MANAGEMENT OF HYPERCALCEMIA IN ONCOLOGIC PATIENTS [NACC,Georgia, Tbilisi]

MANAGEMENT OF HYPERCALCEMIA IN ONCOLOGIC PATIENTS

Hypercalcemia, one of the most common metabolic disorders accompanying neoplasia, with an estimated incidence of 150 new cases per million persons per year, can provide the great discomfort for the patient. Hypercalcemia occurs in 10%-30% of people with cancer.
The cancers most often associated with hypercalcemia are those of the breast, lung, kidney, prostate, head and neck, as well as certain blood, neoplasms particularly multiple myeloma.
Early diagnosis and treatment with drugs and fluids to lower blood calcium levels can improve symptoms in few days, but diagnosis may be difficult. Symptoms of hypercalcemia can appear gradually and may resemble the symptoms of many cancer types or other diseases.
Early diagnosis and treatment is not only lifesaving, but may also increase the patient's ability to complete cancer therapy and improve the quality of life.
Unfortunatelly, due to the lack of updated literature in Georgia language, doctors practicing in general medicine ave not familiar with a symptoms of cancer-related hyper- calcemia and therefore are unable to detect and provide adequate treatment for this very important condition.
In 1997-2001 a special research was conducted in a Georgian National Oncologic Center. A specific data was collected regarding cancer-related hypercalcemia. Given resaults together with the information from western sources were combined to outline clear and definite approach for the management of cancer-related hypercalcemia, which is given in this book. Michael Shavdia

Kidney function

Normal, healthy kidneys are able to filter large amounts of calcium from the blood, excrete the excess not needed by the body, and retain the amount of calcium the body does need. However, in the cases of hypercalcemia the blood calcium may increase to so high levels that kidneys become unable to excrete the excess.
Some tumors produce a substance similar to normal parathyroid hormone (such a parathormone-related peptide that drives the kidneys to increase calcium reabsorbtion) and it can mediate the kidneys to excrete too little calcium. This results in a large amounts of urine to produce, that then may cause dehydration. Dehydration may lead to appetite loss, nausea, and vomiting and make the generalcondotion worse.
Disability caused by weakness and tiredness may increase the blood calcium levels by increasing the amount of calcium resorbed from the bones. Calcium deposits may collect in the kidneys, causing permanent damage.

Causes

The main causes of cancer-mediated hypercalcemia are those that increase the amount of calcium resorbed from the bones, and an interfere with the kidneys labilty to excrete excess calcium. Some cancer cells secrete substances that cause calcium to be absorbed into the bloodstream from the bones.
Immobility, dehydration, anorexia, nausea, and vomiting may also increase the calcium levels.

Symptoms

There is a little relationship between the symptoms of hypercalcemia and the actual level of calcium in the blood. Symptoms of hypercalcemia resemble symptoms of other illnesses, making an early and rapid diagnosis difficult. The severity of the symptoms may depend on other factors, such as previous cancer treatment, reactions to drugs, or other illnesses a patient may have.
Most patients do not experience all the symptoms of hypercalcemia, and some patients may not have any symptoms at all. However, most patients with high calcium levels in the blood do have symptoms.
Some patients develop signs of hypercalcemia when calcium levels are only slightly elevated, while patients laving higher calcium levels for a long time may show few or symptoms.
The most common symptoms of hypercalcemia are

· fetique,

· changes difficulty in mental function;

· anorexia;

· pain;

· frequent urination;

· increased thirst;

· constipation;

· nausea;

· vomiting.

Symptoms may be classified according to the affected body part:

Nervous system
Symptoms of hypercalcemia may include weakness, loss of reflexes in the muscles, and decreased stamina. Patients with central nervous system symptoms may have:

· changes in personality;

· difficulty in thinking or speaking clearly;

· disorientation, or hallucinations. Eventually, coma may result. Headaches can also occur, which may become made by vomiting and dehydration.

Heart

Hypercalcemia affects normal heart rhythms and increases the sensitivity to some cardiac medications (such as digoxin). As calcium levels increase, irregular heartbeats may develop, that may lead to the heart attack.

Gastrointestinal

Hypercalcemia may induce increased gastric acid secretoin and may intensify the loss of appetite, nausea, and vomiting. Hypercalcemia - related dehydration leads to constipation.

