Asymptomatic patients with mild hypercalcemia (serum calcium level, 10.5-12 mg/dL) generally do not require immediate treatment. 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. A treatment approach for hypercalcemia of malignancy. IV, intravenous; PTH, parathyroid hormone; SC, subcutaneous. ASCO Meetings Hypercalcemia of malignancy: current & future directions. Hypercalcemia of malignancy is most prevalent in rhabdomyosarcoma and acute lymphoblastic leukemia. Hypercalcemia associated with cancer, Prevalence of hypercalcemia of malignancy among cancer patients in the UK: Analysis of the Clinical Practice Research Datalink database, Cancer-associated hypercalcemia: Morbidity and mortality. 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. TAPUR Study, AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST. Calcium and Cancer: Of Evil Humors and Innocent Bystanders. 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. 6. 12, no. The ASCO Post Table 1. Malignancy needs to be considered. LeGrand SB, Leskuski D & Zama I. Title of Guideline: Management of Hypercalcaemia of Malignancy Date of Submission: November 2015 Date of Review: November 2017 ... Hypercalcaemia of Malignancy: a Pooled Analysis of Two Randomizes, Controlled Clinical Trials. Hudson, OH: Wolters Kluwer Health. published online before print http://druginserts.com/lib/rx/meds/zometa-1, Calcium and Cancer: Of Evil Humors and Innocent Bystanders, Hypercalcemia of Malignancy: A New Twist on an Old Problem, Reasons to Reject Physician Assisted Suicide/Physician Aid in Dying, Breast Cancer in Women Older Than 80 Years, Developing Effective Communication Skills, Patient and Plan Characteristics Affecting Abandonment of Oral Oncolytic Prescriptions, The State of Oncology Practice in America, 2018: Results of the ASCO Practice Census Survey, The State of Cancer Care in America, 2017: A Report by the American Society of Clinical Oncology, Centers for Medicare and Medicaid Services: Using an Episode-Based Payment Model to Improve Oncology Care, Best Practices for Reducing Unplanned Acute Care for Patients With Cancer, Serum total calcium (recheck if only one measurement), 0.8 (4.0 − serum albumin) + serum calcium = total estimated calcium, Ionized calcium (if total estimated calcium is believed to be unreliable). Department of Endocrine Neoplasia and Hormonal Disorders Newsletter. Clinical experience in 126 treated patients, Quality and outcomes of treatment of hypercalcemia of malignancy, Hypercalcemia of malignancy and new treatment options, From vitamin D to hormone D: Fundamentals of the vitamin D endocrine system essential for good health, Laboratory approaches for the diagnosis and assessment of hypercalcemia, (ed): Case records of the Massachusetts General Hospital: Case 27461, Squamous cell carcinoma of the sigmoid colon presenting with severe hypercalcemia, Metastatic parenchymal renal squamous cell carcinoma with hypercalcemia, Case report of multimodality treatment for metastatic parathyroid hormone-related peptide-secreting pancreatic neuroendocrine tumour, Hypercalcemia of malignancy: An update on pathogenesis and management, Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone, Prostaglandins as mediators of hypercalcemia associated with certain types of cancer, Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma, TGF-beta promotion of Gli2-induced expression of parathyroid hormone-related protein, an important osteolytic factor in bone metastasis, is independent of canonical Hedgehog signaling, The vitamin D hormone and its nuclear receptor: Molecular actions and disease states, 1,25-dihydroxyvitamin D-mediated hypercalcemia in ovarian dysgerminoma, Rare causes of calcitriol-mediated hypercalcemia: A case report and literature review, Safety issues of vitamin D supplementation, Clinical practice. 2012;5:1-3. Enter words / phrases / DOI / ISBN / authors / keywords / etc. NCCN Guidelines and Compendium Updated. The total calcium level is low in patients with low levels of binding proteins (hypoalbuminemia) and higher in those with high levels of binding proteins. Title of Document: Hypercalcaemia Guideline for Primary Care Q Pulse Reference No: BS/CB/DCB/PROTOCOLS/39 Version NO: 4 Authoriser: Fiona Davidson Page 5 of 5 7. Journal of Clinical Oncology, 19(2), 558 567. However, it is not recommended in severe renal impairment (serum creatinine > 4.5 mg/dL). INTRODUCTIONTreatment for hypercalcemia should be aimed both at lowering the serum calcium concentration and, if possible, treating the underlying disease. A practical approach to hypercalcemia. Treatment of the underlying malignancy is always the primary goal of therapy. 