Management of hypercalcemia of malignancy

Abstract

Hypercalcemia is defined as a condition in which the serum calcium level is >10.5 mg/dL (the upper limit of normal) or the ionized calcium level exceeds 5.6 mg/dL. The consequences of abnormally high serum calcium can range from asymptomatic to life-threatening. In addition , excessively high serum calcium causes clinical manifestations that affect the neuromuscular, gastroin-testinal, renal, skeletal, and cardiovascular systems. 1 Malignancy is a common cause of hypercalcemia, particularly when bone metastases exist. Because some tumor cells can resorb or destroy bone tissue, hypercalcemia of malignancy develops more rapidly and more aggressively than hypercalcemia related to other conditions, and includes the classic symptoms of dehydration, anorexia, nausea, vomiting, constipation, confusion, and polyuria. In multiple myeloma, for example, malignant myeloma cells secrete a cytokine-interleukin-6-that activates osteoclasts in the vicinity of the myeloma cells, leading to bone resorption. Hypercalcemia is a common complication of various types of cancer, including squamous-cell carcinoma, multiple myeloma, T-cell lymphoma, and breast carcinoma. PATHOPHYSIOLOGY There are 4 major types of hypercalcemia associated with cancer, including humoral hypercalcemia of malig-nancy (HHM), local osteolytic hypercalcemia, calcitriol-secreting lymphoma, and ectopic hyperparathyroidism. 2 HHM is the most common mechanism of hypercalce-mia in patients with cancer. Many cancer cells secrete parathyroid-hormone-related protein (PTHrP), which binds to the parathyroid receptors in bone and renal tissues , resulting in increased bone resorption and renal tubular reabsorption. 3 Local osteolytic hypercalcemia can be differentiated from primary hyperparathyroidism and humoral hypercalcemia of malignancy by normal or slightly elevated phosphate levels, normal levels of im-munoreactive PTHrP, and the presence of bone metasta-ses or bone marrow infiltration. Local osteolytic hypercalcemia is typically associated with breast cancer, multiple myeloma, and lymphoma. 1 Moreover, osteoblasts secrete a receptor activator of nuclear factor kappa-B ligand (RANKL), which activates osteoclasts and promotes secretion of insulin-like growth factor-1, which then increases calcium levels, which is a point of target for medications to inhibit RANKL. 3 This section provides a quick update of symptomatic conditions in oncology and their management. Readers are invited to submit brief updates following the guidelines provided on page 17. EPIDEMIOLOGY AND ETIOLOGY The most common causes of hypercalcemia in the United States are primary hyperparathyroidism and malignancy. Hypercalcemia occurs in approximately 20% to 30% of patients with cancer at some time during the course of their disease, and is encountered predominantly among hospitalized patients, whereas primary hyperparathyroidism accounts for the majority of outpatient cases. 1,2 SYMPTOM OVERVIEW Clinical manifestations of hypercalcemia vary according to the level of calcium in the blood. The normal range for total serum calcium is 8.5 mg/dL to 10.5 mg/dL, and the normal range for ionized calcium is 4 mg/dL to 5.6 mg/dL. The severity of hypercalcemia is classified into 3 categories based on the level of total serum calcium (Figure). Patients with mild hypercalcemia, defined as total