Hypercalcaemia of malignancy (HCM)

Definition

Hypercalcaemia of malignancy (HCM) is a condition which occurs in cancer patients and can be defined when the serum calcium level (corrected for albumin) is greater than 2.6 mmol/L or greater than the upper limit of normal (ULN) for a given reference value used in a lab.

While there are no formal classification schemes for defining severity of hypercalcaemia, some consider^r:

• mild hypercalcaemia to be a total adjusted serum calcium of 2.6 to 2.9 mmol/L
• moderate hypercalcaemia a level of 3.0 to 3.4 mmol/L, and
• severe hypercalcaemia a level of > 3.4 mmol/L. 

Therapy for hypercalcaemia should be initiated for symptomatic patients and those who have serum calcium concentrations > 3.0 mmol/L

Severe hypercalcaemia is considered to be a medical emergency and must be treated aggressively.

Incidence

HCM is relatively common in patients with cancer, occurring in approximately 20 to 30 percent of cases and it is associated with a poor prognosis.^r Malignant tumours generally cause hypercalcaemia by producing a protein with parathyroid hormone–like action.^r The most common malignancies that cause hypercalcaemia are breast cancer, renal cancer, multiple myeloma, lymphoma, and squamous cell cancers, but may also be caused by other cancers.^r

Pathophysiology

HCM is primarily due to the marked increase in osteoclastic bone resorption and release of calcium from bone. There are three major mechanisms by which this can occur:

• osteolytic metastases with local release of cytokines including osteoclast activating factors (commonly seen in multiple myeloma)
• tumour secretion of parathyroid hormone-related protein (PTHrP) which causes increased bone resorption and enhances renal retention of calcium (commonly associated with breast, head and neck and kidney cancers and squamous cell carcinoma of the lung)
• tumour production of 1,25-dihydroxyvitamin D (calcitriol) leading to increased bone resorption and enhanced intestinal calcium absorption as noted in some lymphomas.^r

Hypercalcaemia in multiple myeloma is thought to be due to osteolysis from other cytokines such as interleukin-1 combined with renal tubular damage due to Bence Jones protein. The receptor activator of nuclear factor-B ligand (RANKL) system is the common molecular pathway that leads to osteoclast recruitment and differentiation and bone resorption in hypercalcaemia associated with cancer.^r

Primary hyperparathyroidism is a common condition and may occur concomitantly with malignancy; this is diagnosed by PTH assay.

As hypercalcaemia can affect several organ systems, initially it may be asymptomatic or present with non-specific symptoms which may be similar to that of advanced malignancy or the side-effects of chemotherapy or analgesia.

• Common symptoms include polydipsia, polyuria, confusion, muscle weakness, fatigue, anorexia, constipation. 
• In severe cases, there may be nausea, vomiting, abdominal pain, lethargy and altered level of consciousness. Cardiac arrhythmias may develop but are rare. Severe hypercalcaemia can result in coma and death.

When symptoms are present, they are related not only to the absolute calcium level but also to how fast the rise in serum calcium occurred.

UKONS Acute Oncology Initial Management Guidelines v.3., accessed November 2022.

Investigations and diagnosis

Abnormalities of parathyroid function, bone resorption, renal calcium reabsorption or dihydroxylation of vitamin D may cause regulatory mechanisms to fail and serum calcium may rise.

To confirm a diagnosis of hypercalcaemia:

• Check calcium level, corrected for serum albumin (as serum calcium is bound to albumin), which gives an indication of the amount of ionised (active) calcium.
  •  [Corrected calcium (mmol/L) = serum calcium (mmol/L) + 0.02 (40 - serum albumin (g/L)) ] ^r
• Additional laboratory evaluations include:^r
  • serum creatinine
  • urea and electrolytes
  • phosphate and magnesium level
  • parathyroid hormone (PTH) to rule out primary hyperparathyroidism
  • PTHrP to rule out humoral hypercalcaemia of malignancy
  • 1,25-dihydroxy vitamin D (1,25(OH)2D)
  • 25-hydroxy vitamin D (25(OH)D) to rule out vitamin D intoxication
  • TSH
  • Vitamin A
  • ECG to look for shortened QT interval or other conduction abnormalities.

