Hypercalcaemia is the commonest life-threatening metabolic disorder in malignancy and affects up to 10–30% of cancer patients.1 It can occur at any time during the natural course of the disease but is most common in its terminal stages.2 Unfortunately, malignancy-related hypercalcaemia has a poor prognosis with 80% of patients dying within a year and a median survival of three to four months. It occurs most frequently in myeloma, breast, renal, lung, lymphoma and thyroid cancer but can also occur with a range of others including gynaecological and head and neck cancers.1 It develops when calcium entry in the extracellular fluid compartment exceeds the capacity of the kidney to excrete the increased filtered load2 and it is the corrected calcium level which is used.

The mechanism of malignant hypercalcaemia is most commonly mediated by parathyroid hormone-related protein (PTHrP), which is produced by many solid tumours. This mimics the bone and renal effects of parathyroid hormone (PTH), activating PTH receptors in the tissue resulting in osteoclastic bone resorption and increasing renal tubular resorption of calcium.3 Other mechanisms leading to hypercalcaemia include excessive bone lysis in the case of bone metastases whereby the local effects of the tumour directly facilitate bone dissolution and calcium mobilisation.4 In some cases of lymphoma, it is increased production of calcitriol that leads to the elevated calcium levels5 and occasionally it is due to ectopic PTH secretion.3
Symptoms and signs can be variable but those that can indicate a raised serum corrected calcium. Clinical suspicion is confirmed by checking the serum corrected calcium. 

Management
Management is dependent on several factors and in the palliative population these include the degree of elevation of the serum calcium concentration, severity of symptoms, performance status of the patient, stage at which they are in the course of their underlying disease in combination with their wishes. In asymptomatic patients with only mildly elevated calcium, it is often best not to try and correct this and these patients do not generally benefit from normalisation of their serum calcium levels.5 Treatment options of cancer-related hypercalcaemia in the palliative population are discussed next.

Rehydration
This is the first step in the acute management of hypercalcaemia. It is vital to expand the extracellular fluid volume by correcting the volume depletion.2 In a hospital setting in non-malignant and/or non palliative populations, rehydration using isotonic saline can be potentially more aggressive in terms of volume and rate. Typically however, at least two litres is required for all patients until they are drinking well. This fluid expansion improves the glomerular filtration rate and promotes filtration and excretion of calcium.2 In the palliative and often elderly population, specific considerations will need to be taken into account. For example, caution is required to avoid signs of fluid overload and higher rates of ischaemic heart disease and cardiac failure will predispose to this. These patients may have also previously received chemotherapy with antracyclines with its associated risks of cardiotoxicity. Loop diuretics used to be previously commonly prescribed in the treatment of hypercalcaemia to promote calciuresis but given its lack of evidence and the effectiveness of bisphosphonates, they are no longer generally recommended unless in cases of fluid overload.6

Other considerations include that for treatment to proceed, venous access must be achieved and therefore the patient must be willing for this to be performed as well for receiving intravenous (IV) therapy. However it must also be remembered that the symptoms of hypercalcaemia itself can cause confusion when considering issues of consent. The patient must also be agreeable to admission to hospital or hospice although in some circumstances treatment in the home setting can be organised. Restoration of extracellular volume rarely achieves complete normalisation of the serum calcium but is necessary for protection of renal function. Subsequent measures, as discussed below, can then be employed.

Bisphosphonates
Bisphosphonates were introduced to clinical practice more than three decades ago and are used for a number of disorders, including hypercalcaemia.7 They have become the most important class of antiresorptive agents used in the management of metabolic bone disorders. 

Markedly increased osteoclast-mediated bone resorption is the basis for the use of bisphosphonates.2 These compounds have a high affinity for calcium ions and so target bone mineral, where they are internalised by the bone-resorbing osteoclasts and inhibit osteoclast function.8 Treatment is via the IV route and the most commonly used agents are pamidronate and zoledronic acid. Both can effectively treat hypercalcaemia although a pooled analysis of two clinical trials demonstrated that zolendronic acid was superior at achieving normocalcaemia faster, for longer and for more patients9 although the clinical significance of the differences is uncertain. The administration of zolendronic acid involves a 15-minute infusion using a dose of 4mg. The dose of pamidronate is normally 90mg given over 90 minutes. Renal function needs to be taken into account with dosing adjusted in cases of renal impairment. A bisphosphonate will typically start to reduce serum calcium in one to two days, together with hydration and normalisation is usually achieved within three to five days. If the serum calcium remains high or the patient is still symptomatic, a further dose can be repeated after five to seven days. In patients treated with pamidronate but who have had only a partial response, a trial of zolendronic acid can be considered. However, without anti-cancer treatment the hypecalcaemia is unfortunately likely to recur within two to four weeks and so bisphosphonate treatment will need to be repeated, if appropriate.1

