Hypercalcemia Associated with Cancer– Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Hypercalcemia associated with malignancy is the most common cause of severe hypercalcemia diagnosed in a hospital setting.
  • Often a very poor prognostic sign
  • Occurs with both solid tumors and hematologic malignancies; most commonly associated with multiple myeloma and breast and lung cancer; also associated with metastases to bone

Epidemiology

Incidence

Hypercalcemia is diagnosed in 20–30% of all cancer patients during the course of illness (1).

Risk Factors

  • Dehydration
  • Immobilization

General Prevention

Encourage adequate hydration and activity, especially in multiple myeloma.

Pathophysiology

  • Increased bone resorption is involved in most cases, caused either by extensive local bone destruction or by humoral factors.
  • Humoral factors can interfere with the normal regulation of calcium by parathyroid hormone, calcitriol, and calcitonin.
  • The humoral factors most commonly associated with cancer are parathyroid hormone–related protein (PTH-rP) and 1,25-dihydroxyvitamin D (calcitriol); however, other bone-resorbing factors, including prostaglandins, transforming growth factors, tumor necrosis factor (TNF), colony-stimulating factors, and interleukins, may be involved in different types of malignancy.
  • PTH-rP increases expression of receptor activator of nuclear factor κB ligand (RANKL) in bone. RANKL binds to receptor activator of nuclear factor κB (RANK) on the surfaces of osteoclast precursors, resulting in differentiation into osteoclasts and leading to bone resorption and the development of hypercalcemia.

Etiology

  • Main mechanisms of hypercalcemia in malignancy:
    • Osteolytic metastases: Most commonly with breast cancer, multiple myeloma, lymphoma, and leukemia; accounts for about 20% of cases of hypercalcemia associated with malignancy
    • Humoral hypercalcemia: Ectopic production of PTH-rP; PTH-rP increases bone resorption by osteoclasts. Associated with
      • Non–small cell lung carcinoma
      • Breast cancer
      • Renal cell carcinoma
      • Prostate cancer
      • Melanoma
    • Ectopic PTH secretion: Very rare; has been seen with ovarian carcinoma, neuroectodermal tumor, thyroid papillary carcinoma, lung cancer, rhabdomyosarcoma, and pancreatic cancer
    • Calcitriol production: Lymphoma (non-Hodgkin, Hodgkin, and lymphomatosis/granulomatosis) and ovarian dysgerminomas
  • In multiple myeloma, the elevated serum calcium may be due to the binding of the monoclonal protein with calcium. Multiple myeloma also may cause impaired renal function that decreases calcium excretion.

Parathyroid hormone, Calcium in biology, tumor necrosis factor, hormone calcitriol, bone resorption, bone destruction, metastases,

Diagnosis

  • The severity of symptoms depends on calcium level, rapidity of onset of hypercalcemia, state of hydration, and underlying malignancy.
  • Early nonspecific symptoms often include nausea, vomiting, anorexia, depression, abdominal pain, constipation, and dizziness (1).
  • Polyuria and polydipsia are more specific early symptoms (1).
  • Cardiovascular:
    • Arrhythmias
    • QT-interval shortening
    • Calcium increases vascular tone.
  • Genitourinary:
    • Nephrolithiasis, especially in the elderly
    • Polyuria because of impaired concentrating ability
  • GI:
    • Peptic ulcers
    • Pancreatitis
    • Constipation
    • Anorexia
    • Nausea, vomiting
  • Musculoskeletal:
    • Weakness, hypotonia
    • Hyporeflexia
    • Osteopenia, fractures
  • Neuropsychiatric:
    • Depression, lethargy
    • Obtundation, coma
    • Memory impairment, confusion
    • Hallucinations
    • Headache
    • Seizures

