Malignant Hypercalcaemia

Introduction

Hypercalcaemia is the commonest metabolic complication of malignancy, affecting perhaps a fifth to a third of patients with cancer at some point in their illness.¹ It is eminently treatable, and the symptoms - confusion, nausea, constipation, thirst and drowsiness - resolve rapidly with treatment, which makes it one of the more satisfying emergencies to manage.

It is also frequently missed, because every one of those symptoms can be plausibly attributed to advanced cancer, to opioids, or to the treatment. The single habit that prevents this is checking a corrected calcium in any patient with cancer who becomes confused, drowsy, constipated or nauseated - a test that costs nothing and changes management.

Finally, it carries prognostic weight. Untreated it is fatal; treated, the median survival is still only a few months, because it reflects a substantial tumour burden. A first episode of malignant hypercalcaemia is therefore an appropriate point to review the treatment plan and to have an honest conversation about what lies ahead.

Calcium physiology and the corrected calcium

About half of circulating calcium is bound to albumin and is physiologically inert; the ionised fraction is what matters. Laboratories measure total calcium, so a low albumin - almost universal in advanced cancer - makes a normal total calcium conceal a raised ionised level.

Normal homeostasis depends on parathyroid hormone, which raises calcium by mobilising bone, increasing renal reabsorption and stimulating renal 1-alpha-hydroxylase to make calcitriol, and on calcitriol itself, which increases gut absorption. Understanding this makes the mechanisms of malignant hypercalcaemia straightforward, since each one hijacks part of the same system.

Mechanisms

PTHrP shares its N-terminal sequence with PTH and binds the same receptor, so it reproduces PTH's actions on bone and kidney - hence the low phosphate. It does not cross-react with the standard PTH assay, which is why intact PTH is suppressed. That single result is the most useful discriminator in the whole topic.

The renal consequences drive the clinical picture. High calcium impairs the action of antidiuretic hormone on the collecting duct, producing a nephrogenic diabetes insipidus with polyuria. The patient becomes dehydrated, often compounded by vomiting and reduced oral intake, so glomerular filtration falls, less calcium is filtered and excreted, and the calcium rises further. Breaking this cycle with fluid is why rehydration is the first treatment rather than an adjunct.

Clinical features

Symptoms correlate with the rate of rise as much as the absolute level: a patient whose calcium has risen quickly to 3.0 mmol/L may be markedly unwell, while someone with chronic hyperparathyroidism at 3.0 mmol/L may have no symptoms at all. Most patients become symptomatic above about 3.0 mmol/L.

The traditional mnemonic - bones, stones, abdominal groans and psychic moans - is a reasonable framework, though renal stones belong more to chronic hyperparathyroidism than to acute malignant hypercalcaemia.

• Neurological - fatigue, lethargy, poor concentration, low mood, confusion, agitation, drowsiness, and ultimately coma. In an older patient this is often mistaken for delirium of infective origin or for opioid toxicity.
• Gastrointestinal - anorexia, nausea, vomiting and constipation, which is often severe and refractory. Rarely, pancreatitis and peptic ulceration.
• Renal - polyuria and polydipsia from nephrogenic diabetes insipidus, dehydration, and acute kidney injury
• Musculoskeletal - bone pain, proximal muscle weakness, hypotonia
• Cardiac - a shortened QT interval, bradycardia, and at very high levels bundle branch block, arrhythmia and cardiac arrest. Hypercalcaemia also potentiates digoxin toxicity.
• General - dehydration with dry mucous membranes, hypotension and reduced skin turgor

Investigations

• Corrected calcium and albumin - the diagnostic test; repeat to confirm and to monitor
• U&Es and creatinine - almost always shows an acute kidney injury from dehydration, and determines bisphosphonate dosing
• Phosphate - low in PTHrP-mediated disease, normal or raised in osteolytic disease and renal failure
• Intact PTH - the crucial discriminator. Suppressed in malignancy; normal or raised in primary hyperparathyroidism and familial hypocalciuric hypercalcaemia.
• Alkaline phosphatase - raised with extensive bone metastases, characteristically normal in myeloma despite lytic lesions, because myeloma suppresses osteoblast activity
• Magnesium - often low, and hypomagnesaemia makes hypocalcaemia after bisphosphonate treatment more likely
• Myeloma screen - serum protein electrophoresis, serum free light chains, urinary Bence Jones protein, especially with anaemia, renal failure and lytic lesions
• ECG - shortened QT interval; look for bradyarrhythmia in severe cases
• Vitamin D and PTHrP - not routinely needed, but calcitriol is measured if lymphoma or granulomatous disease is suspected
• Imaging - to identify the primary and the extent of bone disease where the cancer is not already known

Management

Treatment has a strict order, and getting the order wrong is the commonest error. Rehydrate first, then give a bisphosphonate, then treat the cancer.

