Management of malignant hypercalcaemia

Hypercalcaemia is defined as adjusted calcium > 2.6 mmol/L. Hypercalcaemia of malignancy (HCM) is a common metabolic complication in patients with advanced cancer and is associated with significant morbidity and poor prognosis (especially if further systemic anticancer therapy not appropriate). PTH levels are typically low in HCM, except in rare cases of ectopic PTH production.

Pathophysiology

HCM arises through several mechanisms:

• Humoral Hypercalcaemia of Malignancy (HHM) – ~80% of cases
• Caused by tumour secretion of parathyroid hormone-related peptide (PTHrP), which mimics PTH
• Leads to increased bone resorption and renal calcium reabsorption
• Common in squamous cell carcinomas (lung, head, neck), renal cell carcinoma, breast and bladder cancers
• Osteolytic Hypercalcaemia – ~20% of cases
• Results from direct bone destruction by metastatic lesions, leading to calcium release into the circulation
• Common in breast cancer and multiple myeloma
• Other rare causes:
• Ectopic PTH secretion
• Excess calcitriol (1,25-dihydroxyvitamin D) production, especially in lymphomas

Presenting Symptoms:

• polydipsia
• polyuria
• confusion
• constipation
• anorexia
• life-threatening features: seizures, neurological compromise

Investigations:

• Serum calcium & albumin - always refer to adjusted calcium level
  • If albumin <20g/L, adjusted calcium may need to be calculated manually: Adjusted calcium (mmol/L)=Measured calcium+(0.02×(40−Albumin g/L))
• Vitamin D, PTH and myeloma screen when non-malignant causes are suspected
• review medications: review nephrotoxics and consider stopping or withholding. Stop medications that may be contributing to presentation e.g. calcichew, adcal etc. 

Step 1 - Hydrate

• Aim to administer 3L of 0.9% NaCl over 24 hours - adjust based on patient’s cardiac status.
• For severe HCM (Adj Ca >3.5) that persists 24hrs after IV fluids and is associated with life threatening symptoms, calcitonin may be considered following discussion with endocrinology

Step 2 - Bisphosphonates for persisting HCM

• CrCl >60ml/min: 4mg IV zolendronic acid 
• CrCl 30-60ml/min: 3mg IV zolendronic acid
• CrCl <30ml/min or creatinine >400umol/L - avoid zolondronic acid. Discuss with consultant and give pamidronate if benefit outweighs risk (see notes section below for dosing)

Step 3 - Monitor 

• Check adjusted calcium & UEs in 3-4 days (note that it can take up to 7 days for the full effects of bisphosphonate therapy to manifest). 
  • If calcium remains elevated, can consider repeat bisphosphonate
    • zolendronic acid 2nd dose may be given after 7 days
    • pamidronate 2nd dose may be given after 2-3 weeks

• Calcitonin can be considered in addition to bisphosphate in patients with adjusted calcium > 3.5 mmol/L and where symptoms are life‑threatening (e.g., seizures, severe neurological compromise). Discuss with endocrinology and notify clinical pharmacist.
• Calcitonin has a rapid onset of action and can lower serum calcium by approximately 0.25–0.5 mmol/L, providing short-term control while awaiting the maximal effect of antiresorptive therapy.

• Initial dose: 100 units every 6–8 hours (TDS–QDS), administered subcutaneously (SC) or intramuscularly (IM).
• If calcium levels do not improve after 24 hours, the dose may be increased to a maximum of 200 units TDS-QDS.
• Treatment beyond 72 hours increases the risk of tachyphylaxis (loss of response with repeated dosing).
• Calcitonin is non-formulary, therefore, completion of  Non-Formulary Medicine Request Form and approval via Cancer Medicines Management Committee is mandatory for all patients.

Denosumab may be considered in palliative patients with symptomatic refractory hypercalcaemia.

Refractory hypercalcaemia refers to corrected (adjusted) calcium remaining > 3.0 mmol/L despite appropriate prior treatment, defined as:

• Persistent hypercalcaemia after two or more doses of a bisphosphonate given over a 2‑week period, or
• Rebound hypercalcaemia occurring within 2 weeks of receiving a bisphosphonate.

Patients should also meet all of the following criteria:

• Unlikely to receive systemic anticancer therapy (SACT)
• Symptomatic from hypercalcaemia
• Not in the last days of life

Prescribing Considerations

• Off-label use – completion of Non-Formulary Medicine Request Form & approval via Cancer Medicines Management Committee is mandatory for all patients

• See guideline: Denosumab for Refractory Hypercalcaemia of Malignancy in Palliative Care for dosing schedule and community follow up arrangement

Pamidronate Dosing:

• When using pamidronate in renal impairment, adjust dose according to the level of the corrected calcium as follows:
  • Calcium <3.0: 30mg
  • Calcium 3-3.5: 60mg
  • Calcium >3.5: 90mg
  • If GFR <30ml/min then administer pamidronate at a rate of 20mg/hour (in at least 500ml 0.9% sodium chloride. Volume will depend on renal function)

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Please also refer to ‘Bisphosphonates in Myeloma’ on the haematology intranet site for further information on the use of bisphosphonates in myeloma.