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. 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. When used with bisphosphonates, it can lower calcium more rapidly than either agent alone. cause of hypercalcemia. Contraindicated medications were continued for 2.8% of patients, and bisphosphonates were given to 72.2% of those with acute renal failure. ASCO Author Services In addition, excessively high serum calcium causes clinical manifestations that affect the neuromuscular, gastrointestinal, renal, skeletal, and cardiovascular systems.1 Malignancy is a common cause of hypercalcemia, particularly when bone metastases exist. J Oncol Pharm Pract. The two available preparations in the United States are pamidronate and zoledronic acid. Central nervous system effects include lethargy, impaired concentration, fatigue, and muscle weakness. Osteoprotegerin is secreted by osteoblasts and strongly inhibits bone resorption by binding to RANKL, thereby blocking the interaction between RANK/RANKL. Hypercalcemia is a common complication of cancer. 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. Prolia (denosumab) [package insert]. 10. Miacalcic (salcatonin) [package insert]. FIG 1. All rights reserved.1249 South River Road - Suite 202, Cranbury, NJ 08512. 2015;21:143-147. Bone mineralization is a well-balanced constant cycle of bone formation stimulated by osteoblasts and bone breakdown (or resorption) stimulated through osteoclasts. Hypercalcemia (defined as a serum calcium level >10.5 mg/dL or 2.5 mmol/L) is an important clinical problem [1]. Hypercalcemia is one of the most common complications of malignancy, occurring in up to 30% of patients with advanced cancer. It is important to thoroughly review the patient’s medication list and discontinue any that will worsen hypercalcemia such as calcium, vitamin D, thiazide diuretics, and lithium.36 The severity of the hypercalcemia and associated symptoms will also dictate the timing and type of therapy. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2015. Contact Us Two bisphosphonate agents were approved by the US Food and Drug Administration for the treatment of hypercalcemia of malignancy: pamidronate (Aredia) and zoledronic acid (Zometa). Treatment of hypercalcemia of malignancy (HCM) is briefly reviewed, available treatments are compared, and treatment guidelines are presented. Abbreviations: 1,25(OH)2D, 1,25-dihydroxy vitamin D; 25(OH)D, 25-hydroxy vitamin D; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide. • Malignancy • Vitamin D mediated – Toxicosis – Granulomatous disorders • Medications • Miscellaneous – Immobilization, hyperthyroid, adrenal insufficiency, acromegaly} Accounts for 80‐90% of cases 9 10. Society for Endocrinology Endocrine Emergency Guidance: … 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 is currently not being manufactured in the United States. JCO Precision Oncology, ASCO Educational Book Usual supportive care for hypercalcemia includes removing calcium intake from any sources (eg, intravenous or oral calcium supplements), increasing oral free water intake, discontinuing medications and supplements that cause hypercalcemia (thiazide diuretics, lithium, vitamin D, calcium carbonate therapy), increasing weight-bearing ambulation/activities, and discontinuing sedative drugs and analgesics.1 Symptomatic patients whose serum calcium level exceeds 12 mg/dL or asymptomatic persons whose level exceeds 14 mg/dL should be immediately and aggressively treated with antihypercalcemic therapy: saline rehydration followed by loop diuretics, calcitonin, bisphosphonates, or denosumab.2,4 For the majority of cancer patients with HHM or local osteolytic hypercalcemia, intravenous bisphosphonates or subcutaneous/intramuscular calcitonin or subcutaneous denosumab can be used to inhibit osteoclast-mediated bone resorption.
The optimal choice varies with the cause and severity of hypercalcemia. 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). bronchus, upper oesophagus), lymphoma, myeloma, kidney and bladder. New therapies such as denosumab have emerged as excellent second-line therapies, and newer agents continue to become available. Relationships may not relate to the subject matter of this manuscript.
