Hypercalcaemia of Malignancy
Hypercalcaemia of malignancy is the most common metabolic emergency in oncology, affecting 10-30% of cancer patients, caused by PTHrP secretion or osteolytic metastases, and treated with rehydration and bisphosphonates.
Key Facts
Most common paraneoplastic metabolic emergency; affects 10-30% of cancer patients at some point Three mechanisms: humoral (PTHrP) (80%, squamous cell cancers), osteolytic (bone metastases, breast, myeloma), 1,25(OH)₂D (lymphoma) Symptoms: 'stones, bones, groans, moans' - renal stones, bone pain, abdominal pain/constipation, confusion/depression Corrected calcium = measured Ca²⁺ + 0.02 × (40 - albumin); mild: 2.6-3.0, moderate: 3.0-3.5, severe: >3.5 mmol/L First-line treatment: aggressive IV 0.9% saline rehydration (3-4L/24h) + zoledronic acid 4mg IV over 15 minutes Denosumab 120mg SC: for bisphosphonate-refractory hypercalcaemia; also used in renal impairment (does not require renal dose adjustment) Loop diuretics (furosemide): only use AFTER rehydration and only if fluid overload; no longer recommended routinely Median survival after first episode of hypercalcaemia of malignancy: approximately 3-4 months (reflects advanced disease)
Overview
Key Facts
Hypercalcaemia is the most common metabolic emergency in oncology and is often a sign of advanced disease. Prompt recognition and treatment are essential to prevent life-threatening cardiac arrhythmias, renal failure, and coma.
Epidemiology
- Affects 10-30% of cancer patients during their illness
- Most common with: squamous cell carcinomas (lung, head & neck), breast cancer, renal cell carcinoma, myeloma
- Often indicates advanced disease with poor prognosis
Aetiology
- Humoral hypercalcaemia (80%): PTHrP (parathyroid hormone-related peptide) secretion by tumour
- Most common: squamous cell lung cancer, renal cell, breast, bladder, ovarian
- Osteolytic metastases (20%): local osteoclast activation by cytokines (RANKL, IL-6)
- Breast cancer, myeloma
- Calcitriol-mediated (<1%): ectopic 1,25(OH)₂D production
- Lymphoma (particularly Hodgkin)
- Ectopic PTH production: extremely rare
Pathophysiology
- PTHrP mimics PTH at the PTH receptor: increases osteoclastic bone resorption, increases renal calcium reabsorption, increases phosphate excretion
- Osteolytic metastases: tumour cells in bone produce cytokines that activate osteoclasts (vicious cycle of bone destruction)
- Hypercalcaemia impairs renal concentrating ability → polyuria → dehydration → worsened hypercalcaemia (vicious cycle)
- Calcium affects cardiac conduction (shortened QT), neurological function (confusion), and GI motility (constipation)
Clinical Presentation
Mild Hypercalcaemia (2.6-3.0 mmol/L)
- Often asymptomatic
- Mild fatigue, constipation
- Polyuria, polydipsia
Moderate Hypercalcaemia (3.0-3.5 mmol/L)
- Nausea, vomiting, anorexia
- Constipation, abdominal pain
- Confusion, drowsiness
- Dehydration
- Muscle weakness
Severe Hypercalcaemia (>3.5 mmol/L)
- Obtundation, coma
- Cardiac arrhythmias (shortened QT, bradycardia, heart block)
- Renal failure
- Pancreatitis
- Cardiac arrest
Red Flags
- Corrected calcium >3.5 mmol/L
- Altered conscious level
- ECG changes (shortened QT, wide QRS, arrhythmias)
- Renal failure (oliguria)
- Severe dehydration
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Primary hyperparathyroidism | Chronic mild hypercalcaemia, raised PTH | PTH, calcium, phosphate |
| Vitamin D intoxication | Supplement history, raised 25(OH)D | 25-hydroxyvitamin D |
| Sarcoidosis | Bilateral hilar lymphadenopathy, raised ACE | CXR, ACE level, biopsy |
| Thiazide diuretics | Drug history, mild hypercalcaemia | Drug review |
| Milk-alkali syndrome | Excessive calcium/antacid intake | History, U&Es |