Diagnostic Tests & Interpretation

Lab

  • Serum calcium: Either ionized (“gold standard”) or also must check albumin and correct: Ca(adj) = Ca(tot) + [0.8 × (4.5 - [alb])].
  • Electrolytes including magnesium and phosphate (if hypercalcemia owing to PTH-rP, expect low phosphate, hyperchloremia, and mild alkalosis)
  • Renal function: Urine calcium will be elevated.
  • PTH: Levels of intact PTH should be measured routinely. Although ectopic PTH secretion is rare with malignancy, concomitant primary hyperparathyroidism is common (there is a higher incidence of cancer in patients with primary hyperparathyroidism and a higher incidence of primary hyperparathyroidism in patients with cancer).
  • PTH-rP: In addition to helping with diagnosis, it is also a poor prognostic indicator and can be used to predict the response to treatment. Most commonly elevated in breast and lung cancer.
  • Calcitriol: Should be measured when sarcoidosis, other granulomatous disorders, or the calcitriol lymphoma syndrome is in the differential diagnosis.
  • If underlying malignancy is unknown, commence workup, for example, serum and urine electrophoresis for multiple myeloma.

Alert

Lithium, thiazide diuretics, and vitamin D preparations all can increase serum calcium.

Imaging

None indicated for the immediate management of hypercalcemia, but studies such as bone scan may be helpful for workup of underlying condition.

Differential Diagnosis

  • Hyperparathyroidism
  • Immobilization
  • Calcium administration
  • Renal causes:
    • Chronic or acute renal failure
    • Postrenal transplantation
  • Hypocalciuric hypercalcemias:
    • Familial
    • Hypothyroidism
    • Adrenal insufficiency
    • Bartter syndrome
  • Granulomatous disease:
    • Sarcoidosis
    • Histoplasmosis
    • Coccidioidomycosis
    • Tuberculosis
  • Hyperthyroidism
  • AIDS
  • Hypophosphatemia
  • Pheochromocytoma
  • Acromegaly
  • Drugs:
    • Calcium
    • Lithium
    • Theophylline
    • Thiazides
  • Vitamin A or D toxicity

Treatment

Medication

  • Hydration:
    • The initial therapy of choice because many symptoms are due to dehydration
    • Vomiting and renal losses can cause profound dehydration.
    • Volume expansion with IV normal saline
  • Loop diuretics (e.g., furosemide): Increase renal calcium excretion but only after adequate hydration. Recent literature review suggests that loop diuretics should not be used except in fluid overloaded patients because hydration with saline, particularly when combined with other agents such as bisphosphonates, is more effective and safer than hydration plus diuretic (2)[B].
  • Bisphosphonates: Considered 1st-line medications; by inhibiting osteoclasts, they reduce calcium release from bone, thereby counteracting the main mechanism of hypercalcemia of malignancy, which is bone reabsorption. They also decrease bone pain in patients with bone metastases (3)[B].
    • Zoledronic acid (Zometa):
      • Duration of action is 30 days.
      • Nephrotoxic potential, especially in myeloma patients receiving thalidomide
    • Pamidronate (Aredia): Normalizes calcium in up to 3 weeks
  • Calcitonin: Also requires adequate rehydration; inhibits calcium reabsorption in the distal tubule:
    • Rapid onset of action (within 6–24 h)
    • Side effects include nausea, vomiting, abdominal cramps, rash, flushing, diarrhea, and tachyphylaxis.
    • For life-threatening hypercalcemia, consider calcitonin injections q12h (1)[B].
  • Plicamycin (previously mithramycin):
    • May work via direct toxic effect on osteoclasts; reserved for patients who do not respond to bisphosphonates but can induce normocalcemia in 80% of those who receive it
    • Side effects limit its use (e.g., nausea, vomiting, cellulitis at infusion site, cytopenias, hepatic toxicity, nephrotoxicity, and platelet inhibition); can have rapid rebound hypercalcemia
    • Onset of action within 12 h, with maximal effect seen in 24–48 h
  • Gallium nitrate:
    • Works through multiple mechanisms, including inhibition of osteoclast-mediated bone resorption, alteration in bone structure, and stimulation of bone formation
    • Rarely used, except in cases of more severe hypercalcemia that has been unresponsive to initial therapy, because treatment requires 5-day continuous IV infusion
    • Onset of action 48–72 h
    • Side effects: Nausea, vomiting, nephrotoxicity, hypophosphatemia, anemia, hypotension
  • Inorganic phosphates:
    • Potentially lethal side effects limit use to patients with life-threatening hypercalcemia; IV use no longer supported.
    • Side effects: Precipitation of calcium into tissues of the lung, heart, kidneys, and blood vessels can lead to organ damage, hypotension, and death.
    • Oral and rectal routes safer than IV
  • Glucocorticoids:
    • Direct effects in treating hypercalcemia of malignancy are unclear.
    • Has direct tumoricidal effects on hematologic cancers such as multiple myeloma, lymphoma, and leukemias

