State of the Art Oncology in EuropeFont: aaa

Hypercalcaemia

1. GENERAL INFORMATION

1.1 Definition, incidence, risk factors and pathophysiology

Hypercalcaemia is defined as a plasma cal cium of more than 10.4 mg/dL. It is the most common metabolic emergency in cancer patients with an incidence of 15-20 per 100 000 persons and is reported in 10-30% of them. Hypercalcaemia may be the presenting features at diagnosis but is more commonly seen in patients after diagnosis and with advanced disease. The most common malignancies associated with hypercalcaemia are breast, kidney and lung cancer, multiple myeloma and squamous cell carcinoma of the head and neck. Plasma calcium homeostasis is maintained by 3 hormones: parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol), and calcitonin. These hormones act on the bone, where calcium is stored; the kidney, which secretes calcium; and the small intestine, where calcium absorption takes place. The entire system is controlled through a negative feedback loop and the individual hormones respond as needed to increase or decrease the serum calcium concentration. Calcium homeostasis may be changed by an excess of PTH, calcitriol, or serum factors that can mimic these hormones, or by a calcium load.

In patients with cancer, hypercalcaemia can be the result of
•    Production of a parathyroid hormone-like protein (PTHrP) secreted by the tumour (e.g. breast and lung cancer, multiple myeloma) and increased levels of PTHrP can be detected in plasma. PTHrP stimulates both osteoclast activity and tubular renal re-absorption of calcium resulting in an increased plasma level of calcium.
•    Local bone destruction due to the release of cytokines (e.g. multiple myeloma).
•    Tumour production of vitamin D analogues (e.g. Hodgkin’s disease).

Other causes of hypercalcaemia are primary hyperparathyroidism, granulomatous diseases (sarcoidosis, tuberculosis), medication (thiazide, calcium carbonate, excess intake of vitamin D or A, intoxication with lithium, theophylline, salicylate, or thyroid hormone), milk-alkali syndrome, endocrinopathies (hyperthyroidism, adrenal gland insufficiency and pheochromocytoma), familial hypocalciuric hypercalcaemia, tertiary hyperparathyroidism (post-renal transplant, initiation of chronic hemodialysis), immobilization, hypophosphataemia, acquired immunodeficiency syndrome (AIDS), rhabdomyolysis, Paget disease, parenteral nutrition or advanced chronic liver disease.

2. DIAGNOSIS

2.1 Clinical presentation

Most patients with hypercalcaemia present with non-specific symptoms: fatigue (70%), anorexia (60%), nausea, constipation (60%), weight loss (60%), bone pain (60%), polyuria and polydipsia or dehydration. Neurological symptoms range from muscle weakness and lethargy to confusion, delirium and coma. The most important renal signs are nephrogenic diabetes insipidus (polyuria and polydipsia, dehydration, electrolyte abnormalities) and acute or chronic renal failure. Symptoms correlate with the severity of the hypercalcaemia and the rapidity of onset.
Physical examination may show signs of dehydration and hypo-volaemia due to excessive fluid loss and impaired fluid intake; and hyper-or hyporeflexia due to neurological complications.

2.2 Diagnosis

Diagnosis is made by determination of the serum calcium level. The reference range of serum calcium levels is between 8.7-10.4 mg/dL. More than 40% is protein bound; 50% is ionized – the physiologic active form-; and 10% is bound by complex formation to anions (e.g. citrate). Changes in serum protein concentrations alter the total serum calcium level but do not affect the unbound fraction.
The corrected total calcium (mg/dL) can be calculated by the following formula: (measured total calcium mg/dL) + 0.8 (4.4 – measured albumin g/dL). The reference range of corrected calcium is 9-10.6 mg/dL
The serum creatinine, ions (sodium, potassium, chloride) and alkaline phosphatase should also be determined to exclude renal insufficiency and ion disturbances while an increased alkaline phosphatase indicates bone metastases.
Hypercalcaemia may produce abnormalities on the electrocardiogram (ECG) with QT interval shortening and PR interval prolongation. At very high serum calcium levels, the QRS interval may lengthen, T waves may flatten or invert, and a variable degree of heart block may develop.

3. PROGNOSIS

While in the past hypercalcaemia was a major cause of cancer mortality, the use of bisphosphonates decreased death due to hypercalcaemia substantially. However, the prognosis of cancer-associated hypercalcaemia is poor with a 1-year survival rate of 10-30% and is mainly dependent on the response of the primary tumour to anticancer treatment.

