A new Endocrine Society guideline details how to treat adult patients with hypercalcemia of malignancy, the most common metabolic cancer complication. Despite its high morbidity and mortality rates, this is the very first guideline that directly addresses this condition and confirms the efficacy of denosumab and bisphosphonates.

Adults with hypercalcemia of malignancy should be treated with an injection of denosumab or intravenous bisphosphonate, with a possible slight preference for denosumab. Those are the top two findings of the new “Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline.”

Hypercalcemia of malignancy is the most common metabolic complication of cancer, so it was timely to scrutinize the available evidence and develop this first-of-its-kind guideline on the topic, according to guideline committee chair Ghada El-Hajj Fuleihan, MD, MPH, of the Department of Internal Medicine, American University of Beirut in Lebanon: “Over the last 10 or 20 years, two different kinds of very potent drugs that affect bone resorption have been available, so we really needed to scrutinize the evidence for their efficacy in this disease.”  

The guideline committee reviewed the evidence to answer eight key questions related to hypercalcemia of malignancy, and El-Hajj Fuleihan says that the committee members were surprised at the scarcity of strong evidence. Because the committee had to rely on evidence that was indirect and of low certainty, almost all of its findings are rated as “suggestions.” Only the first point rose to the level of a “recommendation,” and that was because — despite the low-quality of the evidence — it dealt with a benefit in a life-threatening situation.

The Cancer Is the Cause

The guideline notes that the primary objective is to treat the patient’s cancer: “Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence.”

“The cornerstone is managing the primary disease, either surgically or medically,” El-Hajj Fuleihan says, noting that the mortality associated with hypercalcemia of malignancy has declined markedly with the introduction of more effective chemotherapeutic drugs.

“Treatment of hypercalcemia of malignancy substantially and rapidly alleviates symptoms, improves quality of life, and, importantly, provides an opportunity to administer life-saving therapies targeting the primary malignancy. Despite the widespread availability of efficacious medications, evidence-based recommendations to manage this debilitating condition have been lacking.”

Ghada El-Hajj Fuleihan, MD, MPH, Department of Internal Medicine, American University of Beirut. Beirut, Lebanon

But the condition is still associated with high morbidity and mortality, which is the underpinning for the guideline’s first recommendation — that it be treated with denosumab or a bisphosphonate rather than not be treated.

Etiology, Symptomatology, and Severity

El-Hajj Fuleihan says that the guideline addressed eight clinical scenarios encountered in hypercalcemia of malignancy, and that the specific etiology, clinical symptoms, and severity framed the recommendations. The guideline includes a workflow to implement its suggested treatment approaches. “What one would choose to treat mild hypercalcemia is different from what one would choose to treat moderate or severe hypercalcemia, or from what one would choose for refractory or recurrent hypercalcemia,” El-Hajj Fuleihan says.

Furthermore, in addition to the universal use of potent anti-resorptive medications such as IV bisphosphonates and subcutaneous denosumab, there can be a role for disease-specific drugs such as calcimimetics for parathyroid carcinoma and glucocorticoids for some tumors such as lymphomas.

Six Suggestions

In addition to the top two recommendations previously mentioned — that the hypercalcemia be treated and that denosumab may be the preferred choice — the other six suggestions from the guideline are:

• In the initial treatment of adults with severe hypercalcemia of malignancy, which is defined as serum calcium of >14 mg/dL (3.5 mmol/L), the guideline suggests that calcitonin be combined with IV bisphosphonate or denosumab, rather than using the bisphosphonate or denosumab alone. However, calcitonin treatment should be limited to 48 to 72 hours because of tachyphylaxis.
• In adults with refractory/recurrent hypercalcemia of malignancy who are receiving IV bisphosphonate, the guideline suggests adding denosumab.
• In adults with tumors associated with high calcitriol levels, such as lymphomas, who are already receiving glucocorticoid therapy but who continue to have severe or symptomatic hypercalcemia, the guideline suggests adding IV bisphosphonate or denosumab.
• In patients whose hypercalcemia is due to a parathyroid carcinoma, the guideline suggests treatment with either a calcimimetic, IV bisphosphonate, or denosumab. It notes that IV bisphosphonate and denosumab have faster onsets of action and generally better tolerability profiles compared with calcimimetics. It also warns that adverse events are common with higher doses of calcimimetics.
• In patients whose hypercalcemia is due to a parathyroid carcinoma that is not adequately controlled despite treatment with a calcimimetic, the guideline suggests the addition of IV bisphosphonate or denosumab.
• In patients whose hypercalcemia is due to a parathyroid carcinoma and is not adequately controlled with IV bisphosphonate or denosumab therapy, the guideline suggests the addition of a calcimimetic.

Making the GRADE

The guideline was co-sponsored by the American Society for Bone and Mineral Research and the European Society of Endocrinology. It was published online in December 2022 and will appear in the March 2023 print issue of The Journal of Clinical Endocrinology & Metabolism.

As with other recent Endocrine Society guidelines, this one was done with a re-vamped emphasis on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. “A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized eight clinical questions related to the treatment of hypercalcemia of malignancy in adult patients. The systematic reviews queried electronic databases for studies relevant to the selected questions,” the guideline says.

El-Hajj Fuleihan notes that the reviews were wide-ranging, and they also considered “contextual factors, such as resources needed, acceptability, feasibility, equity, and cost-effectiveness, and included a systematic review of patient and physician values and preferences.”

Clinical practice guidelines have been published that focus on the treatment of cancer patients with bone metastases, multiple myeloma, and parathyroid carcinoma, but no guidelines had looked specifically at hypercalcemia.

“Over the last 10 or 20 years, two different kinds of very potent drugs that affect bone resorption have been available, so we really needed to scrutinize the evidence for their efficacy in this disease.”  

Ghada El-Hajj Fuleihan, MD, MPH, Department of Internal Medicine, American University of Beirut. Beirut, Lebanon

“Treatment of hypercalcemia of malignancy substantially and rapidly alleviates symptoms, improves quality of life, and, importantly, provides an opportunity to administer life-saving therapies targeting the primary malignancy,” El-Hajj Fuleihan says. “Despite the widespread availability of efficacious medications, evidence-based recommendations to manage this debilitating condition have been lacking.” This guideline is the first to address this need.

Other members of the Endocrine Society writing committee that developed this guideline include: Matthew T. Drake and M. Hassan Murad of the Mayo Clinic in Rochester, Minn.; Gregory A. Clines and Catherine Van Poznak of the University of Michigan in Ann Arbor, Mich.; Mimi I. Hu of the University of Texas’ M.D. Anderson Cancer Center in Houston, Texas; Claudio Marcocci of the University of Pisa in Pisa, Italy; Thomas Piggott of McMaster University in Hamilton, Ontario, Canada, Queens University in Kingston, Ontario, and Peterborough Public Health in Peterborough, Ontario; and Joy Y. Wu of Stanford University School of Medicine in Stanford, Calif.

Seaborg is a freelance writer based in Charlottesville, Va. He wrote about the newly released “Management of Individuals with Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline” in the January issue.