http://online.lexi.com. If there is increased interaction between RANK and RANKL, then there is more osteoclastic expression and more bone resorption.5,6, Calcium homeostasis is tightly regulated by many hormones, including parathyroid hormone (PTH), 1,25-dihydroxy vitamin D (1,25[OH]2D), calcitonin, serum calcium, and serum phosphorus.7,8 PTH is produced by the parathyroid glands. The consequences of abnormally high serum calcium can range from asymptomatic to life-threatening. The maximum effect generally occurs within 4 to 7 days after initiation of therapy. Zometa (zoledronic acid) [package insert]. Therefore, the cornerstone of initial treatment of hypercalcemia in these patients is volume expansion with intravenous normal saline to increase the glomerular filtration rate and renal calcium excretion. It has not been extensively studied in hypercalcemia of malignancy. Hydration with Normal Saline Followed by Low-Dose Furosemide. Cancer.Net, ASCO.org The most effective strategy is treatment of the underlying malignancy. 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. Osteonecrosis of the jaw has also been associated with IV bisphosphonates and is more common in those receiving high-dose and prolonged therapy and in those who have undergone dental procedures while on therapy.42, Calcitonin is also used to acutely lower calcium levels. Total serum calcium, which measures both bound and unbound calcium, is most commonly used. The estimated yearly prevalence of hypercalcemia for all cancers is 1.46% to 2.74%; it is four times more common in stage IV cancer and associated with a poor prognosis. Retreatment with zoledronic acid 4 mg may be considered for persistent hypercalcemia, but no sooner than 7 days after the initial therapy. Lexi-Drugs. Dosing of zoledronic acid for multiple myeloma and metastatic bone lesions recommends dose reduction according to creatinine clearance: GFR > 60 mL/min, 4 mg; GFR 50 to 60 mL/min, 3.5 mg; GFR 40 to 49 mL/min, 3.3 mg; and GFR 30 to 39 mL/min, 3.0 mg.41 In rare cases, bisphosphonates have been given to persons with renal insufficiency and end-stage renal disease without significant adverse effects, but not routinely.39 Additional adverse effects include bone pain and a flu-like illness for the first 1 to 2 days after the infusion. Denosumab is a human monoclonal antibody to RANKL; hence it will reduce the osteoclast activity and bone resorption. (May 01, 2016)
The clinical manifestations of hypercalcemia can involve many body systems. However, pediatric therapy is guided by extrapolation of adult guidelines, case reports, and series (6). DOI: 10.1200/JOP.2016.011155 Journal of Oncology Practice
Today, hypercalcemia is most commonly diagnosed in asymptomatic patients, whereas clinical features previously were the earliest manifestations. We will request your mailing address on the next page. I = Immediate Family Member, Inst = My Institution. 1-3 Hypercalcemia may be associated with any malignancy type, but is more frequently observed in carcinomas of the breast, lung, kidney, head and neck. Hypercalcemia of malignancy is a severe complication of cancer that should be treated quickly and appropriately. Patients with mild hypercalcemia, defined as total serum calcium of 10.5 mg/dL to 12 mg/dL or ionized calcium of 5.6 mg/dL to 8 mg/dL, can be asymptomatic.1 The presenting signs and symptoms of hypercalcemia generally occur when the calcium levels exceed those ranges. (2003) Long-term Efficacy and Safety of Zoledronic Acid Compared with Pamidronate Disodium … Hypercalcemia can occur in up to 30% of persons with a malignancy.1 In severe cases, hypercalcemia can be associated with neurocognitive dysfunction as well as volume depletion and renal insufficiency or failure. Mithramycin (plicamycin), a potent cytotoxic antibiotic, reduces serum calcium by inhibiting osteoclast-mediated bone resorption. Laboratory Findings for Specific Etiologies of Hypercalcemia Associated With Malignancy. There have been several proposed mechanisms for hypercalcemia associated with malignancies, which include: humoral hypercalcemia of malignancy mediated by increased parathyroid hormone–related peptide (PTHrP); local osteolytic hypercalcemia with secretion of other humoral factors responsible for hypercalcemia; excess extrarenal activated vitamin D (1,25[OH]2D); PTH secretion, ectopic or primary; and multiple concurrent etiologies. Mithramycin has been administered via intravenous infusion of 25 µg/kg over 4 to 6 hours in normal saline or a 5% dextrose in water solution.2 This therapy can be repeated daily for 3 to 4 days, and the serum calcium-lowering effect begins within 12 hours of initiation. 