Hypercalcaemia in cancer patients

V S P Chan 陳瑞波

HK Pract 2001;23:449-452

Summary

Hypercalcaemia is common in advanced cancer patients. It can also occur in breast cancer patients undergoing hormonal therapy and in the pre-terminal multiple myeloma patients. Because its symptoms are non-specific, it is often unrecognised. Successful treatment can result in improvement in quality of life. Family physicians should be aware of the clinical features so that they can provide timely management or referral. Its causes, pathophysiology, clinical features and management options are discussed.

摘要

血鈣過高，在晚期癌症病人極為普遍。它亦可出現在進行激素治療的乳癌病人和末期前的骨髓瘤患者。 因它的症狀和癌症病患者的其他症狀有著共通之處，所以很容易被忽略。成功的治療對生活素質有極大改善，家庭醫生應該意識到血鈣過高的臨床特徵，以便提供適時的治療或轉介。 本文討論了血鈣過高的成因、病理生理和臨床特徵，並論及其治療選擇。

Introduction

Hypercalcaemia occurs in 10-20% of advanced cancer patients. The incidence can be as high as 40% in patients with breast cancer, squamous cell lung cancer and multiple myeloma. However, it is commonly undetected because its symptoms such as nausea and vomiting, constipation, dehydration, uncontrolled pain and confusion can be caused by other more common conditions in advanced cancer patients. This often happens when the patient is in the community under the care of family doctors. Because successful treatment can result in great improvement of the quality of life, the family doctor should always consider this condition and check the serum calcium level when the above symptoms occur. They should also know about the treatment options so that the patients can have immediate appropriate treatment.

Hypercalcaemia is considered when the corrected serum calcium is higher than 2.60mmol/L. It is life threatening if the level is higher than 3.50mmol/L. The serum calcium is partially bound to albumin, and it is the raised ionized calcium that causes symptoms. With low albumin, ionized calcium level can be raised while the serum calcium level is normal. Serum calcium has to be corrected by adding 0.1mmol/L for every 4g/L albumin below 40g/L. Coexisting acidosis increases the ionized calcium level and can precipitate symptoms.

Hypercalcaemia carries a poor prognosis. Fifty percent of patients die in 1 month, 75% in 3 months and 80% in 1 year. However, if hypercalcaemia is caused by myeloma, the median survival rate can be up to 2 years,¹ because it can occur in the relatively early stage of the disease.

Causes

Eighty percent of hypercalcaemia is due to metastatic disease, half of which is due to myeloma and the rest due to metastases from the primary cancers of breast, lung, kidney, prostate, cervix, and head and neck.2 Twenty percent are caused by primary tumours which have specific treatment, such as nephrectomy for renal carcinoma and radiotherapy for squamous cell lung cancer. Hypercalcaemia may also be exacerbated by immobilisation.¹

Clinical features

The symptoms of hypercalcaemia are non-specific. They are also present in conditions that are common in advanced cancer patients. Nausea and vomiting, often mistaken as being caused by gastrointestinal problems, is the commonest feature. Polydipsia and polyuria with dehydration can be confused with diabetes. Constipation is also common. It reduces pain threshold, resulting in uncontrolled pain. It also causes bradycardia, arrhythmia, muscle weakness, lethargy, acute confusional state or drowsiness, later confusion and coma.

It is usually asymptomatic when the corrected calcium is less than 2.8mmol/L and life threatening when more than 3.4mmol/L.

Pathophysiology

Cancer cells can produce parathyroid hormone-related peptide (PTHrP) that stimulates osteoclast activity, increases renal reabsorption of calcium and enhances effect of vitamin D in the gut with more gastrointestinal (GI) absorption. Hypercalcaemia interferes with the renal mechanism of sodium and water reabsorption causing polyuria and dehydration. This, in turn, reduces glomerular filtration rate that further reduces calcium excretion. Hypercalcaemia also causes muscle weakness and the resulting immobilisation causes further bone calcium loss into blood.³

Hypercalcaemia can also be caused by bone resorption in widespread bone metastases. In myeloma, the paraproteins damage the renal tubules, which inhibits the excretion of a calcium load. Treatment of breast cancer with tamoxifen can produce a 'flare' reaction with hypercalcaemia and increased bone pain.⁴

Management

Drugs that enhance hypercalcaemia such as thiazides, vitamin A and D should be ceased. Sedate the patient if confusion or agitation is marked. Non-steroidal anti-inflammatory drugs, when used for increased pain in hypercalcaemia, may impair renal function and aggravate hypercalcaemia. They should be stopped if hyper-calcaemia is present.

If hypercalcaemia is not severe, treat only if the patient is symptomatic.⁵ It causes severe nausea through chemoreceptor stimulation. Therefore the drug of choice is the dopamine receptor inhibitors such as haloperidol given in an aggressive dose as high as 5-20mg subcutaneously in 2-3 divided daily doses. Constipation is often severe. It needs vigorous laxative treatment.¹

The specific treatment of the symptoms of hyper-calcaemia is to reduce the serum calcium level. Patients who have moderate-to-severe symptoms but with well-preserved mental state and those appear to be able to survive with a good quality of life for several weeks or more are most likely to benefit from it.⁶ Correction of hypercalcaemia will not affect the prognosis of cancer disease, but may improve the quality of life and allow the patient to stay at home.

