Hypercalcaemia of Malignancy

Hypercalcaemia of malignancy is a raised albumin corrected serum calcium (over 2.6 mmol/L) caused by cancer. It is the commonest life threatening metabolic complication of cancer, causing dehydration, neuropsychiatric symptoms, renal impairment and arrhythmia, and it usually signals advanced disease.

It affects 20% to 30% of patients with cancer at some point. The commonest associated cancers are breast, lung (especially squamous), myeloma, renal cell carcinoma, head and neck squamous carcinoma, lymphoma, and gynaecological cancers.

Pathophysiology. There are four mechanisms. Humoral hypercalcaemia (about 80%) is caused by parathyroid hormone related protein (PTHrP) from solid tumours. Local osteolytic hypercalcaemia (about 20%) is caused by bone metastases and myeloma releasing cytokines that activate osteoclasts. Calcitriol (1,25-dihydroxyvitamin D) production by lymphomas increases gut calcium absorption. Ectopic PTH secretion is rare.

Severity. Mild (corrected calcium 2.6 to 3.0 mmol/L), moderate (over 3.0 to 3.5 mmol/L) and severe (over 3.5 mmol/L). Corrected calcium (mmol/L) = measured calcium + 0.02 x (40 - albumin in g/L).

Prognosis. Median survival after the onset of hypercalcaemia is about 1 to 3 months, so it often marks end stage disease, though response to treatment can be good in myeloma and breast cancer.

• Dehydration, polyuria, thirst, constipation, nausea, vomiting, anorexia and abdominal pain.
• Fatigue, confusion, drowsiness, depression, hallucinations, coma.
• Muscle weakness, bone pain and renal stones.
• Shortened QT interval, bradycardia, atrial fibrillation or heart block.

Red flags.

• Calcium over 3.5 mmol/L, coma or seizures.
• Acute kidney injury or arrhythmia.

• Corrected or ionised calcium, phosphate, magnesium, creatinine, urea and electrolytes, alkaline phosphatase.
• Parathyroid hormone (suppressed in humoral and osteolytic causes; raised in primary hyperparathyroidism, which also occurs in cancer patients), PTHrP (raised in humoral hypercalcaemia), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (raised in lymphoma and granulomatous disease).
• Protein electrophoresis and free light chains for myeloma. Chest radiograph and imaging for tumour staging and bone metastases.
• ECG for short QT interval, arrhythmia and conduction block.

Differential diagnosis.

• Primary hyperparathyroidism (the commonest cause of hypercalcaemia overall)
• Vitamin D intoxication, thiazide diuretics, lithium, milk alkali syndrome
• Familial hypocalciuric hypercalcaemia, sarcoidosis and tuberculosis
• Thyrotoxicosis, adrenal insufficiency and immobilisation

Immediate measures. Stop calcium, vitamin D, thiazide diuretics and lithium. Correct dehydration, give bisphosphonates, and treat the cancer when possible. Treat symptomatic patients or those with calcium over 3.0 mmol/L; mild asymptomatic hypercalcaemia needs hydration and cancer treatment.

• Rehydration: sodium chloride 0.9% IV 200 to 300 mL/h for the first 24 to 48 hours, adjusted to a urine output of 100 to 150 mL/h (about 3 to 4 L in the first 24 hours); maximum about 6 L in 24 hours; monitoring: fluid balance, weight, creatinine, sodium, potassium, magnesium, signs of fluid overload; adjustment: slow the rate in heart failure or renal impairment, give a diuretic only after rehydration if fluid overload develops, replace potassium and magnesium
• Bisphosphonate (give after rehydration): zoledronic acid 4 mg IV in 100 mL of saline over at least 15 minutes, once, repeated after 7 days if the calcium remains raised; maximum 4 mg in a single dose, with at least 7 days between doses; monitoring: creatinine before each dose, calcium, phosphate and magnesium at 24 to 48 hours and then daily, jaw symptoms and dental health; adjustment: reduce the dose to about 3.0 to 3.5 mg when creatinine clearance is 30 to 60 mL/min, avoid when creatinine clearance is under 30 mL/min (use denosumab), expect an effect in 2 to 4 days with the nadir at 4 to 7 days
• Calcitonin for rapid effect in severe or symptomatic hypercalcaemia: calcitonin salmon 4 units/kg subcutaneously or IM every 12 hours, increased after 24 to 48 hours to 8 units/kg every 12 hours and, if needed, to 8 units/kg every 6 hours for the first 48 hours; maximum 32 units/kg daily; monitoring: calcium at 4 to 6 hours, nausea, flushing, hypersensitivity (intradermal skin test dose first); adjustment: stop after 48 hours because tachyphylaxis develops, no renal dose adjustment, continue the bisphosphonate in parallel
• Denosumab for refractory hypercalcaemia or renal impairment: denosumab 120 mg subcutaneously on days 1, 8, 15 and 29, then every 4 weeks, for hypercalcaemia refractory to a bisphosphonate or when creatinine clearance is under 30 mL/min; maximum 120 mg in one dose; monitoring: calcium at 1 week and before each dose (severe hypocalcaemia is a risk, especially in renal impairment), phosphate, magnesium, jaw symptoms, thigh pain; adjustment: give calcium 500 mg and vitamin D 400 units orally daily once the calcium is normal, no renal dose adjustment but monitor closely, stop for osteonecrosis of the jaw
• Glucocorticoids for lymphoma, myeloma and calcitriol mediated hypercalcaemia: prednisolone 40 to 100 mg orally once daily for 3 to 7 days, for hypercalcaemia from lymphoma, myeloma or calcitriol excess; maximum 100 mg daily; monitoring: calcium at 48 to 72 hours, glucose, blood pressure, infection, gastric symptoms; adjustment: taper once the calcium is controlled, stop after 7 days if there is no response, give gastric protection, avoid in uncontrolled infection

Dialysis. Haemodialysis with a low calcium dialysate for severe hypercalcaemia with renal failure or heart failure where rehydration is not possible.

Cancer treatment. Systemic therapy and radiotherapy for the underlying cancer reduce recurrence. Parathyroidectomy applies if concurrent primary hyperparathyroidism is found.

Monitoring. Calcium, creatinine and electrolytes daily during the acute phase, then weekly. Repeat bisphosphonate treatment is given when the calcium rises again (interval at least 7 days), and recurrent hypercalcaemia is treated with denosumab or by dose adjustment.

Referral and escalation.

• Admission for calcium over 3.0 mmol/L with symptoms, and for all patients with calcium over 3.5 mmol/L.
• Intensive care review for coma, arrhythmia or renal failure.

Special groups.

• Renal impairment: prefer denosumab with close calcium monitoring.
• Palliative patients near the end of life: weigh treatment against symptom benefit and patient wishes.
• Heart failure: slower rehydration with careful monitoring.