Hypercalcaemia

This is the most common serious metabolic disorder associated with malignancy, affecting up to one third of cancer patients at some point in their disease course.^[2] Malignancies most commonly associated include lung cancer, breast cancer, renal cancer, multiple myeloma and adult T-cell lymphoma. Its symptoms may mimic the features of terminal malignancy. Hypercalcaemia is a poor prognostic indicator in malignant disease and may indicate uncontrolled tumour progression and metastasis. The 30-day mortality rate of cancer patients admitted to hospital with hypercalcaemia is almost 50%.^[2]

The symptoms of hypercalcaemia are nonspecific; delayed recognition can worsen morbidity and mortality.^[2] Presenting features include nausea and vomiting, anorexia, thirst and polydipsia, polyuria, lethargy, bone pain, abdominal pain, constipation, confusion and weakness. Renal tract stones may occur. There is no absolute level of calcium at which patients become symptomatic; the rate of increase is usually more significant than the magnitude of elevation.^[2]

Investigation

Ionised calcium is the most reliable laboratory test. If total calcium is used, it is important to calculate the corrected calcium level to allow for hypoalbuminaemia (see separate Hypercalcaemia article for further information).^[2] Other investigations should include alkaline phosphatase, renal function and electrolytes, X-rays (may show lytic or sclerotic lesions of the bone) and a bone scan (to identify any metastases).

Management

There may be a palliative benefit from improving the symptoms of hypercalcaemia, even in patients with advanced malignancies. Urgent intervention is required to treat symptomatic hypercalcaemia. Management includes intensive rehydration and intravenous bisphosphonates (see Hypercalcaemia separate article for further details).

Neutropenic fever^[2]

See also separate article Neutropenic Patients and Neutropenic Regimes.

Febrile neutropenia contributes to 50% of deaths associated with leukaemia, lymphomas and solid tumours.^[1] Neutropenia is most often seen as an effect of cytotoxic therapy. Infection is responsible for at least half of the cases of neutropenic fever. The neutrophil count usually reaches a lowest level 5 to 10 days after the last dose of chemotherapy.

• Gram-positive cocci are now responsible for the majority of culture-positive cases of neutropenic fever, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Enterococcus faecalis and Enterococcus faecium. Corynebacterium is the most likely gram-positive bacillus.
• Gram-negative bacilli include Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa.
• Candida is the most common fungal infection, but aspergillosis and other systemic mycoses can cause more serious infections.
• Often no causative organism is found and the patient improves as the neutrophil count increases.

The vulnerability to infection substantially rises at an neutrophil count less than 1 x 10⁹/L, but the risk continues to increase as the neutrophil count falls.

Management

• The patient should have an infection screen, including blood cultures, urine cultures, swabs of any indwelling catheters, venflons and central lines, CXR, sputum cultures, cultures from any open wounds and stool cultures.
• Empirical antibiotic therapy should be started immediately based on local guidelines, with modification based on the results of microbiological investigations. The addition of antifungal coverage should be considered in high-risk patients who remain febrile after 4 to 7 days of broad-spectrum antibiotics with no identified causative organism.
• Growth colony stimulating factor can be given if the patient is haemodynamically unstable or if the neutropenia is slow to improve. It has been shown to be more effective in refractory gram-negative and fungal infections than in gram-positive infections.

Acute tumour lysis syndrome

Tumour lysis syndrome is caused by the abrupt release of large quantities of cellular components into the blood following the rapid lysis of malignant cells. It occurs most often in patients with haematologic malignancies, eg acute lymphoblastic leukaemia (ALL) or Burkitt's lymphoma. Treatment-provoked tumour lysis syndrome can occur following chemotherapy, radiotherapy, surgery or ablation procedures.^[2] In some cases, tumour lysis syndrome can lead to acute kidney injury and death.^[3] Patients particularly at risk have treatment-sensitive tumours, renal impairment or volume depletion. High pre-treatment urate, lactate and lactate dehydrogenase (LDH) are also risk factors.

Onset is usually within 1-5 days of starting therapy (but can be delayed by days or weeks in patients with a solid tumour) and symptoms/biochemical features include weakness, paralytic ileus, cardiac arrhythmias, seizures, acute kidney injury, sudden death, hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia.

Investigation

Full metabolic and biochemical profile to detect the above abnormalities. Monitoring of serum lactate, urate and LDH may predict the imminent onset of the syndrome.

Management

The key to the management of tumour lysis syndrome includes awareness of its causes, identification of high-risk patients, implementation of appropriate prophylactic measures, vigilant monitoring of electrolyte levels in patients undergoing chemotherapy, and initiation of more active treatment measures when necessary.