Kidney

Hypercalcemia causes the kidneys not to function correctly, leading to the production of large volumes of urine. The large amount of urine combined with less liquid intake leads to symptoms of dehydration, including thirst, dry mouth, little or no sweating, and concentrated urine. Patients with myeloma often have kidney problems due to hypercalcemia. Kidney stones may result from long-tern hypercalcemia

Bone

Although more than 80% of patients with hypercalcemia have osseous metastases, the extent of bony disease does not correlate with the level of hypercalcemia. During the course of their disease, about 42% of patients vith breast carcinoma metastatic to the bone will develop hypercalcemia. Bone metastases or loss of bone may result in hypercalcemia that may contribute to fractures, bone disfigurement and pain.

Clinical assessment

Patients with high calcium levels should be examined for the following symptoms:

· Nerves and muscles (muscle strength, muscle tone, reflexes, tiredness, indifference, depression, confusion, restlessness);

· Heart (high blood pressure, changes in heart functoin, irregular heartbeats, digitalis poisoning);

· Kidneys (production of too much urine, noctural urination, glucosuria, excessive thirst);

· Gastrointestinal (loss of appetite, nausea, abdominal pain, constipation, abdominal bloating);

· Other (muscle and bone pain, itching).

History

· How fast did the symptoms appear?

· Is there X-ray evidence of primary or metastatic bone disease?

· Has the patient been taking tamoxifen, estrogen, or androgens?

· Is the patient taking digoxin?

· Is the patient receiving intravenous fluids containing calcium?

· Is the patient receiving thriazide diuretics, vitamins A or D, or lithium?

· Is there another disease that could cause dehydration or difficulties on movement?

· Are there effective treatments for the patient's cancer?

Treatment

Management of hypercalcemia
Fluids are given to treat dehydration. Medication is given to stop the breakdown of bone. The cancer causing the hypercalcemia should be treated effectively.
The severity of hypercalcemia determines the amount of treatment necessary.
Severe hypercalcemia - corrected total serum calcium greater than 14 mg/dL (>7 mEq/L or 3,5 mmol/L) - should be treated immediately and aggressively.
Less severe hypercalcemia - corrected total serum calcium equal to 12-14 mg/dL (6-7 mEq/L or 3,0-3,5 mmol/L) - should be treated according to the symptoms. Response to treatment is shown by the disappearance of the symptoms of hypercalcemia and a decrease in the level of calcium in the blood.
Mild hypercalcemia does - corrected total serum calcium less than 12 mg/dL (6 mEq/L or 3,0 mmol/L) not usually need to be treated aggressively. Patients with mild hypercalcemia with related central nervous system symptoms are harder to treat. Younger patients are especially difficult to treat because they tolerate hypercalcemia better.To rule out the central nervous system symptoms caused be hypercalcemia, other causes of CNS symptoms should be excluded.
Treatment of hypercalcemia can improve symptoms. Increased urination and thirst, central nervous system symptoms, nausea, vomiting, and constipation improve with treatment more easily than other symptoms, such as loss of appetite, and tiredness. Pain may be more easily controlled once calcium levels are normal. Effective therapy that lowers calcium usually improves symptoms, enhances the quality of life, and may allow the patient to leave the hospital.
After calcium levels return to normal, urine and blood should be checked frequently to make sure in the adequacy of treatment.

Mild hypercalcemia

Giving fluids intravenously and observing the patient is an accepted treatment for patients with mild hypercalcemia (but no symptoms) and for those who also have cancer that responds well to anticancer therapy (such as lymphoma, breast cancer, ovarian cancer, head and neck cancers, or multiple myeloma).
If the patient has symptoms, or has a cancer that does not responds well to treatment, then drugs to treat the hypercalcemia should be started. Other treatment modalities should focus on controlling nausea, vomiting, and fever, encouraging continued activity, and limiting the use of drugs that cause sedation.

Moderate to severe hypercalcemia

Ffluids replacement is the first and most important step in the treatment moderate or severe forms of hypercalcemia. Replacing fluids will not restore normal calcium levels in all patients, but it is still important to do first.
The patient's mental state should improve, nausea and vomiting should decrease within the first 24 hours, but this improvement is only temporary. If cancer therapy (surgery, radiation, imuno or chemotherapy) is not started immediately, then drugs to lower the calcium levels must be used to control the hypercalcemia.

Patient and family education

Because hypercalcemia affects the quality of life and can become life-threatening if not treated, patients and their health care providec should be aware of the symptoms. They should also learn how to prevent hypercalcemia, what makes it worse, and when to consult the doctor.

