Clinical Pearls & Morning Reports
Cancer-associated hypercalcemia is a complication of advanced cancers and portends a poor prognosis. Despite the current availability of more effective treatments, outcomes remain poor, with a median survival of 25 to 52 days. Read the NEJM Clinical Practice Article here.
Q: Hypercalcemia is most common in which subset of cancers?
A: Hypercalcemia frequently complicates the care of patients with cancer, occurring in up to 30% of such patients during the course of their disease. Hypercalcemia has been reported in association with most cancers, but it is most common in patients with non–small-cell lung cancer, breast cancer, multiple myeloma, squamous-cell cancers of the head and neck, urothelial carcinomas, or ovarian cancers.
Q: What is the first goal of therapy for patients with cancer-associated hypercalcemia?
A: Hypercalcemia is associated with anorexia, nausea, vomiting, and nephrogenic diabetes insipidus. These factors often produce extreme dehydration and lead to a reduced glomerular filtration rate, which limits the ability of the kidney to excrete calcium. Thus, the first goal of therapy is to correct volume depletion. Sodium delivery to the distal tubule promotes urinary calcium excretion and increases calcium clearance by the kidneys. Therefore, it has become common practice to add loop diuretics, such as furosemide, after rehydration has been achieved. However, no controlled studies have been conducted to determine whether the addition of loop diuretics lowers calcium levels more rapidly than hydration alone, and the authors of a critical review of nine case series concluded that the routine use of loop diuretics in the treatment of cancer-associated hypercalcemia was not helpful. If used, diuretics should be administered only after volume status has been fully restored or during the care of patients with hypercalcemia who are at high risk for the development of fluid overload after aggressive fluid resuscitation.
A: In most instances, cancer-associated hypercalcemia occurs as a result of excessive bone resorption. Therefore, the mainstay of therapy is the administration of powerful antiresorptive agents —primarily bisphosphonates or denosumab — and, in some instances, calcitonin. Calcitonin is a peptide hormone secreted by the parafollicular cells of the thyroid gland that inhibits osteoclast activity and promotes renal calcium excretion. When administered, calcitonin lowers serum calcium levels rapidly, within 12 to 24 hours. However, the reductions are small (approximately 1 mg per deciliter), and the effects are lost within 48 to 96 hours owing to the down-regulation of calcitonin receptors. Calcitonin is primarily useful in the initial lowering of very high calcium levels while waiting for the more prolonged onset of action of other antiresorptive agents.
A: Denosumab is a fully human monoclonal antibody that binds to receptor activator of nuclear factor қB ligand (RANKL). In doing so, denosumab inhibits the formation, differentiation, activation, and functioning of osteoclasts, greatly reducing bone resorption. Denosumab is not cleared by the kidney and has no renal toxicity, making it useful in patients with impaired renal function who cannot take bisphosphonates. Both bisphosphonates and denosumab are associated with rare adverse events, such as osteonecrosis of the jaw and atypical femoral fractures. Most cases of cancer-associated hypercalcemia are life-threatening, and the benefits of treatment far outweigh these small risks.