Hypercalcemia of Malignancy

Aka: Hypercalcemia of Malignancy, Malignant Hypercalcemia, Humoral Hypercalcemia of Malignancy

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II. Epidemiology

  1. Incidence: 10-30% of cancer patients
    1. Most common metabolic Oncologic Emergency

III. Mechanisms

  1. Paraneoplastic Syndromes (nearly all cases)
    1. Tumor secretes Parathyroid Hormone related peptide or PTHrP (80% of all cases)
      1. Present in Squamous Cell Carcinoma and Lymphoma
      2. Results in increased Calcium reabsorption in Kidney
    2. Osteoclast-Activating factor production (20% of all cases)
      1. Present in Multiple Myeloma and metastases
      2. Results in osteolysis
    3. Endogenous Calcitriol (Vitamin D, 1,25-dihydroxyvitamin D, <1% of all cases)
      1. Present in Lymphomas
      2. Calcitriol acts as a bone-resorbing Cytokine
  2. Other rare mechanisms
    1. Immobilization
    2. Medications
    3. Parathyroid carcinoma

IV. Causes: Primarily Breast, lung and Bone Cancers

  1. Most common causes
    1. Breast Cancer
    2. Lung Cancer
    3. Multiple Myeloma
  2. Other causes
    1. Squamous Cell Carcinoma of head and neck
    2. Kidney Cancer
    3. Cervical Cancer

V. Findings

  1. See Hypercalcemia
  2. Neurologic
    1. Altered Level of Consciousness (confusion to coma)
    2. Hyporeflexia
    3. Generalized weakness
  3. Gastrointestinal Symptoms
    1. Nausea or Vomiting
    2. Constipation
    3. Anorexia
  4. Dehydration
    1. Acute Kidney Injury
    2. Excessive Thirst and polydipsia
    3. Initial Polyuria and then decreased Urine Output
  5. Cardiovascular
    1. Risk of lethal Arrhythmia

VI. Labs

  1. Serum Electrolytes
  2. Serum Calcium
    1. See Corrected Serum Calcium
    2. Adjust for albumin, as Malnutrition is common (obtain Ionized Calcium if available)
    3. Mild Hypercalcemia: 10.5 to 11.9 mg/dl
    4. Moderate Hypercalcemia: 12.0 to 13.9 mg/dl
    5. Severe Hypercalcemia: >14 mg/dl

VII. Diagnostics

  1. Electrocardiogram (EKG)
    1. Short QT Interval
    2. Prolonged PR Interval
    3. Wide QRS Complex
    4. Bradycardia
    5. First degree AV Block
    6. J Wave (Osborn Wave)

VIII. Management

  1. See Hypercalcemia for other management
  2. Consult Oncology, Endocrinology, Nephrology
  3. Aggressive Intravenous Fluids as Initial Management ( emergency department)
    1. Aggressive rehydration alone normalizes Serum Calcium in 30% of cases even within 12 hours
    2. Start 250 to 500 ml/hour with goal Urine Output 100-150 ml/hour
    3. Requires up to 4 liters Lactated Ringers or Normal Saline per 24 hours
  4. Monitor serum Electrolytes
    1. Serum Calcium (may start as high as 14 mg/dl)
  5. Hypophosphatemia specific management
    1. Indication for Phosphorus Replacement: Serum Phosphate <3 mg/dl
    2. Neutro-Phos 250 mg Phosphorous PO or NG daily
  6. Hypercalcemia specific management
    1. Indications
      1. Serum Calcium >14 mg/dl if asymptomatic
      2. Serum Calcium >12 mg/dl if symptomatic
    2. Methods
      1. Glucocorticoids
        1. Indicated calcitriol overproduction as mechanism for Hypercalcemia
        2. Decrease intestinal Calcium absorption
      2. Bisphosphonates
        1. Inhibit Osteoclast mediated bone resorption (delayed effect over 1-3 days)
        2. Avoid if recent Fracture (risk of impaired bone healing)
        3. Zoledronic acid: 4 mg IV over 15 min (preferred over Pamidronate)
        4. Pamidronate (Aredia) 60-90 mg IV given over 2 hours q4 hours
        5. Major (2001) J Clin Oncol 19:558-67 [PubMed]
      3. Calcitonin
        1. Calcitonin 4 IU/kg IM or SQ
        2. Inhibits Osteoclasts (but diminishing returns after first dose due to tachyphylaxis)
      4. Monoclonal antibodies
        1. Denosumab (inhibits Osteoclasts) may be considered when Hypercalcemia is refractory to Bisphosphonates
  7. Other measures
    1. Hemodialysis Indications (severe, refractory Hypercalcemia)
      1. Refractory Acute Kidney Injury (GFR <20)
      2. Total Serum Calcium >18 mg/dl
      3. Congestive Heart Failure
      4. Neurologic Deficits
    2. Loop Diuretics (e.g. Furosemide)
      1. Indicated in Renal Failure or Congestive Heart Failure
      2. Consider after initial fluid Resuscitation
      3. Furosemide 10-20 mg IV q6-12 hours after initial rehydration

IX. Prognosis

  1. Hypercalcemia of Malignancy is a poor cancer prognostic sign
  2. Associated with >50% mortality in 30 days

X. References

  1. Aurora and Herbert in Majoewsky (2013) EM:Rap 13(10): 1-4
  2. Long, Long and Koyfman (2020) Crit Dec Emerg Med 34(11): 17-24
  3. Higdon (2006) Am Fam Physician 74:1873-80 [PubMed]
  4. Higdon (2018) Am Fam Physician 97(11):741-8 [PubMed]
  5. Stewart (2005) N Engl J Med 352:373-9 [PubMed]
  6. Zuckerman (2012) Blood 120(10): 1993-2002 [PubMed]

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