1. Intravenous rehydration

Intravenous 0.9% sodium chloride, typically 3 to 4 litres over 24 hours, is the first and most important step.^4,6 It restores intravascular volume and glomerular filtration, and the resulting sodium load promotes calcium excretion in the proximal tubule. Expect a fall of around 0.3 to 0.5 mmol/L from fluids alone.

Reduce the rate in the frail, in heart failure and in renal impairment, and monitor closely for fluid overload. Reassess volume status, urine output and electrolytes at least daily, and replace potassium and magnesium, which are lost with the diuresis.

2. Bisphosphonate

Bisphosphonates inhibit osteoclast-mediated bone resorption, which is the source of the calcium in all the common mechanisms. Zoledronic acid 4 mg intravenously over at least 15 minutes is the usual UK choice, with pamidronate 30 to 90 mg as an alternative. The dose is reduced in renal impairment, and both are given after rehydration because they are nephrotoxic in a volume-depleted patient.⁵

• Onset is slow - calcium begins to fall at 2 to 4 days and reaches its nadir at around 4 to 7 days, so a bisphosphonate never substitutes for fluids in the acute phase
• Duration is typically 3 to 4 weeks, after which repeat dosing may be needed
• Do not repeat within 7 days - the response has not yet been fully seen, and repeating risks profound hypocalcaemia
• Adverse effects - a transient flu-like reaction after the first dose, hypocalcaemia, hypophosphataemia, renal impairment, and with prolonged use osteonecrosis of the jaw and atypical femoral fracture
• Dental assessment is advised before long-term bisphosphonate therapy for the same reason it is before head and neck radiotherapy

3. Second-line and specific treatments

4. Treat the underlying cancer

This is the only durable solution. Hypercalcaemia will recur, usually within weeks, unless the tumour is controlled - by chemotherapy, endocrine therapy or radiotherapy as appropriate. Regular bisphosphonate or denosumab therapy reduces recurrence and other skeletal-related events in myeloma, breast and prostate cancer.

5. Supportive care

• Stop contributing drugs - thiazides, lithium, calcium and vitamin D supplements, and calcium-containing antacids
• Review the drug chart for accumulation - opioids, and any renally cleared drug, will accumulate in an acute kidney injury and add to confusion
• Treat the constipation aggressively, since it both results from and worsens the picture
• Mobilise where possible - immobility increases bone resorption
• Do not restrict dietary calcium - gut absorption is not the driving mechanism and restriction can paradoxically increase PTH

Complications

Untreated severe hypercalcaemia causes progressive dehydration, acute kidney injury, coma and fatal arrhythmia. Even when treated, the acute kidney injury may not fully recover, and repeated episodes contribute to chronic renal impairment and to nephrocalcinosis.

Treatment carries its own risks. Hypocalcaemia after bisphosphonate or denosumab is common, particularly where vitamin D or magnesium is low, and may present with paraesthesiae, tetany, Chvostek's and Trousseau's signs, or a prolonged QT interval; calcium and magnesium should be rechecked at 48 hours to a week. Fluid overload from aggressive rehydration is a real hazard in frail patients with cardiac or renal disease. Long-term bisphosphonate exposure carries a small risk of osteonecrosis of the jaw and atypical femoral fracture.

The commonest problem in practice, though, is recurrence. Hypercalcaemia comes back within weeks in most patients whose underlying disease is not controlled, and each episode is usually accompanied by a further decline in function.

Red flags

Prognosis

The biochemical response to treatment is excellent - most patients are normocalcaemic within a week and their symptoms resolve well before that. The underlying prognosis is much less good. Median survival after an episode of hypercalcaemia of malignancy is in the region of 3 to 4 months, and a substantial minority of patients die within a month.^2,3

Prognosis is better where the tumour is responsive - myeloma, lymphoma and hormone-sensitive breast or prostate cancer - and worse in squamous lung and head and neck cancers, in which hypercalcaemia usually signifies uncontrolled advanced disease. Recurrent hypercalcaemia despite adequate treatment is a particularly poor sign.

Because of this, correcting the calcium is only half the task. A first episode should prompt reassessment of the anti-cancer plan, referral to specialist palliative care if not already involved, and a conversation about what matters to the patient and where they wish to be cared for. It is also reasonable, in a patient close to the end of life with recurrent hypercalcaemia, to decide with them that further episodes will be managed symptomatically rather than with repeated admissions and infusions - hypercalcaemic coma is a peaceful death, and treating it is not always the kind thing to do.