• Those at risk should have preventative management by receiving intravenous hydration with normal saline 3-6L/24 hours, with sodium bicarbonate.
• Acetazolamide is used to alkalinise the urine and prophylactic allopurinol is given.
• Hyperkalaemia is treated with a dextrose infusion and insulin.
• Hypocalcaemia can be treated with intravenous calcium gluconate.
• Hyperphosphataemia is treated with restriction of phosphate intake and phosphate binders (aluminum hydroxide or aluminum carbonate).
• Allopurinol is used to treat hyperuricaemia. Rasburicase (recombinant urate oxidase) appears to be effective and safe and is currently undergoing full evaluation.^[4] Unlike allopurinol, rasburicase does not cause accumulation of xanthine and hypoxanthine, which can worsen renal function, but it is expensive.
• Dialysis may be needed in severe cases.

Leukostasis^[2]

Leukostasis is associated with a very high white cell count, respiratory failure, intracranial haemorrhage (but it can affect any organ system) and early death. Without prompt treatment the mortality rate can be up to 40%. Leukostasis occurs in 5-13% of patients with acute myeloid leukaemia (AML) and 10-30% in adult patients with acute lymphoblastic leukaemia (ALL). The risk is greater for younger patients, and infants are most often affected. A white cell count greater than 50,000/m³ indicates a particularly poor prognosis.

There is usually a high fever and examination may show papilloedema, retinal vein bulging, retinal haemorrhage and focal neurological deficits. Myocardial infarction, limb ischaemia, renal vein thrombosis and disseminated intravascular coagulation may occur. Thrombocytopenia is usually present.

Management

• Rapid cytoreduction is the initial treatment, ideally with induction chemotherapy, which can dramatically reduce the white cell count within 24 hours.
• There is a very high risk of tumour lysis syndrome and so close monitoring of electrolytes and prophylaxis with allopurinol or rasburicase are required.
• Leukophoresis is usually started when the blast count is greater than 100,000/m3 or in the presence of symptoms.
• Cytoreduction can also be achieved by hydroxyurea, but is usually reserved for patients with asymptomatic hyperleukocytosis who are unable to receive immediate induction chemotherapy.

Raised intracranial pressure

Cranial metastases affect around a quarter of patients who die from cancer.^[5] Lung, breast and melanoma are the tumours that most commonly metastasise to the brain. The clinical picture varies with site of metastases and the rate of rise of intracranial pressure. Small metastases may bleed and cause acute symptoms. Common symptoms and signs include:

• Headache.
• Nausea and vomiting.
• Behavioural changes.
• Seizures.
• Focal neurological deficit.
• Falling level of consciousness.
• Papilloedema.
• Unilateral ptosis or third and sixth cranial nerve palsies.
• Bradycardia (late sign).

Investigation

CT or MRI scanning should be conducted urgently to delineate the lesion, if the result is likely to affect the patient's management.

Management

• If the patient has lost consciousness and requires ventilation, then high respiratory rate should be used to lower pCO₂ which helps reduce intracranial pressure.
• Mannitol may be given as a diuretic along with dexamethasone to reduce symptoms and the likelihood of cerebral herniation.
• Further management may involve cranial irradiation, surgery ± radiation or 'gamma knife' radiosurgery, depending on the site, type and number of metastases.

Spinal cord compression

This condition must be diagnosed and treated quickly to prevent permanent neurological disability. It may occur because of extradural spread from a vertebral body metastasis, direct metastases or from a vertebral crush fracture. Cancers that most often metastasise to bone and cause spinal cord compression are cancers of the breast, kidney, thyroid, prostate and lung. See separate article Spinal Cord Injury and Compression for further information.

Cauda equina syndrome

See separate Cauda Equina Syndrome article.

Superior vena cava obstruction

This may be due to compression of the superior vena cava, caused by primary or secondary tumours. Lung cancer (~85% of cases), lymphoma and metastatic tumours are the most common causes.

Management

Therapy is directed at the underlying cause. This is normally chemotherapy for lymphoma/small-cell lung cancer, with early response and resolution of superior vena cava obstruction within weeks being the usual outcome. Radiotherapy is usually used for non-chemosensitive tumours or patients who do not respond to chemotherapy. See separate Superior Vena Cava Obstruction article for further details.

Syndrome of inappropriate ADH secretion

See also separate article on Hyponatraemia.

Tumour cells may secrete ADH, particularly in the case of small-cell lung cancer. The syndrome of inappropriate ADH secretion affects 1-2% of cancer patients. The condition should be considered whenever a patient with malignancy presents with hyponatraemia. It is often asymptomatic but may cause:

• Depression and lethargy.
• Irritability and other behavioural changes.
• Muscle cramps.
• Seizures.
• Depressed consciousness leading to coma.
• Neurological signs (such as impaired deep tendon reflexes and pseudobulbar palsy).

Management

Successful treatment of the underlying malignancy will improve the condition.