3.5 Malignant hypercalcaemia

3.5 Malignant hypercalcaemia^1,2

Definition

Hypercalcaemia occurs when ionised calcium is >1.32 mmol/l and can be divided into:

Mild hypercalcaemia: ionised calcium 1.32–1.70 mmol/L
Moderate hypercalcaemia: ionised calcium 1.7–2.4 mmol/L
Severe hypercalcaemia, similar to hypercalcaemic crisis: ionised calcium > 2.4 mmol/L or ionised calcium > 2.0 mmol/L + p-creatinine > 200 μmol/L

Causes

A number of mechanisms can trigger hypercalcaemia in cancer patients, including production in the tumour of parathyroid hormone-related protein (PTH-rP), endo- and paracrine stimulation of osteoclasts from bone metastases, as well as ectopic production of vitamin D analogues or PTH. However, regardless of pathogenesis, osteoclast-induced bone resorption often plays a prominent role.

Other causes of hypercalcaemia that should be considered

Hyperparathyroidism
Thyreotoxicosis
Thiazides
Immobilisation
Granulomatous diseases
Vitamin poisoning
Renal insufficiency

Symptoms

Symptoms are often non-specific and not always correlated to the level of ionised calcium. Rapidly increasing ionised calcium is often associated with more symptoms than slowly increasing ionised calcium. There are rarely symptoms of ionised calcium <1.5 mmol/L, but in patients with bone metastases there are almost always symptoms of ionised calcium >1.60 mmol/L.

CNS and PNS: Fatigue, drowsiness, confusion, blurred consciousness, hallucinations, hypotonia and hyporeflexia
Circulation: Hypertension, prolonged AV conduction, short QT, increased sensitivity of digitalis, arrhythmias and asystole
Renal: Polyuria, thirst and dehydration. Free water loss, K⁺, Mg²⁺ and H⁺. Declining renal function
Gastrointestinal: Anorexia, nausea, vomiting and constipation

Investigation

Ionised calcium, creatinine, Na⁺, K⁺ and albumin, possibly ECG
For first-time cases also phosphate, Mg²⁺ and PTH

Treatment

The most important treatment for malignant hypercalcaemia is treatment of the patient’s basic malignant disease. In addition, it is prevention. With detected bone metastases, preventative treatment with bisphosphonates (zoledronic acid) or the monoclonal antibody denosumab will prolong the time to the next skeletal event (pain, pathological fracture/collapse and hypercalcaemic crisis).

Mild hypercalcaemia (ionised calcium 1.32–1.7 mmol/L) and unaffected patient:

Increased fluid intake orally/intravenously is often sufficient

Intermediate to severe hypercalcaemia (ionised calcium 1.7–2.4 mmol/L):

Discontinuation/pause of predisposing medication (thiazides, calcium with vitamin D supplements, lithium, calcitriol)
2–4 litres of isotone NaCl IV daily (rehydration + increased renal calcium excretion). In patients with heart failure or hypertension, rehydration should be carried out with caution/close monitoring
Furosemide increases calcium excretion, but is rarely indicated, as the condition itself causes polyuria and the patient is usually dehydrated (Furosemide 20–40 mg po or iv can be given 1–2 times daily)
Correct any hypokalaemia and hypomagnesaemia present
Bisphosphonate IV (observe dose reduction in case of affected renal function, see below). Bisphosphonate inhibits bone resorption via direct inhibition of the osteoclast activity. Suppression is measurable only after 24–72 hours and lasts for a median of 3 weeks

The dose of zoledronic acid is reduced in renal impairment according to the table below:

ESTIMATED GFR (EGFR) AT BASELINE	ZOLEDRONIC ACID DOSE	4 MG/5 ML ZOLEDRONIC ACID CONCENTRATE
> 60 ml/min	4.0 mg	5.0 ml
50-59 ml/min	3.5 mg	4.4 ml
40-49 ml/min	3.3 mg	4.1 ml
30-39 ml/min	3.0 mg	3.8 ml
< 30 ml/min	0	0

The patient should be assessed with:

Large fluid schedule
Daily weight
Daily measurement of electrolytes (ion-calcium, Na⁺, K⁺, Mg²⁺, phosphate)

Patients with nephropathy (P-creatinine > 300 micromol/L, eGFR <20 ml/min):

There is an indication for dialysis to reduce the level of ionised calcium, which is arranged in cooperation with the on-duty nephrologist

Hypercalcaemic crisis (ionised calcium > 2.4 mmol/L):

Frequent BP and pulse rate, monitors with fluid schedule and hourly diuresis
Catheter placement (CAD)
4–6 litres of isotonic NaCl IV per 24 hours
Furosemide 20–40 mg iv pn/regularly until hourly diuresis is 100 ml/hour
Calcitonin 600 IU is infused in 1 litre of isotone NaCI over 6 hours. Calcitonin increases renal excretion of calcium and decreases bone resorption. Works after a few hours, but the effect is short-lived (1–3 days). Is nausea-inducing. A potential complication is hypophosphataemia
Bisphosphonate iv (obs dose reduction in affected renal function)

With treatment-refractory hypercalcaemia, the following may be attempted:

Calcitonin 600 IU is infused in 1 litre of isotone NaCI over 6 hours. Works after a few hours, but the effect is short-term (1–3 days)
Tablet Prednisolone 50–100 mg daily, which corresponds to 40–80 mg sc/iv daily. Corticosteroids inhibit bone resorption and inhibit GI absorption (vitamin D antagonist)