A Case of Resistant Hypercalcemia of Malignancy with a Proposed Treatment Algorithm

Abstract

To report and describe a case of refractory hypercalcemia of malignancy (HCM) associated with metastatic, transitional-cell carcinoma of the left ureter. A 71-year-old male complaining of generalized weakness and night sweats for the past 3 months was sent to the emergency department when routine laboratory tests revealed a corrected serum calcium concentration of 14.4 mg/dL. Intravenous crystalloid fluids and pamidronate were administered with achievement of normocalcemia, and the patient was discharged. Computed tomography scan and liver biopsy revealed recurrent transitional-cell carcinoma with extensive liver metastasis. The patient returned approximately 1 week after discharge with a serum calcium level of 13.9 mg/dL. An initial decrease in serum calcium was observed with intravenous fluids, pamidronate, and calcitonin, but the normalization slowed and reversed within 3 days. Normocalcemia was achieved upon administration of zoledronic acid and the patient was discharged on day 14. The patient died 1 week after discharge from complications unrelated to hypercalcemia. Hypercalcemia is common in patients with malignancy and is associated with potentially life-threatening sequelae. Four mechanisms of HCM have been recognized thus far, with ectopic tumor production of parathyroid hormone-related protein (PTHrP) being the leading cause. Treatment of HCM revolves around 2 principles: treatment of the underlying malignancy along with reduction of the serum calcium level. Evidence-based therapies for management include: intravenous crystalloid fluids with or without loop diuretics, bisphosphonates, calcitonin, gallium nitrate, and corticosteroids. Therapies used for this patient included aggressive hydration, calcitonin, and 3 distinct treatment courses of intravenous bisphosphonates with varying success. Other potential agents were explored for use in the event of continued hypercalcemia. These therapies remain viable options based on individual patient factors. To our knowledge, no published guidelines or algorithms exist for choosing between additional modalities in the treatment of refractory HCM. For patients with HCM who do not achieve a response from bisphosphonates, or for those who need repeated dosing more often than expected, changing to a different drug class could be an alternative. The specific mechanism of hypercalcemia should be considered when developing a treatment regimen for patients who have had a suboptimal response to initial therapy with bisphosphonates. Multiple treatment modalities exist for the treatment of hypercalcemia, each with a different mechanism of action. As with the treatment of other disease states, we can use this knowledge to more specifically target the mechanism of the patient's disease.