5. It is important to understand the pathogenesis, work-up, and treatment options for hypercalcemia associated with malignancy so that timely intervention can occur. Hypercalcaemia is defined as a serum calcium concentration of 2.6 mmol/L or higher, on two occasions, following adjustment (correction) for the serum albumin concentration. Obtaining a serum calcium is the first step in the work-up of suspected hypercalcemia. 2-5 Bisphosphonate therapy should be initiated as soon as hypercalcemia is detected, because it takes 2 to 4 days to lower the calcium level. • Malignancy • Vitamin D mediated – Toxicosis – Granulomatous disorders • Medications • Miscellaneous – Immobilization, hyperthyroid, adrenal insufficiency, acromegaly} Accounts for 80‐90% of cases 9 10. 8. This paper reviews the cancers associated with hypercalcemia and their proposed mechanisms, nontumor-mediated hypercalcemia, as well as diagnosis and treatment strategies for each condition. Laboratory Findings for Specific Etiologies of Hypercalcemia Associated With Malignancy. Normal ionized calcium levels are 4 to 5.6 mg per dL (1 to 1.4 mmol per L). IV, intravenous; PTH, parathyroid hormone; SC, subcutaneous. Through direct mechanisms they induce osteoclast apoptosis, and through indirect mechanisms acting on the osteoblasts they can reduce osteoclastic bone resorption. PTH and PTHrP are similar molecules; therefore, both are not concurrently elevated unless there are multiple etiologies. Denosumab binds to RANKL (soluble protein essential for the formation, function, and survival of osteoclasts) and inhibits osteoclast activity, resulting in decreased skeletal-related events and tumor-induced bone destruction.8-10 Unlike bisphosphonates, denosumab is not cleared by the kidneys, and there is no restriction on its use in patients with chronic renal impairment in whom bisphosphonates are used with caution or are contraindicated.7 In case reports of hypercalcemia in patients with multiple myeloma and severe renal impairment, denosumab decreased the serum calcium level within 2 to 4 days of administration, and in one case it was associated with improvement in renal function.7, Glucocorticoids are a treatment option for hypercalcemia in patients with excessive vitamin D or endogenous overproduction of calcitriol secondary to lymphoma.2 In those conditions, agents such as oral prednisone (60 mg/d for 10 days) can be used or intravenous hydrocortisone (200 mg daily for 3 days), or equivalents.1,2, Calcitonin is an alternative to saline hydration therapy for patients who have severe chronic heart failure or moderate to severe renal dysfunction.6, Subcutaneous administration of calcitonin may result in a more rapid reduction in serum calcium levels (maximum response within 12-24 hours) than is possible with other agents, but the effect and extent of the reduction are often erratic.2, Gallium nitrate is approved for treatment in hypercalcemia of malignancy. Hypercalcemia is most common in those who have later-stage malignancies and predicts a poor prognosis for those with it. Contraindicated medications were continued for 2.8% of patients, and bisphosphonates were given to 72.2% of those with acute renal failure. The mainstays of therapy are IV hydration, bisphosphonates, and calcitonin. Denosumab was dosed as 120 mg subcutaneously on days 1, 8, 15, and 29 and every 4 weeks thereafter; it lowered serum calcium in 64% of patients within 10 days.47 Denosumab is not renally cleared, but the effect may be more pronounced in patients with renal failure; therefore, dose reduction is recommended to avoid hypocalcemia.13 Lower-dose, less-frequent administration of denosumab in patients with hypercalcemia and renal dysfunction is associated with less hypocalcemia. bronchus, upper oesophagus), lymphoma, myeloma, kidney and bladder. NCCN has published updates to the NCCN Guidelines and the NCCN Compendium® for Multiple Myeloma. In advanced untreatable cancer, the decision to not treat hypercalcemia may be very appropriate. When used with bisphosphonates, it can lower calcium more rapidly than either agent alone. New therapies such as denosumab have emerged as excellent second-line therapies, and newer agents continue to become available. The pattern of PTH, PTHrP, 25(OH)D, and 1,25(OH)2D values can often be helpful when determining the cause of hypercalcemia (Table 2). If the serum calcium is believed to be inaccurate, then ionized calcium can be used, but this also has its limitations and can be inaccurate. This can create a treatment dilemma because hypercalcemia is also commonly associated with renal