Hypercalcaemia
Abstract
Hypercalcaemia is quite common in advanced cancer patients. It can also occur in breast cancer patients undergoing hormonal therapy and can occur in the pre-terminal stage of multiple myeloma. Because its symptoms occur also in other conditions common in cancer patients, it is often missed. Successful treatment can result in great improvement of the quality of life. Family physicians should be aware of the clinical features so that they can provide timely management or referral. Discussed are its causes, pathophysiology, clinical features and management options.
INTRODUCTION
It is quite common and 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. Unfortunately, it is commonly missed because its symptoms such as nausea and vomiting, constipation, dehydration, uncontrolled pain and confusion can be caused by other 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 suspect 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.
It is considered to occur when the corrected serum calcium is higher than 2.60 mmol/L. It is severe and life threatening if the level is higher than 3.50 mmol/L. Some of serum calcium is bonded to albumin and it is the raised ionized calcium that causes the 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 4gm albumin below 40gm. 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 years1, because it can occur in the relatively early stage of the disease.
Eighty percent of hypercalcaemia are due to metastatic disease, half of which are 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
All symptoms are quite 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 confuse it with diabetes. Constipation is also common. It reduced 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 3.4 mmol/L.
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 GI absorption. Hypercalcaemia interferes with 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
Drugs promoting 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, which might have been given for increased pain in hypercalcaemia, may impair renal function and aggravate hypercalcaemia. Stop them when hypercalcaemia is suspected.
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 hypercalcaemia is to reduce 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 due to cancer but may greatly improve the quality of life allowing them to stay at home.
If hypercalcaemia is mild, rehydration only is already enough to lower serum calcium level.5 It increases glomerular filtration rate which in turn increases calcium in renal tubules for excretion. Admit for intravenous rehydration 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. If admission is really impossible, the patient can be rehydrated at home by subcutaneous infusion of normal saline. Two bags of normal saline can be given simultaneously at two different sites on the body.
Sodium excretion also promotes calcium loss. Frusemide are often prescribed after the patient is rehydrated to cause calciuresis. However some claim that the extra benefit is limited and it may exacerbate hypovolaemia, hypokalaemia and hypomagnesaemia.7 Never use thiazide for diuresis because it enhances renal calcium reabsorption.
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 value in this context.7 Perform regular calcium and albumin level. They may need IV 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 not as effective as pamidronate.9 However, it can be very useful in confused patients who tend to pull out intravenous lines or the patient stays at home. Subcutaneous infusion can be set up at home 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 four 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 the response.
An extra benefit of bisphosphonate therapy is the pain reduction of bone metastases.10
Gallium nitrate given as continuous intravenous infusion for 5 days is superior to calcitonin.11 It can produce normocalcaemia in 80 percents 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. It can be given as dexamethasone 4-8mg twice to three times a day intravenous or subcutaneously reducing by 4mg/day until a maintainenance dose of 2-4mg mane orally. Alternative, 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, steroid 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 hyperphosphataemia.
After correction of hypercalcaemia, the patient should be encouraged to increase fluid intake up to 3 litre/day if possible. Avoid immobilisation, excessive milk, calcium and vitamin A and D supplement, antacid 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
If left untreated in a really terminal patient, he may die in 1 week. However, he should continue to receive mild sedation, oral hygiene and good nursing care.
KEY MESSAGES
1. Hypercalcaemia is quite common and occurs in 10-20% of advanced cancer patients.
2. Its symptoms include nausea and vomiting, constipation, polyuria and polydipsia, dehydration, weakness, reduced pain threshold, drowsiness, confusion and coma. Have a high level of suspicion because treatment can greatly improve the quality of life.
3. Rehydrate immediately and treat the symptoms vigorously.
4. If indicated, reduce serum calcium level by intravenous pamidronate in hospital or subcutaneous clodronate at home.
5. Maintain normal level with oral clodronate, monitor serum level and readmit for intravenous pamidronate if indicated.
6. Calcitonin acts more rapidly. Steroid is indicated for hypercalcaemia caused by haematological malignancies. Gallium nitrate is indicated if pamidronate is not effective.
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