Hypercalcemia

Hypercalcemia is the most common metabolic emergency seen in individuals with cancer, occurring in an estimated 10% to 20% of patients.

Etiology

The malignancies most commonly associated with hypercalcemia include myeloma, lung cancer (epidermoid tumors more often than small-cell tumors), and renal cancer. In some cases, the pathogenesis of hypercalcemia may relate to the release of parathyroid-like hormones, prostaglandins, and osteoclast-activating factor.

Signs and Symptoms

Symptoms of hypercalcemia may involve various organ systems, including the central nervous, cardiac, GI, and renal systems (Table 1).

Bony metastasis vs paraneoplastic syndrome

The signs and symptoms of hypercalcemia secondary to bony metastases are often indistinguishable from those of hypercalcemia as a paraneoplastic syndrome. The laboratory findings may vary. A tumor secreting an immunoreactive parathyroid hormone (iPTH)-like substance will have increased levels of cyclic adenosine monophosphate, low levels of serum phosphorus, and variable levels of iPTH, depending on the specificity of the assay. Many patients with bony metastases also exhibit features consistent with “ectopic” hyperparathyroidism.

Diagnosis

An accurate history and physical examination are often the most helpful diagnostic tools to exclude correctable nonmalignant causes of hypercalcemia. Hypercalcemia in association with occult malignancies is rare. The presence of weight loss, fatigue, or muscle weakness should increase clinical suspicion of malignancy as the cause of hypercalcemia.

TABLE 1Symptoms associated with hypercalcemia by organ system

Laboratory findings

In patients with hypercalcemia of malignancy, serum iPTH levels, determined by a double-antibody method, are extremely low or undetectable; levels of inorganic phosphorus are low or normal; and levels of 1,25-dihydroxyvitamin D are low or normal.

Use of additional tests to identify the underlying malignancy responsible for the hypercalcemia often depends on the history and physical findings.

Treatment

Asymptomatic patients with minimally elevated calcium levels (< 12 mg/dL) may be treated as outpatients, with close monitoring of calcium levels and symptoms. Encouragement of oral hydration, mobilization, and elimination of drugs that contribute to hypercalcemia are essential. Patients who are symptomatic or have calcium levels of 12 mg/dL or higher should be considered for inpatient management if medically appropriate. An algorithm for the acute and chronic treatment of hypercalcemia of malignancy is shown in Figure 1.

Volume expansion (eg, lactated Ringer solution, 0.9% NaCl)

Volume expansion and natriuresis increase renal blood flow and enhance calcium excretion secondary to the ionic exchange of calcium for sodium in the distal tubule. The volume required depends on the extent of hypovolemia as well as the patient’s cardiac and renal function. Often, infusion rates of 250 to 500 mL/h are needed. Typically, the onset of action is 12 to 24 hours.

FIGURE 1Algorithm for the treatment of hypercalcemia of malignancy.

Loop diuretics

There is much controversy over the effectiveness of loop diuretics in the treatment of hypercalcemia. In theory, furosemide-induced natriuresis should enhance urinary calcium excretion. However, in most cases of significant hypercalcemia, hypovolemia is present. Thus, once euvolemia has been achieved with saline infusion, diuretics may be useful in preventing hypervolemia. Diuretic dosages depend on the patient’s underlying renal function, and the dosing frequency should be based on hourly urine output. In patients with normal renal function, furosemide, at 20 to 40 mg IV, may be initiated after volume expansion is achieved, with subsequent doses given when urine output is less than 150 to 200 mL/h.

Bisphosphonates

Bisphosphonates (etidronate, clodronate [Bonefos], pamidronate, and zoledronic acid [Zometa]) bind avidly to hydroxyapatite crystals and inhibit bone resorption. Their antiresorptive effects may be mediated by the inhibition of osteoclasts and activation by cytokines. Bisphosphonates also inhibit recruitment and differentiation of osteoclast precursors. They are poorly absorbed from the GI tract, have a very long half-life in bone, and appear to accumulate at sites of active bone turnover.

Zoledronic acid (at 4 mg IV over a minimum of 15 minutes) is a second-generation bisphosphonate that can be infused more quickly and has fewer systemic adverse effects than pamidronate and other bisphosphonates and is considered the agent of choice for hypercalcemia due to malignancy.

Pamidronate has been shown to be effective in restoring normocalcemia in 60% to 100% of patients with hypercalcemia secondary to malignancy. The recommended dose is 60 to 90 mg IV over 2 to 24 hours. Adverse effects include low-grade fever and mild hypocalcemia and hypomagnesemia. Clodronate, a first-generation bisphosphonate indicated for cancer-associated hypercalcemia, is a relatively weak bone resorption inhibitor compared with pamidronate and zoledronic acid. It is dosed at 300 mg IV daily for 5 consecutive days (infused over at least 2 hours) or 800 to 3,200 mg/d orally.

Corticosteroids

In certain malignancies, such as lymphomas and hormone-sensitive breast cancers, corticosteroids may be of some value in producing a direct antitumor effect. In the majority of solid tumors, however, corticosteroids are of limited or no value.

The onset of action is 3 to 5 days. Doses of prednisone (or its equivalent) may range from 10 to 100 mg/d.

Calcitonin

This drug inhibits bone degradation by binding directly to receptors on the osteoclast. It has few serious adverse effects (rare hypersensitivity) and can be given to patients with organ failure.

The onset of action of calcitonin is 2 to 4 hours, but its hypocalcemic effect is of short duration and peaks at 48 hours. There is little response to continued treatment. Doses range from 2 to 8 U/kg SC or IM every 6 to 12 hours. Because of its short onset of action, calcitonin may be appropriate in conjunction with volume expansion and bisphosphonate treatment, in symptomatic patients with extremely high calcium levels.

Plicamycin (Mithracin)

This drug has direct osteoclast-inhibitory effects and may also block the effects of vitamin D or parathyroid hormone. It reportedly is effective in approximately 80% of patients with hypercalcemia secondary to malignancy.

The onset of action of plicamycin is 24 to 48 hours. The duration of normocalcemia varies, but re-treatment is required in 72 to 96 hours in most patients. The usual dose is 25 μg/kg (range, 10 to 50 μg/kg).

Significant toxicity increases with multiple injections and includes renal and liver toxicity. Thrombocytopenia is a common adverse effect.

Gallium nitrate (Ganite)

Gallium nitrate directly inhibits osteoclasts and increases bone calcium without producing cytotoxic effects on bone cells. It successfully restores normocalcemia in 75% to 85% of patients.

The onset of action of gallium nitrate is 24 to 48 hours. The dose range is 100 to 200 mg/m² given by continuous IV infusion for 5 days.

A study by Bertheault-Cvitkovic et al suggested that gallium nitrate may be superior to pamidronate for the acute normalization of cancer-related hypercalcemia. In other comparative trials, gallium nitrate proved to be more effective than both calcitonin and etidronate in patients with hypercalcemia that is secondary to malignancy.

There are some disadvantages to gallium nitrate therapy, including the need for inpatient care and daily IV infusions, and its potential nephrotoxicity. It has been recommended that the drug not be used in patients with creatinine levels greater than 2.5 mg/dL.