Hypercalcaemia

Introduction

Incidence

Cancers producing hypercalcaemia

Significance of hypercalcaemia

Appropriate assessment to identify cause and severity of symptoms

Common symptoms and signs

Management

Explanation to patient and family

Institute non-pharmacological interventions

Prescribe appropriate first-line treatment

Guideline to use of Pamidronate

Review assessment and management

Maintenance treatment to prevent recurrence

Treatment- resistant hypercalcaemia

Introduction 

Hypercalcaemia is a para-neoplastic condition associated with advanced cancer. It describes a raised level of corrected calcium in the blood. Total plasma calcium is the combination of free, ionised calcium and  protein-bound calcium. If the albumin level is low, protein bound calcium is low. This may mask a high concentration of free, ionised calcium. Calcium is, therefore, ‘corrected’ for albumin level. 

Hypercalcaemia occurs as a result of increased osteoclastic activity (which releases calcium from bone) and  decreased excretion of urinary calcium. This is attributed to locally active substances produced by bone metastases or by factors such as ectopic parathyroid hormone-related protein (PTHrP) or cytokines produced by some tumours and occurs in 10% of the cancer population. 

Incidence 

• 10-20% of all cancer patients 
• 20-40% of patients with cancer of the bronchus, breast or myeloma will have hypercalaemia 

Cancers producing hypercalcaemia 

• Multiple myeloma is the most likely tumour to produce hypercalcaemia 
• Lymphoma 
• Carcinoma of lung and  breast account for over half of the cases seen, e.g. squamous cell carcinoma of the bronchus. 
• Other squamous cell tumours of breast, bronchus, head and neck 
• Renal and genito-urinary cancers. 

Hypercalcaemia from carcinoma of the prostate is surprisingly rare. 

Significance of hypercalcaemia 

Hypercalcaemia from malignancy is caused by the secretion of at PTH-like substance by the tumour. Contrary to popular belief, it can occur in the absence of bone metastases. Conversely, patients can have widespread bone metastases and remain normocalcaemic. 

Hypercalcaemia usually indicates disseminated disease (74%). 95% of patients with breast cancer and hypercalcaemia have disseminated disease. 61% of patients with lung cancer and hypercalcaemia have disseminated disease. Hypercalcaemia usually means a very poor prognosis – 4 out of 5 patients die within a year. 

Appropriate assessment to identify cause and severity of symptoms 

A corrected plasma calcium concentration above 2.6 mmol/l defines hypercalcaemia. It is often mild and asymptomatic and significant symptoms usually only develop with levels above 3.0 mmol/l, although some patients may have significant symptoms at lower levels. It is probable that the rate of rise determines symptoms. Levels of 4.0 mmol/l and above will cause death in a few days if left untreated. 80% of hypercalcaemic patients with cancer survive less than one year. 

Common symptoms and signs 

• Thirst 
• Polyuria, polydipsia, dehydration 
• Nausea and vomiting 
• Worsening pain (usually bone) that is difficult to control (Hypercalcaemia lowers the pain threshold) 
• Constipation 
• Drowsiness and lethargy 
• Muscle weakness 
• Confusion 
• Coma 

Management 

Treatment is only necessary if there are symptoms or there is a high likelihood of symptoms developing. Treatment may be unnecessary if the patient is very near to death. 

Treatment is aimed at improving well-being and symptoms for symptomatic patients for weeks or even months. 

Before treatment, the following issues need to be considered: 

• Is the patient symptomatic or is the serum corrected calcium >3mmol/l ? Symptoms are only likely if the correct calcium is >2.8 mmol/l. 
• Is this the first episode? If so, an oncology opinion is warranted. A change in anti-tumour therapy may be indicated 
• Is the patient’s quality of life good (in their opinion)? Is the patient willing to undergo IV therapy/blood tests? 
• Will the treatment work? (What response was there to previous treatment?) 

Explanation to patient and family 

The symptoms experienced are due the spread of cancer to the bones and calcium from the bones in the blood stream. Fluids and medication can reduce the calcium levels and improve the patient’s symptoms. Additional medication may be required at intervals to prevent this from happening again 

Institute non-pharmacological interventions 

• Fluid replacement – patients are often dehydrated and need adequate fluid replacement. A high oral intake of fluid is essential if this is possible. Extra fluid intravenously is necessary especially if the patient is significantly dehydrated, which is likely. Give 0.9% saline iv, 1 litre every 6 hours before bisphosphonates if calcium is >3.5 or patient is clinically dehydrated. Continue 0.9% saline 1 litre every 6-8 hours for a further 48 hours after bisphosphonates, if the patient is able to tolerate fluids and as clinically indicated. Fluid replacement alone improves symptoms but rarely achieves total control. 
• Control associated symptoms – such as pain, confusion and constipation 

Prescribe appropriate first-line treatment 

• The treatment of choice is an intravenous bisphosphonate infusion: Pamidronate or Zoledronic acid. 
• Bisphosphonates inhibit osteoclast activity and thereby inhibit bone resorption. Because of poor alimentary absorption, they are usually given intravenously initially. Bisphosphonates are effective in 70-80% of patients for an average of 2-3 weeks. 

Treatment is usually simple and well tolerated. Sometimes transient flu-like symptoms occur which respond to paracetamol. A typical dosing schedule is given below: 

• Disodium pamidronate: 60-90mg in sodium chloride 0.9%. 500ml over 2-4 hours
• Zoledronic acid: 4mg in 100ml sodium chloride 0.9% over 15 minute IVI, has a longer (4 week) period of action and a short (15 minute) period of administration.

Guideline to use of Pamidronate 

Review assessment and management 

A single infusion will usually maintain normocalcaemia for three weeks. Hypercalcaemia tends to recur. Consider monitoring the serum calcium every 2 weeks or monthly and ensure the patient and family know the symptoms to watch for. Pamidronate infusions can be repeated every 3-4 weeks according to the serum calcium. 

Plasma calcium levels start to fall after 48 hours and fall progressively for the next 6 days. The dose can be repeated after a week if the initial response is inadequate. If calcium remains high or rises again shortly following a bisphosphonate infusion, it may be useful to try an alternative bisphosphonate. If it is not possible to reduce the calcium levels, attention should be paid as always to the management of symptoms particularly pain, confusion and constipation. Check U&E before giving Zoledronic acid, if creatinine >400 μmol/l it is not recommended. 

• Check calcium after 3-4 days if symptoms have not significantly improved 
  • Normocalcaemia should be achieved in 3-7 days 
  • If calcium is not falling, repeat dose of bisphosphonate or try a different bisphosponate 
• Be aware that the mean length of response is 2-4 weeks for Pamidronate and 4-6 weeks for Zoledronic acid. 
• Arrange for serum calcium to be checked every 2 weeks or monthly. 
• If symptoms of hypercalcaemia recur, or there is a general deterioration in the patient’s condition after a few weeks, recheck serum calcium. 
• Institute maintenance therapy after two episodes of hypercalcaemia. 

Maintenance treatment to prevent recurrence 

• Pamidronate 90 mg IV every 4 weeks, or 
• Zoledronic acid 4 mg IV every 4 weeks, or 
• Ibandronic acid IV or PO 

Treatment – resistant hypercalcaemia 

Pamidronate may be progressively less effective when hypercalcaemia recurs (90% response to first treatment, 15% to third treatment). This is observed mainly in patients with hypercalcaemia of humoral origin, i.e. usually without bone metastases or tumours other than breast. The usefulness of pursuing further therapy has been questioned, although resistance can sometimes be overcome by the use of increasing doses of Pamidronate or by a more potent bisphosphonate, e.g. Zoledronic acid.