Bisphosphonate treatment can also confer additional benefits including a reduction in skeletal complications, in malignant bone pain and in the need for analgesia.10,11 Complications associated with bisphosphonate use include the side effects of infusion related fever, bone pain, fatigue and nausea and vomiting. These symptoms can of course, also be due to the hypercalcaemia itself. Nephrotoxicity is also a risk. A feared complication is that of osteonecrosis of the jaw. This is a rare but serious condition in which bone of the maxilla or mandible becomes exposed and necrotic and is often complicated by infection. Predisposing factors include recent tooth extraction or other invasive dental procedures and poor dental hygiene. 12

Denosumab
Denosumab is a fully human monoclonal antibody that is targeted against receptor activator of nuclear factor kappa-B ligand (RANKL).13 In the body, RANKL is a key molecule for osteoclast differentiation and activation. Inhibition of RANKL activity by an anti-RANKL antibody reduces osteoclastogenesis, resulting in inhibition of bone resorption.14 Studies have shown that denosumab is effective in prolonging the time to skeletal-related events, which include pathological bone fractures, spinal cord compression, radiological treatment for bone deposits, surgical procedures for bone lesions and hypercalcaemia. It was also shown to be effective in inhibiting the onset of pain. A greater effect of denosumab compared with zolendronic acid has been demonstrated, particularly in patients with breast or prostate cancer.13 

Denosumab is administered subcutaneously. Its main use at present in the cancer population is in the treatment of bone metastases, rather than in the acute hypercalcaemia of malignancy. However, several studies have demonstrated its potentially effective role here15-17 and its clinical application in this indication is increasing. This tends to be in patients who have not responded to initial treatment with rehydration and bisphosphonate therapy. 

Disadvantages of denosumab include the cost and the risk of jaw osteonecrosis although the American Society of Clinical Oncology (ASCO) guidelines state that this risk is comparable to that of bisphosphonate preparations.13 Paradoxically, it may also cause symptomatic hypocalcaemia.18

Steroids
Steroids are mainly used in the management of hypercalcaemia in those patients with haematological malignancies such as lymphoma and multiple myeloma, where it is often used as first-line therapy after fluids.5 The mechanism is through their effect in inhibiting 1α-hydroxylase conversation of 25-hydroxyvitamin D to calcitriol. A typical regimen may be, for example, IV hydrocortisone 200–300mg/d for three to five days, which if the patient responds to, can be maintained on oral prednisolone 10–30mg/d. However, dosing guidelines vary primarily because the efficacy of corticosteroids is based in the main, on case reports.4

Calcitonin
Calcitonin is a polypeptide hormone produced by the parafollicular cells of the thyroid gland. Its main physiological action is on the bone where it inhibits osteoclast bone resorption and increases calcium excretion in the urine.4 Synthetic calcitonin is derived from salmon, as it is more potent than human and porcine forms19 and is administered either intramuscularly or subcutaneously. It does have a rapid action reducing calcium levels within two to six hours.4 However, effects may be only modest and are short lived. It also exhibits tachyphylaxis due to repeated administration leading to down-regulation of the calcitonin receptors on osteoclasts with the associated diminution in effect.20 There is some evidence that calcitonin is best used when in combination with steroids or bisphosphonates19 but overall there is little evidence that calcitonin use has better efficacy over rehydration and bisphosphonate therapy alone.4 Side effects include nausea, vomiting and injection site pain but are generally minimal.

Gallium nitrate
This is another option in the management of hypercalcaemia although is generally less widely used than those discussed above.21 Its exact mechanism of action is not known but is thought to involve a reduction in osteoclast activity. It is administered IV in a continuous infusion typically over a five-day period. It has a relatively slow onset of action, taking two to three days, with maximal effects seen six to eight days post treatment. Studies have shown an efficacy comparable to that of the bisphosphonates19 and to that of calcitonin.22 Gallium nitrate may cause renal failure and so should not be used in cases of renal impairment and the patient should also be well hydrated prior to initiation of treatment.19 In the palliative patient, the five-day infusion may be deemed inappropriate compared to the simpler administration of other treatment options. Side effects includes nausea, vomiting, lethargy, altered mental status, diarrhoea and constipation.4

Dialysis
For patients with acute hypercalcaemia, haemodialysis may be considered using a low calcium dialysate. However, in our sub-population of patients, this is rarely appropriate.

Conclusion
Long term, effective control of cancer associated hypercalcaemia is ultimately dependent on treating the underlying tumour. In palliative patients, for whom commencing or continuing anti-cancer treatment is not appropriate, anti-hypercalcaemic therapy remains an important palliative measure.21 Management is primarily achieved with normal saline rehydration and bisphosphonate therapy. This complication carries with it a poor prognosis and wherever diagnosed, should prompt discussion regarding goals of care and advanced directives.1 Additionally, it should be remembered that it is not always appropriate in every case to treat hypercalcaemia as it may represent a terminal event for which effective symptom control should be the priority.


Conflict of interest: none declared.
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