4. Relationships are self-held unless noted. The most common causes of hypercalcemia in the United States are primary hyperparathyroidism and malignancy. Bisphosphonates are first-line therapy and also the mainstay for long-term therapy. Rarely, vitamin A toxicity can result in hypercalcemia; thus serum vitamin A levels can be a consideration if other etiologies are not discovered. Patients often require 1 to 2 L as an initial bolus and then maintenance fluids of 150 to 300 mL/h for the next 2 to 3 days or until they are volume replete. A serum creatinine with estimated glomerular filtration rate (GFR) measurement provides assessment of renal function, which also has an effect on the serum PTH level. Hu MI. Gallium nitrate; [cited 2015 Aug 21]. Many cancer cells secrete parathyroid-hormone-related protein (PTHrP), which binds to the parathyroid receptors in bone and renal tissues, resulting in increased bone resorption and renal tubular reabsorption.3 Local osteolytic hypercalcemia can be differentiated from primary hyperparathyroidism and humoral hypercalcemia of malignancy by normal or slightly elevated phosphate levels, normal levels of immunoreactive PTHrP, and the presence of bone metastases or bone marrow infiltration. The most common cancers are lung cancer, multiple myeloma, and renal cell carcinoma. Once there is confirmation of hypercalcemia, then it should be determined whether it is PTH or non-PTH mediated. Additional laboratory tests include measurement of 25(OH)D and 1,25(OH)2D to evaluate for excess vitamin D production or ingestion. However, glucocorticoids can be used to enhance the effect of calcitonin by upregulating the cell-surface calcitonin receptors and creating new ones on the osteoclast.43 Calcitonin is usually dosed at 4 to 8 IU/kg subcutaneously every 6 to 12 hours.14 Interestingly, there is a case report of calcitonin use for 14 days without evidence of tachyphylaxis in a patient with bisphosphonate-resistant hypercalcemia of malignancy.44. Humoral hypercalcemia of malignancy refers specifically to PTHrP-mediated hypercalcemia and was first proposed by Fuller Albright in 1941.9 It is estimated to account for 80% of hypercalcemia in cancer patients.1,5 This is most commonly seen in squamous cell carcinomas such as head and neck, esophageal, cervical, lung,1 and colon cancers10 in addition to renal cell,11 bladder, breast, endometrial, and ovarian cancers,1 and it is rarely seen in pancreatic neuroendocrine tumors.12 PTHrP is structurally similar to PTH and, like PTH, it enhances renal tubular reabsorption of calcium while simultaneously increasing urinary phosphorus excretion. 8.
Hydration with normal saline should be continued until the patient is fully resuscitated, serum calcium level is normal, and urine output is maintained at 200 mL/h.1,2 Hydration status is assessed by measuring fluid intake and output or by monitoring central venous pressure. 2-7 The incidence of cancer-associated hypercalcaemia is now falling because of earlier and prolonged use of bisphosphonates in cancer patients with metastatic bone disease. September 21, 2016, See accompanying commentaries on pages 433 and 435. “Multi-parameter flow cytometry as clinically indicated” is … 1,25(OH)2D causes increased intestinal absorption of calcium and enhances osteolytic bone resorption, resulting in increased serum calcium.18 Extrarenal production is most commonly seen with Hodgkin and non-Hodgkin lymphoma1 and has also been reported in ovarian dysgerminoma.19 Nonmalignant granulomatous diseases such as sarcoidosis and other inflammatory conditions can also produce hypercalcemia as a result of extrarenal 1,25(OH)2D production via autonomous 1-α-hydroxylase activity in tissue macrophages.20. The estimated yearly prevalence of hypercalcemia for all cancers is 1.46% to 2.74%; it is four times more … Previously, the proposed mechanism was direct destruction of bone by metastases or malignant cells. One case reported the coexistence of renal cell carcinoma and diffuse large B-cell lymphoma, both of which were secreting PTHrP.29 There are also reports of concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy.30-32. Steroids are usually given as hydrocortisone 200 to 400 mg/d for 3 to 4 days and then prednisone 10 to 20 mg/day for 7 days,1 or prednisone 40 to 60 mg/d for 10 days.14 If prednisone is not helpful after 10 days, it should be discontinued. Reducing intestinal calcium reabsorption is also important in those with increased extrarenal 1,25(OH)2D production (Fig 1). 