Anaphylaxis is therefore more likely to affect practitioners when it occurs as an idiosyncratic reaction to a cytotoxic agent. First, if the drug is being administered by infusion, the infusion must be stopped. Antihistamine and/or corticosteroid therapy should be given according to the gravity of the clinical signs. Intravenous fluid support may be required if there is a failure of maintenance of systemic vascular pressure.
Many cases simply develop urticaria. The most frequent context in which I have encountered urticaria as a possible chemotherapy-associated effect is in the context of a dog with mast cell neoplasia. I believe that the mast cell tumour creates an environment of inflammatory lability. Appropriate prophylactic therapy should then be administered prior to any further administration of the presumed trigger agent or that agent should not be administered again.
In cases of iatrogenic emergency, changes must be made to the treatment protocol to ensure that similar events do not affect that patient in the future.