4. TREATMENT

4.1 Prevention

The incidence of hypercalcaemia has decreased recently due to the long-term prophylactic bisphosphonate-therapy. This treatment is standard, on a type 1 level of evidence, in patients with bone metastases of solid tumours and multiple myeloma to prevent skeletal-related complications. Oral (e.g. clodronate, ibandronate) and intravenous (e.g. pamidronate, etidronate, zoledronic acid) are standard options, on a type 1 level of evidence , as they have shown to decrease pain in patients with different tumour types and should be an integral part of pain control treatment in patients with bone metastases, standard treatment, on a type 1 level of evidence. Dosing regimens of bisphophonates should follow the respective regulatory recommendations and adjustments due to pre-existing medical conditions. The treatment to reduce skeletal-related events can be continued for 2 years even if a patient experiences a bone event, as an individualised option, on a type R basis. Continuation of therapy beyond 2 years based on an individual risk assessment is recommended as an individualised option, on a type R basis. 

4.2 Treatment of hypercalcaemia

Untreated, symptomatic hypercalcaemia is a life-threatening complication that needs immediate intervention, as a standard option, on a type C basis. However, when it occurs in patients with advanced untreatable cancer, it may be appropriate to start comfort measurements only, as anindividualised option , on a type C basis.

The treatment of hypercalcaemia is by:

· Discontinuation of calcium sources (e.g. oral calcium supplements) and medications that increase calcium level (e.g. thiazide diuretics, vitamin D), as a standard option, on a type C basis.

· Correction of hypovolaemia by intravenous (IV) saline: saline 250-500 mL/h IV until euvolaemia is achieved and 100-150 mL/h IV after volume repletion in patients without impaired cardiac function, as a as a standard option , on a type C basis. The administration of diuretics (furosemide 20-40 mg IV twice daily), after adequate rehydration, should be limited to patients with fluid overload, as an individualised option, on a type R basis. Hydration and forced diuresis alone are usually ineffective to maintain normocalcaemia (observed in only 20-30% of treated patients).

· Blocking the osteoclastic bone resorption by bisphosphonates (e.g. pamidronate, etidronate, clodronate, alendronate, ibandronate and zoledronic acid), is a standard option , on a type C basis.
o Pamidronate (60-90 mg IV during 2-4 h) is a standard option, on a type 2 level of evidence: itinduces normocalcaemia within 48 hours in 70-90% of patients, and normocalcaemia is maintained for 2-4 weeks. In comparative studies, pamidronate 90 mg is more potent and has a longer effect than oral clodronate. Pamidronate 60 mg as a single IV infusion over 2-24 hours is suitable for patients with mild hypercalcaemia and bone metastases, as an individualised option, on a type R basis.
o Etidronate (7.5 mg/kg given as a 2-hour infusion daily for 3 days) normalized serum calcium levels in 41% of patients and is less effective compared to 60 mg of pamidronate. This treatment should not be used as standard treatment of hypercalcaemia, but as an individualised option, on a type 2 level of evidence.
o Clodronate (1500 mg as a single IV infusion) achieves normocalcaemia in approximately 80% of patients. This treatment should not be a standard option in the treatment of hypercalcaemia, but it is an individualised option, on a type 3 level of evidence.
o Alendronate (10-15 mg intravenously over 2 or 24 hours) results in a decrease in calcium level in 75-90% of patients within 8 days of treatment for a median time to relapse of 15 days. This treatment should not be used routinely, but it is an individualised option, on a type 3 level of evidence.
o Zoledronic acid (4 mg IV during 15-30 min) proved to be more potent than pamidronate to control hypercalcaemia. The complete response rate by day 10 is 88.4%. Normalization of hypercalcaemia occurs by day 4 in approximately 50% of patients and the median duration of complete response is 32 days. Zoledronic acid 4 mg is the dose recommended for initial treatment of hypercalcaemia, as a standard option, on a type 1 level of evidence and 8 mg for relapsed or refractory hypercalcaemia is an individualised option, on a type 2 level of evidence.

Side effects of bisphosphonates are mild and include low-grade fever (10-15%), venous irritation, asymptomatic hypocalcaemia, nausea/vomiting (2%), and elevation of serum creatinine (2-5%).
Bisphosphonates should be used cautiously in patients with renal insufficiency. Pamidronate is usually safe in patients with hypercalcaemia and mild renal insufficiency; however, since hypocalcaemic crises have been described in patients with moderate to severe renal failure, a dose reduction of bisphosphonates (e.g. pamidronate 30-45 mg) is suitable for individual clinical use, on a type R basis, in order to avoid symptomatic hypocalcaemia.

There are some other medications that are also active in the treatment of hypercalcaemia but with the use of bisphosphonates, their use is limited.