insufficiency. Aredia (pamidronate sodium) [package insert]. (2003) Long-term Efficacy and Safety of Zoledronic Acid Compared with Pamidronate Disodium … Patients should be adequately hydrated before administration of zoledronic acid, and a single dose of 4 mg IV should be given over no less than 15 minutes. Malignancy needs to be considered. Hydration with Normal Saline Followed by Low-Dose Furosemide. Gastrointestinal symptoms include nausea, vomiting, anorexia, weight loss, constipation, abdominal pain, pancreatitis, and peptic ulcer disease. Annals of Internal Medicine 2008 149 259 – 263. Furosemide therapy is often discussed as a means to provide increased calciuresis.1 However, its overall efficacy has been shown to be limited, and it often exacerbates dehydration and fluid loss.37 Hence, furosemide should be reserved only for patients with heart failure and those who need diuresis.13 If furosemide is used, other electrolytes such as potassium and phosphorus also need to be monitored and replaced. The treatment of hypercalcemia will be reviewed here, with emphasis on the management of hypercalcemia … Hypercalcemia is defined as a condition in which the serum calcium level is >10.5 mg/dL (the upper limit of normal) or the ionized calcium level exceeds 5.6 mg/dL. It might be classified according to severity: Hypercalcemia (defined as a serum calcium level >10.5 mg/dL or 2.5 mmol/L) is an important clinical problem [1]. Gallium nitrate; [cited 2015 Aug 21]. “Multi-parameter flow cytometry as clinically indicated” is … In contrast, severe, rapidly progressive hypercalcemia can be associated with significant volume depletion and acute renal insufficiency, as well as dramatic neurocognitive symptoms ranging from altered mental status to coma. Overall, primary hyperparathyroidism occurs in 1 of 1,000 people; it is three times more common in women than in men, especially after the age of 45, with a peak incidence in the seventh decade.22,23 It is also more common in those with a history of head and neck irradiation24,25 and chronic lithium therapy.26 It is estimated that 5% to 10% of cases of primary hyperparathyroidism are the result of hereditary hyperparathyroid syndromes, including multiple endocrine neoplasia types 1 and 2.27 Parathyroid carcinoma is a rare cause of primary hyperparathyroidism.28, There have also been many case reports of multiple concurrent etiologies for hypercalcemia in patients with malignancy. The zoledronic acid package insert recommends that in hypercalcemia of malignancy, patients with mild to moderate renal impairment before initiation of therapy (serum creatinine < 4.5 mg) do not need dose adjustment. *Treatment mechanism. Scenario: Follow-up in primary care: covers the monitoring and follow-up of people with hypercalcaemia who have not undergone curative parathyroid surgery, or people with hypercalcaemia of malignancy. Rosen LS, Gordon D et al. Ranges of serum calcium concentration are used to classify the severity of hypercalcaemia: Mild hypercalcaemia is an adjusted serum calcium concentration of 2.6–3.00 mmol/L. It commonly occurs in multiple myeloma and metastatic breast cancer and less commonly in leukemia and lymphoma. Major, P., Lortholary, A., Hon, J. et al. Primary hyperparathyroidism, Asymptomatic primary hyperparathyroidism: Diagnostic pitfalls and surgical intervention. However, additional therapies, especially for moderate to severe hypercalcemia, are essential when simultaneously treating the underlying malignancy. If the albumin is abnormal, the serum calcium should be corrected for the serum albumin using the formula in Table 1. Hypercalcaemia Guidelines KMCC format v3 final.doc Page 3 of 7 1.0 Signs and symptoms of hypercalcaemia of malignancy Hypercalcaemia is defined as a serum calcium concentration of 2.65mmol/L(or higher) on two occasions, following adjustment for the serum albumin concentration. It occurs in approximately 10% of patients with cancer. 1. Renal function must be carefully monitored with serum creatinine before additional doses of zoledronic acid are given; if renal function has declined, then redosing may not be appropriate. A treatment approach for hypercalcemia of malignancy. Hypercalcaemia is the commonest life-threatening metabolic disorder associated with advanced cancer. Lymphoma, myeloma, T-cell lymphoma, and reduced intestinal absorption of calcium the. Matter of this manuscript keywords / etc ( 2 ), 558 567 squamous-cell! Types of cancer that should be treated quickly and appropriately the optimal choice varies with cause! 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