HYPERCALCEMIA

Definition – A corrected blood calcium level above 10.5mg/dL  [2.6mmol/L] is defined as hypercalcemia. In fact, in the hypercalcemia of malignancy, symptoms are unusual until blood calcium levels are above 12.0mg/dL. [3.0mmol/L].

Mechanism of hypercalcemia – Although hypercalcemia is associated with extensive bone metastases in diseases such as carcinoma of the breast, it has been recognized for 30 years that hypercalcemia can occur in malignancies without bone involvement.

Increased tumor mass leads to greater production of parathyroid hormone related protein which acts on the kidneys to increase calcium reabsorption. Osteolytic cytokines probably cause hypercalcemia only if the first mechanism is also operating.

Incidence – Hypercalcemia occurs in about 8.5% of patients with cancer. It is more common in advanced disease (80% of patients with hypercalcemia die within one year), but it can occur at any stage and can be self-limiting. In one study, checking calcium levels of patients with breast cancer on admission to the hospital showed 5.3% had hypercalcemia, but checking levels every 6 weeks showed that 43% had hypercalcemia at some stage. Most cases were mild (levels below 12.0mg/dL) [3.0mmol/L] and severe cases (levels above 16.0mg/dL) [4.0mmol/L] were rare, occurring only in about 4% of cases.

Tumors causing hypercalcemia — It is particularly associated with squamous carcinomas and hematological malignancies (myeloma, lymphoma, leukemia).

It is commonest in carcinomas of:

• Breast

• Bronchus

It occurs in about 25% of patients with squamous carcinoma of the bronchus but it is rare in small (oat) cell and adenocarcinomas.

It can occur in a wide variety of tumors, including:

• Kidney

• Head and neck

• Esophagus

• Cervix

• Ovary

• Uterus

It is very rare in adenocarcinomas of the:

• Stomach

• Pancreas

• Colon

• Prostate

Symptoms – The most important symptoms suggestive of hypercalcemia in patients with malignant disease are:

• Drowsiness

• Nausea

• Thirst

• Polyuria

The combination of these symptoms makes hypercalcemia very likely.

Hypercalcemia also causes other symptoms: lethargy, anorexia, dry mouth, muscular weakness, constipation, confusion and anxiety.

These are all common symptoms in any patient with advanced malignancy and therefore hypercalcemia can easily be missed.

Management options – Even if the patient has a short prognosis of only a few weeks, it is worthwhile to treat hypercalcemia to relieve symptoms. Untreated, the patient will die in a few days if calcium levels rise above 16.0mg/dL [4.0mmol/L]. (It may occasionally be decided that the hypercalcemia is a terminal event and should not be treated.) 

Levels above 14.0mg/dL [3.5mmol/L] require IV rehydration with 2 to 3 liters normal saline per day with potassium supplements (monitor serum electrolytes) combined with daily IV infusions of etidronate disodium (7.5mg/kg/day) for 3 days. This regime is simple and effective.

After rehydration, calcitonin SC (by subcutaneous injection, 200 units 2 times a day) is often used, but has only modest, short-lived effects (2 to 3 days). It can have a place in treating moderate hypercalcemia (12.0mg/dL to 14.0mg/dL)[3.0mmol/L to 3.5mmol/L]. It commonly causes nausea and vomiting. It is expensive.

Once calcium levels have returned to normal, patients should maintain good fluid intake, and calcium levels should be monitored regularly, weekly at first and then monthly. Maintenance therapy is required.

The options include:

• Oral phosphate

• Oral steroids (for myeloma, lymphoma, leukemia)

• Hormone therapy (breast cancer)

• Oral etidronate disodium

Oral phosphate 500mg 1 or 2 times a day effectively maintains normal calcium levels. Start gradually to avoid nausea. Almost all patients develop diarrhea (even if on morphine) and require loperamide. Renal damage due to renal calcification is a long term risk, but not significant in patients with a prognosis of 6 months or less.

Steroids are often given for hypercalcemia, but are usually effective only in hematological malignancies.

In breast cancer (for patients with hormone sensitive tumors) hormone therapy can effectively prevent hypercalcemia recurring.

Biphosphonates – Etidronate disodium IV is effective and is the current drug treatment of choice for severe hypercalcemia. Oral etidronate disodium is available for maintenance therapy but current evidence suggests it is effective in fewer than 50% of patients. A newer generation of biphosphonates (now available only for investigational use) is effective both orally and IV. These can be used for long periods and are relatively non-toxic. These include aminopropilidine biphosphonate (APD), and dichloromethylene-biphosphonate. When available, these drugs will offer greater efficacy in the maintenance treatment of hypercalcemia of malignancy.

The author and publisher have taken precautions to ensure that the information in this book is error-free. However, readers must be guided by their own personal and professional standards of good practice in evaluating and applying recommendations made herein. The contents of this book represent the views and experience of the author, and not necessarily those of the publisher.