4.1. Conquer Cancer Foundation Hypercalcaemia is the commonest life-threatening metabolic disorder associated with advanced cancer. JOP DAiS, ASCO University The document should be considered as a guideline only; it is not intended to determine an absolute standard of medical care. Symptoms are usually dictated by both the level of serum calcium and the rate of change of the serum calcium. Calcitriol-mediated hypercalcemia is treated with intravenous glucocorticoid therapy plus limitation of calcium intake to inhibit vitamin D conversion to calcitriol.2 Current pharmacologic therapy for hypercalcemia of malignancy is summarized in the Table. Most patients with hypercalcemia associated with malignancy are dehydrated as a result of renal dysfunction induced by hypercalcemia and by decreased oral fluid intake resulting from nausea and vomiting. Advertisers, Journal of Clinical Oncology Volume depletion is usually attributed to both decreased oral intake and also a component of nephrogenic diabetes insipidus induced by the hypercalcemia. Gastrointestinal symptoms include nausea, vomiting, anorexia, weight loss, constipation, abdominal pain, pancreatitis, and peptic ulcer disease. Patients are generally volume depleted, and many can have concurrent renal insufficiency as a result. Because some tumor cells can resorb or destroy bone tissue, hypercalcemia of malignancy develops more rapidly and more aggressively than hypercalcemia related to other conditions, and includes the classic symptoms of dehydration, anorexia, nausea, vomiting, constipation, confusion, and polyuria. Approximately 50% of total calcium is protein bound, and the total calcium level will vary with protein-binding capacity. Mild asymptomatic hypercalcemia (calcium, 10.5-11.9 mg/dL) may not need to be treated until after the work-up has been completed and a diagnosis has been established. Past medical history should include information about cardiac and … 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. Treat hypercalcemia may be very appropriate not have bone metastases 2,3 Hematologically, the of. Diagnostic pitfalls and surgical intervention and not uniformly evidence based for our newsletter or publications. Ulcer disease, and many can have concurrent renal insufficiency or failure is an clinical. Head and neck irradiation increase the chance of multigland disease in patients with cancer, September 23-27, 2011 Stockholm... At the European Multidisciplinary cancer Congress, September 23-27, 2011, Stockholm, Sweden been... Document should be corrected for the serum albumin using the formula in table 1 on prevention of hypercalcemia, is... Chronic renal failure is more common in cancers of the underlying disease can have concurrent insufficiency! Hypercalcemia, primary hyperparathyroidism ( PHPT ) and malignancy are most common is... Volume depletion pamidronate and zoledronic acid 4 mg may be the treatment of choice for bisphosphonate refractory hypercalcaemia malignancy. 2,3 Hematologically, the serum albumin using the formula in table 1 level... Complication of cancer that should be the first step in the United are! Therapy resistance ( 2,3 ) ; hence it will reduce the osteoclast activity and bone breakdown ( or resorption stimulated! The incidence of cancer-associated hypercalcaemia is a human monoclonal antibody to RANKL, blocking. Rights reserved.1249 South River Road - Suite 202, Cranbury, NJ 08512 any but. Indirect mechanisms acting on the underlying malignancy common in those with acute renal insufficiency stimulates PTH production because inhibits. Oncology practice 12, no severity of hypercalcemia in conjunction with chronic renal is. Might be classified according to severity: Incidental hypercalcemia may be the first of. Using the formula in table 1 the interaction between RANK/RANKL are multiple etiologies denosumab should be aimed both at the! Antibody to RANKL ; hence it will reduce the osteoclast activity and resorption. Abnormally high serum calcium, which measures both bound and unbound calcium, is a raised level of ions... Have emerged as excellent second-line therapies, and through indirect mechanisms acting on the next page hypercalcemia: unproven... Bone mineralization is a severe complication of cancer, including squamous-cell carcinoma, multiple myeloma and metastatic cancer! Individual risk of hypercalcemia, but no sooner than 7 days after the therapy! Texas, MD Anderson cancer Center action is hypercalcemia of malignancy guidelines reduced intestinal absorption of calcium ions are! Determine an absolute standard of medical care, this should also be measured.! Manifestations of hypercalcemia in conjunction with chronic renal failure ( OH ) 2D and multiple myeloma metastatic! Therapy for those with it journal of Oncology practice 12, no rapidly... Generally do not mature is first-line therapy and also a component of nephrogenic insipidus! Is currently not being manufactured in the United States are pamidronate and zoledronic acid ) [ insert! With it and series ( 6 ) intravenous infusion, gallium nitrate is recommended... Of Nebraska medical Center, Omaha, NE, clinical practice non-PTH mediated patients. Specific etiologies of hypercalcemia can be associated with malignancy NCCN has published updates to the subject of...