Hydration

If hypercalcaemia is mild, rehydration can lower the serum calcium level.⁵ It increases glomerular filtration rate which in turn increases calcium excretion. Intravenous rehydration is required if oral rehydration is impossible. Give intravenous normal saline up to three litres in the first twenty-four hours. More rapid rehydration can lead to cardiovascular overload with heart failure, hypokalaemia and hypernatraemia. Give smaller volume in elderly people. Daily serum electrolyte analysis may be necessary.

Sodium excretion can enhance calcium loss. Frusemide is often prescribed after the patient is rehydrated to induce calciuresis. However the extra benefit may be limited and it may also exacerbate hypovolaemia, hypokalaemia and hypomagnesaemia.⁷ Never use thiazide for diuresis because it enhances renal calcium reabsorption.

Bisphosphonates

In more severe cases, rehydrate with intravenous saline and infuse 30-90mg pamidronate in 4-8 hours.⁸ Lower dosages have been shown to be equally effective but higher dose (60-90mg) have a longer duration of control lasting for up to 4 weeks.⁷ It inhibits the activity of osteoclasts and inhibits release of calcium from bone by binding to hydroxyapatite. The clinical and biochemical benefits become obvious in 48 hours and the maximum effect in 5-7 days. It may cause marked fever 1-3 days after administration. The patient can return home with oral bisphosphonates (clodronate 1600mg daily or etidronate) for maintenance. However, their gastrointestinal toxicity may limit their use in this context.⁷ Perform regular calcium and albumin levels. They may need intravenous treatment again every 2-8 weeks. If the patient is in the terminal stage, or hypercalcaemia recurs very rapidly such as in 1-2 weeks, it is not justified to continue intravenous bisphosphonates.

Clodronate is less effective than pamidronate.⁹ However, it is useful in confused patients who tend to pull out intravenous lines or if the patient stays at home. Subcutaneous infusion can be set up and be better maintained than intravenous infusion. 1500mg in 1 litre of normal saline can be administered over 6-24 hours subcutaneously. Normocalcaemia can be achieved at a mean of 4 days following infusion. If the patient can tolerate orally, 2400-3200mg (3-4 tablets of 800mg each) can be given daily in a single or divided doses more than 2 hours after food. The dose can be reduced to 1600mg/day according to response.

An additional benefit of bisphosphonate therapy is the pain reduction of bone metastases.¹⁰

Other useful medications

Calcitonin inhibits bone resorption and increases renal excretion of calcium. It acts more rapidly with a fall in serum calcium within 4 hours and a nadir within 12-24 hours. Hence it is indicated in life-threatening hypercalcaemia of more than 4.0mmol/L. A dose of 8iu/kg can be given six hourly as subcutaneous or intramuscular injection.⁷ It has a short action and needs other agents such as pamidronate to maintain the low calcium level.

Gallium nitrate given as continuous intravenous infusion for 5 days is superior to calcitonin.¹¹ It can produce normocalcaemia in 80 percent of patients with hypercalcaemia of malignancy. However, it may cause nephrotoxicity and needs more prolonged inpatient treatment. It is suitable as the second line management when hypercalcaemia is resistant to bisphosphonate.⁷

Steroid inhibits growth of neoplastic lymphoid tissue such as lymphoma, myeloma and leukaemia. It also counteracts the effect of vitamin D and helps control nausea. Dexamethasone 4-8mg two to three times a day intravenously or subcutaneously can be given. The dose can be reduced by 4mg/day until a maintenance dose of 2-4mg mane orally. Alternatively, prednisolone 40-100mg/day can be given with tapering according to response. At this high dose, elderly patients undergoing vigorous rehydration are at risk of heart failure.¹ It is not effective in hypercalcaemia caused by non-haematologic cancer except that caused by the flare effect of hormone therapy of breast cancer.⁴ Therefore, steroids should not be used blindly if the underlying diagnosis is unknown.¹

Sodium cellulose phosphate at a dose of 1-3gm three times daily orally, binds calcium in the gut. However, it can cause nausea and diarrhoea and should be avoided in patients with renal failure or hyper-phosphataemia.

Maintenance of normocalcaemia

After correction of hypercalcaemia, the patient should be encouraged to increase fluid intake up to 3 litres a day if possible. He should avoid immobilisation, excessive milk, calcium and vitamin A and D supplement, antacids and thiazide diuretics. Better control of the underlying disease, where possible by radiotherapy, hormonal therapy or chemotherapy, can help in maintaining normal calcium level. Oral clodronate or phosphate may also be useful.

Terminal stage

If left untreated in a terminal patient, he may die in one week. However, he should continue to receive mild sedation, oral hygiene and good nursing care.