Supporting Hypercalcemia of Malignancy Treatment Guidelines

Abstract and Introduction

Abstract

Context: Hypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.

Objective: To support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults.

Methods: We searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence.

Results: We reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.

Conclusion: The evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients' values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

Introduction

Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies.^[1–6] It is most commonly associated with squamous cell carcinomas, breast and renal carcinomas, and multiple myeloma and other hematologic malignancies. HCM may affect up to 30% of patients during the course of their disease.^[4,7] Its presence confers a poor prognosis, and, if left untreated, it can be life threatening.^[8] HCM treatment substantially and rapidly alleviates symptoms; improves quality of life; and, importantly, provides an opportunity to administer therapies to target the primary malignancy. The underlying pathophysiology of HCM is most often through stimulation of parathyroid hormone–related peptide (PTHrP)-mediated osteoclastic bone resorption. Treatment is directed at hydration to enhance renal calcium excretion and at decreasing bone resorption via the use of potent antiresorptive medications. These include intravenous (IV) bisphosphonates (BPs) as the cornerstone therapy for HCM, with denosumab (Dmab) more commonly used in patients with refractory HCM and in those with renal failure. In tumors secreting calcitriol, glucocorticoids are used, while calcimimetics are indicated in parathyroid hormone (PTH)–secreting tumors.^[1,3,9]

While several published clinical practice guidelines (CPGs) target the treatment of cancer patients with bone metastases, multiple myeloma, parathyroid carcinoma, and small cell carcinoma of the ovary,^[10–19] we are unaware of any guidelines that are specific for the treatment of HCM. In this context, the Endocrine Society gathered a multidisciplinary panel of clinical experts, together with experts in systematic literature review, to develop CPGs for the treatment of HCM. These CPGs apply to adults with HCM from humoral hypercalcemia of malignancy, local osteolytic hypercalcemia, calcitriol-mediated hypercalcemia, and parathyroid carcinoma. The CPGs apply to inpatient and outpatient settings alike and provide a framework to guide endocrinologists, oncologists, and primary care and palliative care experts as well as other concerned stakeholders. The writing panel identified several clinical scenarios frequently faced by health care providers who manage patients with HCM of various underlying pathophysiologic mechanisms. The writing panel also identified important clinical outcomes that would determine the selection of specific treatment strategies for each clinical scenario. To support the guideline development process and summarize the evidence base for the CPGs, we conducted this systematic review and meta-analysis.