· Calcitonin (4-8 IU/kg SC or IV every 12 h) reduces calcium levels by inhibiting bone resorption and increasing renal calcium excretion and achieves normocalcaemia in 30% of patients for 1-2 days. Owing to the rapid onset of action (within 2 to 4 hours of administration), its use in combination with pamidronate or zoledronate acid is suitable for individual clinical use, on a type 3 level of evidence in patients with acute severe hypercalcaemia. Calcitonin is not a standard treatment for hypercalcaemia of malignancy, but it can be considered suitable for individual clinical use, on a type 2 level of evidence.

· Mithramycin or plicamycin (25 µg/kg administered IV over 4-6 h as a single dose) reduces serum calcium in 45% of patients but is inferior compared with pamidronate in percentage of patients becoming normocalcaemic and the duration of normocalcaemia. Mithramycin is not standard treatment in patients with cancer-related hypercalcaemia but it can be considered suitable for individual clinical use, on a type 2 level of evidence . Toxicity (hepatotoxicity, renal insufficiency, haemorrhagic diathesis, thrombocytopenia) occurs after multiple injections.

· Gallium nitrate (100-200 mg/m² continuous IV for 5 days) is a potent inhibitor of bone resorption and reduces serum calcium in 69-80% of patients within 48 hours for a median duration of 11-14 days. It is superior compared to calcitonin and etidronate and has a similar effect as pamidronate. Gallium nitrate can be considered suitable for individual clinical use, on a type 2 level of evidence, for treating cancer-related hypercalcaemia. This drug is associated with a higher frequency of renal toxicity (10%) than bisphosphonates and the prolonged infusion is also a disadvantage.

· Glucocorticosteroids (prednisone, 60 mg/d orally; hydrocortisone, 100 mg every 6 h IV) aresuitable for individual clinical use, on a type 3 level of evidence in malignancies producing 1-25 (OH)2 vitamin D, such as multiple myeloma, lymphoma, or leukaemia.

· Dialysis may be appropriate for patients with renal failure or congestive heart failure when aggressive hydration and bisphosphonates cannot be used safely, but they can be consideredsuitable for individual clinical use, on a type R basis.

· Anticancer treatment can be started after correction of hypercalcaemia, as an individualized treatment , on a type C basis.

Newer drugs are tested in this indication such as denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) (investigational only; type R basis).

INDEX

Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R, Costa L, Crinò L, Dirix L, Gnant M, Gralow J, Hadji P, Hortobagyi GN, Jonat W, Lipton A, Monnier A, Paterson AH, Rizzoli R, Saad F, Thürlimann B. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 2008; 19: 420-32.

Cvitkovic F, Armand JP, Tubiana-Hulin M, Rossi JF, Warrell RP Jr. Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J 2006; 12: 47-53.

Gucalp R, Ritch P, Wiernik PH, Sarma PR, Keller A, Richman SP, et al. Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia. J Clin Oncol 1992; 10: 134-142 [Medline]

Lumachi F, Brunello A, Roma A, Basso U. Medical treatment of malignancy-associated hypercalcemia. Curr Med Chem 2008; 15: 415-21.Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, Yunus F, Bell R, Body J, Quebe-Fehling E, Seaman J. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001; 19: 558-67.

Nussbaum SR, Younger J, Vandepol CJ, Gagel RF, Zubler MA, Chapman R, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 1993; 95: 297-304 [Medline]

Ralston SH, Thiebaud D, Herrmann Z, Steinhauer EU, Thurlimann B, Walls J, et al. Dose-response study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997; 75: 295-300 [Medline]

Thürlimann B, Waldburger R, Senn HJ, Thiébaud D. Plicamycin and pamidronate in symptomatic tumor-related hypercalcemia: a prospective randomized crossover trial. Ann Oncol 1992; 3: 619-23.

Warrell RPJ, Israel R, Frisone M, Snyder T, Gaynor JJ, Bockman RS. Gallium nitrate for acute treatment of cancer-related hypercalcemia. A randomized, double-blind comparison to calcitonin. Ann Intern Med 1988; 108: 669-674 [Medline]

Warrell RPJ, Murphy WK, Schulman P, O’Dwyer PJ, Heller G. A randomized double-blind study of gallium nitrate compared with etidronate for acute control of cancer-related hypercalcemia. J Clin Oncol 1991; 9: 1467-1475 [Medline]

Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999; 21: 389-406 [Medline]

Dr. Dirk Schrijvers (Reviewer)
University Hospital Antwerp – Antwerp, Belgium
mail: Dirk.Schrijvers@zna.be

Dr. Silvia Spinazzé (Associate Editor)
START Programme
mail: silvia.spinazze@poste.it