Management

The aim of treatment is to improve symptoms and reduce corrected calcium level to within the normal range and, if possible, treating the underlying disease. Effective treatments reduce serum calcium by inhibiting bone resorption, increasing urinary calcium excretion, or decreasing intestinal calcium absorption.^r The timing and type of treatment are dependent on the severity of the hypercalcaemia and associated symptoms.

It is also important to review the patient’s other medications and consider discontinuing or dose reducing (if appropriate) any medications that may be contributing to hypercalcaemia (e.g., thiazide diuretics, calcitriol, calcium supplementation, antacids, lithium).

Symptomatic hypercalcaemia requires prompt and often inpatient management with intravenous rehydration and administration of a bisphosphonate.

Fluid replacement

Patients with HCM are volume depleted as a result of impaired renal concentrating ability and decreased oral intake. The dehydration leads to a reduction in the glomerular filtration rate that further reduces the ability of the kidney to excrete the excess serum calcium. Rehydration reverses this situation and is a critical component of therapy.   

Intravenous sodium chloride 0.9% is recommended, with the rate and duration dependent on the patient’s volume, cardiovascular and renal status.^r Volumes and times should be determined by the treating clinician, and local institutional policy should be followed. For acute severe hypercalcaemia a reasonable infusion rate for an adult is:

• sodium chloride 0.9% 4 to 6 litres by intravenous infusion over 24 hours.^r

Practice points

• Monitor for fluid overload if renal impairment or elderly.
• Loop diuretics rarely used and only if fluid overload develops; not effective for reducing serum calcium.^r If loop diuretics are used, other electrolytes e.g. potassium and phosphate need to be monitored and replaced.
• Monitor serum calcium response – with nadir reached at 2 to 4 days.
• May need to consider dialysis if severe renal failure.

Bisphosphonate therapy

Intravenous bisphosphonates are used because they have a faster onset of action and the burden of treatment is more favourable than with oral bisphosphonates. The choice of bisphosphonate may be determined by local policy i.e. either zoledronic acid or pamidronate. However, zoledronic acid may be more favourable as it is more potent than pamidronate and can be administered over a shorter time period (15 minutes compared with two hours).

Practice points

• Bisphosphonates can cause nephrotoxicity, adequate hydration can enhance renal protection.
• In patients with renal impairment, bisphosphonates may be contraindicated or dose adjustments may be required. Refer to product information for detail.
• Monitor serum calcium response – maximum effect occurs at 2 to 4 days. For pamidronate, if plasma calcium does not decrease within 48 hours, further treatments may be given.^r For zoledronic acid, dose may be repeated after at least 7 days in patients who are refractory to initial treatment or who subsequently relapse.^r
• Can cause hypocalcaemia if vitamin D deficiency or suppressed PTH.

Denosumab

Denosumab is a RANKL monoclonal antibody which inhibits osteoclast activation and function. It may be an option for patients with hypercalcemia that is refractory to zoledronic acid or in whom bisphosphonates are contraindicated due to severe renal impairment. Regular monitoring of calcium is important as the risk of hypocalcaemia is high, particularly in patients with reduced renal function.

Calcitonin

Calcitonin blocks osteoclast activity and also renal tubular reabsorption of calcium. Calcitonin effect is rapid, usually within a few hours of first administration. Clinical use is limited by the transient effect and development of tolerance within days of use. Because of its limited duration of effect, calcitonin is most beneficial in symptomatic patients with severe hypercalcemia i.e. serum calcium > 3.5 mmol/L, when combined with hydration and bisphosphonates. Calcitonin and hydration provide a rapid reduction in serum calcium concentration, while a bisphosphonate provides a more sustained effect.

No dose adjustments are required in patients with renal insufficiency. In Australia, calcitonin is available as salcatonin.

Glucocorticoids

Corticosteroids can be given, but may only be useful where hypercalcaemia is due to sarcoidosis, lymphoma or vitamin D intoxication or multiple myeloma.  Additionally they often take several days (~ 2-4 days) to achieve the desired effect.

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