hypercalcemia is a sign of a hormonally advanced cancer

Background

Up to 30 percent of patients with cancer develop hypercalcemia. Approximately 50% of these patients will die within 30 days of a hypercalcemia diagnosis, even if the hypercalcemia is corrected, which suggests that hypercalcemia is a sign of a hormonally advanced cancer. It is most associated with squamous cell cancers of lung, head and neck, and esophagus, breast cancer, renal cell carcinoma, lymphomas and multiple myeloma.
 
Pathophysiology

Hypercalcemia of malignancy is typically a distinct process from other common non-malignancy etiologies of hypercalcemia such as hyperparathyroidism or a medication side effect. Cancer can lead to hypercalcemia from a variety of mechanisms of action including:

  • Local osteolytic hypercalcemia due to direct effect of bone metastases.
  • Humoral Hypercalcemia of Malignancy – secretion of parathyroid hormone related protein (PTHrP) by malignant tumors.
  • 1,25(OH)2D (vitamin D) secreting lymphomas.
  • Ectopic secretion of authentic PTH (very rare).
 
Symptoms/Signs

Symptoms roughly correlate with the degree of hypercalcemia (corrected) and the rapidity of rise: Mild (10.5-11.9 mg/dl); Moderate (12-13.9 mg/dl); Severe (>14 mg/dl).

  • Neurologic: fatigue, sedation, delirium, coma.
  • Gastrointestinal: anorexia, nausea, vomiting, constipation.
  • Renal: dehydration, polyuria, thirst/polydipsia, nephrolithiasis, renal dysfunction.
  • Musculoskeletal: weakness, bone pain, osteopenia.
  • Cardiovascular: bradycardia, QT interval shortening
 
Diagnostics

  • Total serum calcium, corrected for albumin (Formula: [(4 – albumin) x 0.8] + Ca++]).
  • Ionized calcium.
  • Renal function, phosphate, magnesium, and potassium—monitor during treatment.
Anti-tumor therapy

Treatment of the underlying malignancy with systemic therapy (e.g., chemotherapy) is the most definitive way to control hypercalcemia of malignancy long-term. In cases where further anti-neoplastic therapy is not feasible, the decision to treat or not treat hypercalcemia should be made by careful exploration of the patient’s goals of care. In advanced untreatable cancer, the decision to not treat hypercalcemia may be very appropriate.

Bisphosphonates are the drug class of choice to treat hypercalcemia of malignancy for most patients. They can be given with or without anti-tumor therapy. Bisphosphonates work via blocking osteoclastic bone resorption. Pamidronate and zoledronic acid are used in the US with full efficacy noted 2-4 days after administration: responses last 1-3 weeks. Hypocalcemia or azotemia may result; use with caution in renal dysfunction. Pamidronate = 60-90 mg. Repeat only after 7 days have elapsed after 1st dose. Repeat infusions every 2-3 weeks or longer according to the degree and of severity of hypercalcemia. Zoledronic acid = 4 mg (maximum). Wait at least 7 days before considering retreatment
 
Supportive measures

  • Saline hydration and loop diuretics: Normal saline 200-500 ml/hr increases GFR, increases filtered load of calcium, and is calciuretic. Loop diuretics (e.g., furosemide) blocks calcium resorption in the loop of Henle. Note: only use diuretics once dehydration has been corrected.
  • Discontinue medications that can increase serum calcium (e.g., lithium, Vitamin D, supplements containing calcitriol, thiazides, calcium antacids); remove calcium from TPN.
  • Increase mobility if possible.
  • Calcitonin may lead to transient reductions in serum calcium by promoting urinary calcium excretion. Efficacy is noted within 4-6 hours, but responses often max out at 48 hours. It is administered intramuscularly or subcutaneously; initially 4 units/kg every 12 hours; may increase up to 8 units/kg every 6-12 hours. Monitor patients for tachyphylaxis.
  • Denosumab is a human monoclonal antibody that is a potent inhibitor osteoclast mediated bone resorption. In repeated studies, it has led to durable responses in over 60% of patients with hypercalcemia refractory to bisphosphonates. Its cost may be prohibitive in hospice settings.
  • Other Agents: Glucocorticoids are useful in lymphoid malignancies that secrete 1,25(OH)2 Vitamin D. Mithramycin was the standard agent prior to bisphosphonates; now it is used only rarely due to a higher side effect profile. Gallium nitrate is usually impractical due to the need for a 5-day IV infusion. Renal Dialysis can be used in cases of acute/chronic renal failure
 
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Summary

Hypercalcemia is a common oncologic complication that often portends a short prognosis. The decision to attempt reversal should be made after first exploring the goals of care and assessing the feasibility of future systemic anti-cancer treatments. Vigorous hydration and bisphosphonates are the cornerstones of short-term hypercalcemia therapy.
 
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