Hypercalcemia in Cancer: Causes, Symptoms, and Management

Hypercalcemia affects up to 30% of patients with cancer.¹ It has been seen in most cancers but is most common in patients with non-small cell lung cancer, breast cancer, multiple myeloma, head and neck squamous cell carcinoma, urothelial cancer, and ovarian cancer.

“Hypercalcemia seen in cancer patients may have underlying nonmalignant causes, as well as cancer-mediated etiologies,” said Raquel E. Reinbolt, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“Some of the nonmalignant causes of hypercalcemia that may be seen in cancer patients are similar to those found in the general population,” she added.

Subtypes and Symptoms of Hypercalcemia

Hypercalcemia is defined as having serum calcium concentrations 2 standard deviations above the mean values.² Hypercalcemia can be classified as mild (10.5-11.9 mg/dL), moderate (12.0-13.9 mg/dL), or hypercalcemic crisis (14.0-16.0 mg/dL).

Cancer-associated hypercalcemia has been classified into 4 subtypes: humoral, local osteolytic, 1,25-dihydroxyvitamin D-mediated, and ectopic hyper-parathyroidism.¹

Humoral hypercalcemia of malignancy is typically caused by tumor secretion of parathyroid hormone-related protein (PTHrP). This increases osteoclastic bone resorption and renal tubular reabsorption of calcium by binding the parathyroid hormone (PTH)-PTHrP type 1 receptor in the bones and kidneys.

Local osteolytic hypercalcemia, which is characterized by extensive bone metastasis, is due to tumor cells in bone producing cytokines that increase osteoclastic bone resorption and suppress osteoblastic bone formation.

With ectopic hyperparathyroidism, tumors produce parathyroid hormone (PTH), which can act alone or in concert with PTHrP to stimulate bone resorption.

With hypercalcemia mediated by excess production of 1,25-dihydroxyvitamin D, tumors upregulate the expression of Cyp27B1, which encodes 1-alpha-hydoxylase, the enzyme that converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Excess 1,25-dihydroxyvitamin D increases intestinal calcium absorption and bone resorption.

Patients with hypercalcemia may present with kidney stones; chronic renal insufficiency; bone pain; excessive urine production; gastrointestinal symptoms such as nausea, vomiting, and constipation; pancreatitis; peptic ulcers; and neuropsychiatric symptoms such as anxiety, depression, lethargy, and confusion.^2,3

Clinical Significance

Hypercalcemia is the first presenting sign of cancer in some cases of hematologic malignancy, but it often goes unrecognized by non-oncologists, according to Ann F. Mohrbacher, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles.

“Patients may have very vague symptoms and think they are just tired and dehydrated,” she said. “Sometimes, this goes on for a long time, and the patient finally lands in the ER.”

This is typically not a problem once a patient is under oncology care, as providers monitor calcium levels as part of routine laboratory testing, according to Dr Mohrbacher.

“However, in some cases, patients have fallen out of follow-up with oncology, and their internist doesn’t recognize the problem,” Dr Mohrbacher said. This underscores the need for long-term follow-up after cancer treatment.

For patients in remission, if “calcium levels are higher than expected, this might be a sign of the cancer coming back, especially if patients are also complaining of weakness and confusion,” noted Roby A. Thomas, MD, of the UPMC Hillman Cancer Center in Pittsburg, Pennsylvania.

“I think clinicians are doing a better job of recognizing this,” Dr Thomas added. “It’s something that can easily go unnoticed and something that can be well managed.”

Testing for Hypercalcemia

Hypercalcemia can be detected by testing serum PTH, calcitonin, vitamin D, ionized calcium, phosphorus, magnesium, alkaline phosphatase levels, renal function, and urinary calcium-creatinine ratio.²

“Serum total calcium, along with albumin to correct for protein abnormalities, are tests included in most comprehensive metabolic screening panels done routinely on all patients,” said Theresa A. Guise, MD, of the University of Texas MD Anderson Cancer Center in Houston. “Ionized calcium can also be measured, but accurate results are highly dependent on prompt handling of the sample.”

“Determining the mechanism of hypercalcemia is important to ensure that the best management approach is undertaken, and the severity of hypercalcemia may also impact the therapies chosen,” Dr Reinbolt noted.

Treating Hypercalcemia in Cancer Patients

Mainstays of treatment for hypercalcemia include intravenous (IV) hydration to correct dehydration and antiresorptive therapies such as bisphosphonates or denosumab.^1,4 Calcitonin, glucocorticoids, and dialysis may also be used in some cases.

Ultimately, for patients with hypercalcemia of malignancy to improve, their underlying malignancy must be treated.³

Guidelines from the Endocrine Society outline several recommendations for treating hypercalcemia of malignancy in adults, including:

• Hypercalcemia of malignancy should be treated with an IV bisphosphonate or denosumab, but denosumab is recommended over an IV bisphosphonate.
• For the initial treatment of severe hypercalcemia (serum calcium >14 mg/dL [3.5 mmol/L]), a combination of calcitonin (limited to 48-72 hours due to tachyphylaxis) and an IV bisphosphonate or denosumab is recommended.
• For refractory or recurrent hypercalcemia in patients taking an IV bisphosphonate, denosumab is recommended.
• For persistent symptomatic or severe hypercalcemia in patients with tumors associated with high calcitriol levels who are already on glucocorticoid therapy, the addition of an IV bisphosphonate or denosumab is recommended.
• For hypercalcemia due to parathyroid carcinoma, treatment with a calcimimetic, an IV bisphosphonate, or denosumab is recommended. A calcimimetic is suggested for mild symptomatic hypercalcemia, and an IV bisphosphonate or denosumab is suggested for moderate-to-severe symptomatic hypercalcemia.
• For hypercalcemia due to parathyroid carcinoma not adequately controlled with a calcimimetic, the addition of an IV bisphosphonate or denosumab is recommended.
• For hypercalcemia due to parathyroid carcinoma not adequately controlled with an IV bisphosphonate or denosumab, the addition of a calcimimetic is recommended.⁴

“In addition to the initial management approach, patients with a history of malignancy-associated hypercalcemia may benefit from ongoing treatments to prevent hypercalcemia recurrence,” Dr Reinbolt noted. “If a patient presents with new hypercalcemia and has no known cancer diagnosis, it is important to exclude malignancy-associated etiologies.”

Given the low survival rates associated with cancer-related hypercalcemia, providers may need to consider engaging palliative care services in some cases.³ For example, hypercalcemia detected during treatment “may mean the treatment is not working as well as hoped, and it may be time to have an end-of-life conversation with the patient,” Dr Thomas said.

Disclosures: Dr Thomas, Dr Mohrbacher, and Dr Guise have no conflicts of interest. Dr Reinbolt is a consultant for LaGrange Medical Software.

References

1. Guise TA, Wysolmerski JJ. Cancer-associated hypercalcemia. N Engl J Med. 2022;386(15):1443-1451. doi:10.1056/NEJMcp2113128

2. Sadiq NM, Naganathan S, Badireddy M. Hypercalcemia. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2023 Jan-. Updated September 5, 2022.

3. Zagzag J, Hu MI, Fisher SB, Perrier ND. Hypercalcemia and cancer: Differential diagnosis and treatment. CA Cancer J Clin. 2018;68(5):377-386. doi:10.3322/caac.21489

4. El-Hajj Fuleihan G, Clines GA, Hu MI, et al. Treatment of hypercalcemia of malignancy in adults: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2023;108(3):507-528. doi:10.1210/clinem/dgac621

This article originally appeared on Cancer Therapy Advisor