Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature.

Hypercalcemia of malignancy is the most common life-threatening metabolic disorder in patients with advanced stage cancers and is a sign of poor prognosis. It usually presents with markedly elevated calcium level and is severely symptomatic. It is associated with hematological malignancies, such as multiple myeloma, non-Hodgkin lymphoma, leukemias and solid cancers, particularly renal and breast carcinomas as well as squamous cell carcinomas of any organ. Several mechanisms have been implicated in the development of hypercalcemia of malignancy amongst them the osteolytic related hypercalcemia, parathyroid hormone-related peptide (PTHrP) mediated hypercalcemia, extrarenal 1,25 dixydroxyvitamin D (calcitriol) mediated hypercalcemia and parathyroid hormone (PTH) related hypercalcemia either ectopic in origin or in patients with parathyroid carcinoma. Clinical history and and physical examination could point towards the correct diagnosis confirmed by the above-mentioned biochemical mediators of hypercalcemia. Early diagnosis and treatment lowering calcium levels in the blood can improve symptoms and the quality of life of these patients and avoid delays for further antitumor therapy.

Endocrine-related adverse events associated with immune-checkpoint inhibitors in patients with melanoma.

BACKGROUND: Immune-checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune-related endocrinopathies, especially hypophysitis and thyroid dysfunction. METHODS: To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune-checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow-up. RESULTS: The total incidence of endocrinopathies was 11.8%, 13.4% due to anti-PD1/PDL1, 5% due to anti-CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty-one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow-up. Endocrinopathies occurred after a median of 22 weeks (range: 4-156) from treatment initiation. Of note, sequential and/or combination therapy with anti-CTLA4 and anti-PD1/anti-PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti-CTLA4 monotherapy developed primary hypothyroidism. CONCLUSIONS: Our cohort demonstrated an increased incidence of hypophysitis with anti-PD1/anti-PDL1 in contrast to the rarity of primary thyroid dysfunction with anti-CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy.

Hypercalcemia of malignancy treated with cinacalcet.

Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced cancer stage. Among all cancer in females, breast cancer is the most common malignancy, and it has the highest prevalence of hypercalcemia. Approximately 70% of patients with breast cancer have bone metastases and 10% of them will have hypercalcemia as a complication at some point in the disease. Herein, we report a 69-year-old female patient with metastatic breast cancer, who developed severe hypercalcemia in the course of her disease and was diagnosed with humoral hypercalcemia of malignancy (HHM). Intense hydration along with corticoisteroids and antiresorptive medication (calcitonin, bisphosphonates and denosumab) were administered to the patient. Despite the above treatment, serum calcium levels remain elevated and calcimimetic cinacalcet was added. Upon discontinuation of cinacalcet, calcium levels were raised and returned back to the normal levels following re-initiation of the calcimimetic. Her calcium level restored to normal, and she was discharged with the following medical treatment: denosumab monthly, and cinacalcet at a titrated dose of 90 mg per day. The patient is followed as an outpatient and 11 months later, her calcium level remained within the normal range. LEARNING POINTS: Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients.Breast cancer has the highest prevalence of hypercalcemia.The cornerstone of therapy remains the intense hydration and intravenous bisphosphonates (preferably zoledronic acid).In case of persistent hypercalcemia of malignancy, the administration of calcimimetic cinacalcet could be an additional effective therapeutic option.