| Thyrotoxicosis | Weight loss, tremor, tachycardia | TFTs |
Diagnosis / Investigation
Bedside
- ECG: shortened QT interval, wide QRS, arrhythmias
- Fluid balance chart
- Observations including GCS
Bloods
- Corrected calcium (adjusted for albumin) or ionised calcium
- Phosphate: low in PTHrP-mediated (PTH-like effect), variable in osteolytic
- PTH: suppressed in malignancy (distinguishes from primary hyperparathyroidism where PTH is raised/inappropriately normal)
- PTHrP: elevated in humoral hypercalcaemia
- U&Es (renal function; dehydration)
- Albumin (for calcium correction)
- ALP (bone metastases; often raised)
- Vitamin D (25(OH)D and 1,25(OH)₂D)
- Myeloma screen: protein electrophoresis, Bence-Jones protein, immunoglobulins
Imaging
- CXR (primary lung cancer, lymphadenopathy)
- Bone scan or skeletal survey (myeloma; osteolytic metastases)
- CT if staging/primary unknown
Special Tests
- Urine calcium:creatinine ratio (to exclude familial hypocalciuric hypercalcaemia)
Management
Non-pharmacological
- Aggressive IV rehydration: 0.9% saline 3-4L over first 24 hours (most important initial step)
- Mobilise if possible (immobility worsens hypercalcaemia)
- Stop offending drugs (thiazides, calcium supplements, vitamin D supplements)
- Strict fluid balance and urine output monitoring
- Cardiac monitoring if calcium >3.5 mmol/L
Pharmacological
- Zoledronic acid 4mg IV over 15 minutes (onset 2-4 days; peak effect 7 days; duration 3-4 weeks)
- Caution: dose adjust for eGFR 30-60; avoid if eGFR <30
- Pamidronate 60-90mg IV over 2-4 hours: alternative bisphosphonate
- Denosumab 120mg SC: for bisphosphonate-refractory cases or renal impairment; onset 4-10 days; monitor for hypocalcaemia
- Calcitonin 4-8 units/kg SC/IM 12-hourly: rapid onset (hours) but tachyphylaxis within 48 hours; useful as bridge
- Prednisolone 40-60mg OD: for lymphoma/myeloma-related hypercalcaemia (vitamin D-mediated or steroid-responsive tumours)
- Loop diuretics (furosemide 20-40mg IV): ONLY after adequate rehydration and if fluid overload; not routine
- Definitive: treat underlying malignancy (chemotherapy, hormonal therapy, radiotherapy)
Surgical/Interventional
- Haemodialysis: for life-threatening hypercalcaemia refractory to medical treatment (Ca >4.5 mmol/L or with renal failure)
Referral Criteria
- Moderate-severe hypercalcaemia: acute medical/oncology admission
- Corrected calcium >3.5 mmol/L: consider HDU/ITU monitoring
- Refractory hypercalcaemia: discuss with endocrinology and oncology
- If underlying malignancy unknown: urgent investigation for primary
Prognosis
- Median survival after first episode: approximately 3-4 months (indicates advanced disease)
- Response to bisphosphonates: normalisation of calcium in 60-90% within 7 days
- Recurrence is common: repeat bisphosphonate/denosumab as needed
- Patients with hypercalcaemia responding to cancer treatment have better prognosis
- Myeloma patients may have better outcomes as the hypercalcaemia is more treatment-responsive
Other Relevant Information
Severity Classification
| Severity | Corrected Calcium | Symptoms | Management |
|---|---|---|---|
| Mild | 2.6-3.0 mmol/L | Often asymptomatic | Oral rehydration, consider bisphosphonate |
| Moderate | 3.0-3.5 mmol/L | Symptomatic | IV fluids + IV bisphosphonate |
| Severe | >3.5 mmol/L | Severe/life-threatening | Aggressive IV fluids + IV bisphosphonate + cardiac monitoring |
Mechanism of Hypercalcaemia by Cancer Type
| Cancer | Mechanism | Frequency |
|---|---|---|
| Squamous cell lung | PTHrP | Very common |
| Breast (metastatic) | Osteolytic + PTHrP | Common |
| Myeloma | Osteolytic (RANKL, MIP-1α) | 30% |
| Renal cell | PTHrP | Common |
| Lymphoma | 1,25(OH)₂D | Uncommon |
| Head & neck SCC | PTHrP | Common |