Supportive care

Even with improved treatment for hypercalcemia, many patients do not survive this complication of cancer. Only effective anticancer therapy improves the patient's chances for long-term survival.
Supportive care includes measures to provide the patient with protection from injury, prevention of fractures, and treatment of symptoms.
Treatment of symptoms is important, especially the prevention of accidental or self-inflicted injury if a patient is confused. Nausea, vomiting, and constipation may also need to be controlled until calcium levels go down. Broken bones may occur due to weakening, so patients need to be moved gently, and falling must be prevented. Activity and weight-bearing exercises should be encouraged. Any new bone pain should be reported so that it can be evaluated for possible fractures.
Supportive care to comfort terminally ill patients and their family members becomes necessary in the last stages of the disease. Changes in the patient's thinking and behavior may especially upset the family.

Psychosocial management

Usually, treatment of the hypercalcemia will eliminate delirium, agitation, or mental changes, but some patients may need other medications to treat these symptoms. Mental changes may take some time to get better, even after calcium levels return to normal.
Lethargy (mental and physical sluggishness) is often a symptom of hypercalcemia. Family members (and sometimes, medical staff) may think that the patient is depressed until the actual cause is determined. Most patients will not have symptoms of depression (such as hopelessness, helplessness, guilt, worthlessness, or thoughts of suicide) and instead will appear to be indifferent.
Patients and family members should report symptoms of hypercalcemia such as lethargy, fatigue, confusion, loss of appetite, nausea, vomiting, constipation, and excessive thirst to the health care provider.

Prevention

Patients at risk of developing hypercalcemia may be the first to recognize its symptoms, such as fatigue. Measures to prevent hypercalcemia include drinking enough fluids, controlling nausea and vomiting, walking and being active, and cautious use or elimination of drugs that can contribute to the development of hypercalcemia or affect its treatment. Calcium in the diet should not be reduced or eliminated, however, because the body's absorption of calcium is reduced in the patients with hypercalcemia.

The principles of management of cancer-associated hypercalcemia

According to the analyses of presented material, in order to optimal and adequate management of cancer-associated hypercalcemia, the consideration of the following recommendations is appropriate:

1. Doctors should stress on:

· the investigation of the patients with cancer of different localization (for solid tumors - breast, lung, kidney, prostate, head and neck, pancreas, esophagus, stomach, urinary bladder, also melanoma and pheochromocytoma, and as for hematologic malignancies - multiple myeloma, adult acute leukemias and lymphomas), not to exclude cancer-associated hypercalcemia. Appropriate laboratory assessment is necessary for this reason;

· the monitoring of cancer patients to consider the possibilities of the presence of hypercalcemia and the patients should be conducted to perform standard biochemical analyses (determination of serum calcium and protein levels);

· the patients with terminal illness. The symptoms appeared in these patients often are similar to the severe forms of clinically manifested hypercalcemia, but the relief of presented symptoms is possible in few days due to the adequate treatment.

2. The coleagues of biochemical laboratories should assess the serum calcium concentration in cancer patients with decreased plasma protein levels.
Since hypoalbuminemia is not uncommon among patients with cancer, it is necessary to "correct" the total plasma calcium concentration for the percent of calcium that would have been measured if the albumin level were within normal range.

The calculation is as follows:
TOTAL SERUM CALCIUM CORRECTED FOR ALBUMIN LEVEL

[( normal albumin - patient's)*0,8]+ patient's measured total calcium

3. Correction of dehydration mediated by calciuresis and vomiting with intravenous saline solutions.

4. Prevention or management of fluid overload with a diuretic agent such as furosemide 20-40 mg every 12 hours.

5. Treatment of hypercalcemia with one of the folowing agents:

· Aredea (pamidronic acid) - 60-90 mg intravenous (IV) over 2-24 hours, or

· Bondronate (ibandronic acid) - 2-4 mg¤ml IV over at least 2 hours, or

· Bonefos (clodronic acid) - 300 mg IV over at least 2 hours for 3-5 consecutive days;

· Calcitonin 4 IU¤kg SC or IM every 12 hours;

· Plicamycin 25-30 ug¤kg IV over 30 minutes;

· Gallium nitrate 200 mg per square meter per day IV over 24 hours for 5 consecutive days.

6. Management mental status changes:

· Haloperidol 0,5 - 5 mg IV or po 2-4 times a day for agitation or confusion;

· Benzodiazepines such as Lorazepam 0,5 - 2 mg every 4 - 6 hours as needed for sedation.

7. Provide patient and family education - signs and symptoms of hypercalcemia to report to the health care provider:

· Lethargy;

· Fatique;

· Confusion;

· Loss of appetite;

· Nausea;

· Vomiting;

· Constipation;

· Excessive thirst.

8. Povide supportive care:

· Protect from injuries;

· Prevent fractures;

· Manage related symptoms (e.g. anorexia, nausea, vomiting, constipation…).

9 Preventive measures:

· Be physically active;

· Ensure adequate hydration.