Additional Treatment

In cases where saline diuresis and medications fail, hemodialysis is an option. Hemodialysis is the treatment for patients with renal failure and life-threatening hypercalcemia (1)[B].

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General Measures

  • Treatment of underlying malignancy
  • Monitor for hypophosphatemia. Hypophosphatemia is common in hypercalcemia and can worsen hypercalcemia (3)[B]. Replace phosphorus PO or by nasogastric tube (3)[B].
  • Discontinue use of oral calcium supplements and remove calcium from parenteral feeding solutions.
  • Discontinue medications that can independently cause hypercalcemia (e.g., thiazides).
  • Promote weight-bearing ambulation.

Ongoing Care

Follow-Up Recommendations

Avoid bed rest or immobilization as much as possible.

Patient Monitoring

Frequent serum calcium and electrolyte determinations; expect relapse.

Prognosis

  • Median survival after diagnosis of tumoral hypercalcemia depends on type and extent of the malignancy but usually indicates a poor prognosis.
  • >50% of patients die within 50 days of diagnosis of hypercalcemia (3).

References

1. Zojer N, Ludwig H. Hematological emergencies. Ann Oncol. 2007;18(Suppl 1):i45–i48.

2. LeGrand SB, Leskuski D, Zama I. Narrative review: furosemide for hypercalcemia: an unproven yet common practice. Ann Intern Med. 2008;149:259–63.

3. Higdon ML, et al. Treatment of oncologic emergencies. AFP. 2006;74:1874–80.

4. Deftos LJ. Hypercalcemia in malignancy and inflammatory diseases. Endocrinol Metab Clin N Am. 2002;31:141–58.

5. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373–9.

Additional Reading

Horwitz MJ, Stewart AF. Hypercalcemia associated with malignancy. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. American Society of Bone and Mineral Research.2006;31:195.

Lipton A. Management of metastatic bone disease and hypercalcemia of malignancy. Am J Cancer. 2003;2(6):427–38.

See Also (Topic, Algorithm, Electronic Media Element)

Addison Disease; HIV Infection and AIDS; Hyperparathyroidism; Hyperthyroidism; Milk-Alkali Syndrome; Rhabdomyolysis; Sarcoidosis; Tuberculosis

Algorithm: Hypercalcemia

Codes

ICD9

275.42 Hypercalcemia

Snomed

  • 66931009 hypercalcemia (disorder)
  • 47709007 humoral hypercalcemia of malignancy (disorder)

Clinical Pearls

  • Hypercalcemia of malignancy carries with it a very poor prognosis. The median survival after diagnosis is 6 weeks (3).
  • Diagnosis may be difficult unless the patient has a known malignancy. Even with a known malignancy, other causes of hypercalcemia should be ruled out (4).
  • The mnemonic for remembering the effects of hypercalcemia: Stones (kidney stones), bones (bone pain), moans (psychosis), groans (abdominal discomfort, constipation), and psychiatric overtones (including depression and confusion).
  • Patients with hypercalcemia of malignancy do not need a low-calcium diet. Hypercalcemia decreases the absorption of calcium in the intestine (5).
  • For severe hypercalcemia of malignancy, the initial treatment of choice is IV hydration. Volume depletion is t

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