Hypercalcemia in cancer patients

Hypercalcaemia occurs in an estimated 10-20 per cent of all patients with cancer1 and is associated with a poor prognosis. According to one study, mortality is up to 50 per cent within 30 days.2 It causes distressing symptoms in this patient group and symptom palliation is important.

The tumour types most often associated with hypercalcaemia are bronchus, breast, myeloma and prostate, although it can also be associated with head and neck, bladder, female genital tract, oesophagus, lymphoma, renal, large bowel and thyroid.

Pathogenesis and classification
Hypercalcaemia is a result of increased osteoclastic activity induced bone resorption, decreased renal excretion of calcium or increased gut absorption of calcium. The condition is classified in two categories: local bone metastases induced osteoclastic activity and humoral hypercalcaemia of malignancy (HHM).

Local bone metastases induced osteoclastic activity causes bone resorption, raising calcium levels in the blood. This is the cause in 80 per cent of patients with hypercalcaemia of malignancy.

HHM is due to humoral mediators produced by certain cancers. Parathyroid hormone-related protein (PTHrP) is the most important humoral mediator in patients with and without bone metastasis.1,3,4 It causes increased osteoclastic bone resorption and increased renal tubular calcium resorption.

Between 70 and 80 per cent of patients with tumour-induced hypercalcaemia have increased levels of PTHrP. Increased levels of PTHrP are a predictor of poor control of hypercalcaemia after treatment with bisphosphonates.5 Calcitriol, the active form of vitamin D produced by certain lymphomas, promotes renal and gut absorption of calcium. There have been reports of ectopic parathyroid hormone causing hypercalcaemia. Other mediators known to be involved in osteoclastic bone resorption are prostaglandins, transforming growth factors (TGF-beta) and interleukins (TNF-alpha, IL1, IL6).3 Immobility, thiazide diuretics, and hormones such as oestrogens, androgens and anti-oestrogens are contributing factors.

Clinical presentation and diagnosis
The severity of symptoms depends not only on serum calcium level, but also on factors such as the patient's age, medical problems, and the rapidity of onset of hypercalcaemia. Box 1 lists symptoms that may be seen in patients with hypercalcaemia.

Calcium in extracellular fluid is 50 per cent free ionised, 40 per cent protein-bound and 10 per cent non-ionised and diffusible. Total serum calcium can vary according to the serum albumin; that is, if the albumin is high or low, it may falsely represent the total calcium as high or low. The level of ionised calcium is clinically relevant. Most laboratories use formulae to calculate the corrected calcium. For example: Corrected calcium = measured calcium + (40 - serum albumin g/L x 0.02). An alternative is to add 0.8mg/dL to the total calcium level for every 1g/L of serum albumin below 3.5g/dL serum albumin.

In patients with cancer, hypercalcaemia is most likely to be due to the cancer itself, but it is also important to consider other causes, such as primary hyperparathyroidism and granulomatous diseases. Checking parathyroid hormone, PTHrP and plasma calcitriol may be relevant, especially when the cause of hypercalcaemia is unclear. Investigations such as bone scan (or skeletal survey in myeloma) and chest X-ray may be of value.

Management of the condition involves four steps. Step one is clinical assessment, to check the baseline level of dehydration, renal function and cardiovascular status.

Step two is to remove calcium from feeding and to stop oral calcium supplements and thiazide diuretics. If present, hypomagnesaemia and hypokalemia should be corrected.1,3,4

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