Hypercalcemia in the
Palliative Care Setting

Nausea, vomiting, constipation, anorexia, fatigue and confusion are symptoms commonly experienced by terminally ill cancer patients. As clinicians we should be aware of hypercalcemia as a potential cause.

Hypercalcemia is a common problem occurring in approximately 10% of cancer patients. The incidence may rise to as high as 40% in some types of malignancy including breast, squamous cell cancer of the lung, and multiple myeloma. Awareness of the disorder can assist practitioners in their management of some difficult symptoms and improve the quality of life of their patients.

There are at least three potential mechanisms for hypercalcemia in malignancy and they include:

1. Calcium mobilized from bone in amounts that overwhelm renal excretory capacity.
    
2. Increased renal reabsorption or decreased renal excretion.
    
3. Increased absorption from the gut.

A detailed discussion of the pathopysiology will not be attempted here. However some points are worth mentioning.

In many patients hypercalcemia is related to a substance produced by the tumor itself, Parathyroid Hormone-related Protein (PTH-RP).This protein increases bone reabsorption by osteoclasts with increased release of calcium from bone, and increases reabsorption of calcium from the distal renal tubule.

Hypercalcemia is also caused by direct invasion of bone by tumors. This bony destruction is mediated by a wide range of cytokines and other chemicals including, tumor growth factor, prostaglandins.

Many other factors may play a role in hypercalcemia including use of thiazide diuretics, patient immobilization, oral calcium supplements, primary hyperparathyroidism, and drugs. E.G. Tamoxifen (usually transient).

1. Gastrointestinal: Nausea, Vomiting, Abdominal pain, Constipation, Anorexia
    
2. Neuro/Psychiatric: Fatigue, Irritability, Confusion, somnolence, Coma
    
3. Renal: Polyuria with dehydration
    
4. Others: Bone pain, itch.

Early symptoms such as nausea, anorexia, and vomiting increase the risk of dehydration aggravating the hypercalcemia.

Hypercalcemia reduces renal concentration ability. Urine high in calcium causes polyuria with worsening overall volume depletion, decreasing GFR, and increasing tubular damage and sodium loss.

Neuropsychiatric symptoms may then occur. Apathy, fatigue, decreased mood, muscle weakness, confusion, coma.

These signs and symptoms can challenge the clinician to ascertain the correct diagnosis. They are commonly attributed to the signs and symptoms of the malignancy itself, ongoing oncology treatments or the side effects of any number of drugs used in the palliative care setting.

Having considered the diagnosis, simple laboratory assessment will confirm it. The diagnosis is made by measuring the serum calcium and adjusting it based on the patientsŐ serum albumin. Various formulas exist and I would advise checking with your local lab. One method to consider is; for each unit of albumin less than 40 add .02calcium. I.e. Calcium corrected = calcium measured + [0.02X (40-albumin conc.)] SI units.

While it is possible to grade hypercalcemia into mild, moderate, and severe, it is important to remember that severity of symptoms does not always correlate with the serum calcium level. Therefore, the physician should be guided more by the severity of the symptoms than any specific calcium threshold when deciding when to treat.

TREATMENT

1. Stopping oral calcium supplements.
    
2. Stopping Thiazide diuretics.
    
3. Using caution when ordered drugs with negative renal effects, e.g. NSAIDS.
    
4. Improving oral fluids.
    
5. Increased mobilization.

In the palliative care setting many of the above options may have already failed or may no longer be practical. Treatment therefore usually involves the use of rehydration and biophosphonates +/- other therapies.

Most patients with hypercalcemia have significant volume depletion as much as 5-10 liters. It is important to rehydrate with Normal Saline prior to instituting other therapies. The rehydration rates should be determined by assessing the degree of dehydration and considering other medical problems with the patient e.g. (cardiac function). Rehydrating at rates of 200-300 cc/hr may be appropriate. Clinicians should expect to see dependent edema in patients with low serum albumin.

Following hydration, use of Furosemides (Loop Diuretic) may increase renal excretion of calcium by 30%. This is unlikely to be enough to result in any sustained clinical improvement and therefore may best be reserved as an adjunct to better treatments i.e. Biophosphonates, especially in the occasional circumstance of hypercalcemia and fluid overload. Given that increased bone reabsorption is the final pathway in the majority of cases of hypercalcemia of malignancy, the best treatment is directed at osteoclasts i.e. Biophosphonates. Biophosphonates have become the main treatment for achieving and sustained reduced serum calcium levels and improving symptoms.

Pamidronate is a commonly used agent. It is often given in doses of 60-90mg in 500cc's of N/S given IV over 2-4hours. Improvements in serum calcium and symptoms may be seen within 1-3 days with response rates as high as 70% by day 10. The treatment is generally well tolerated and may be repeated (depending on the clinical setting) every 2-4 weeks. Side effects may include nausea and/or transient fever. Other Biophosphonates are becoming available which may have quicker infusion times.

OTHER TREATMENTS

Calcitonin causes rapid suppression of osteoclast activity and enhances net calcium uptake in bone. It may also increase urinary excretion of calcium. It probably has an analgesic effect and seems to have a place in treating metastatic bone pain further research is required.

The decrease in serum calcium occurs within approximately 2 hours and may last for 6-8 hours. The recommended dose is 4 I.U. /Kg every 12 hours by subcutaneous or intramuscular injection.Unfortunately the effects are often short lived. However, it may be used when rapid reduction in serum calcium is required while waiting Biophosphonates to become effective. Side effects include nausea, vomiting and tacyphylaxis. My experience with Calcitonin in the Palliative Care setting is limited and further study is required.

Steroids may have a role to play in certain tumor types which are corticosteroid sensitive, e.g. myelomas and some lymphomas, but the general effectiveness in most other settings has not been proven.

SUMMARY:
Keep hypercalcemia in mind in patients with cancer especially with certain types and with advanced disease. Relieving their symptoms with simple treatment may significantly improve the quality of their lives.

- Michael MacKenzie

Thanks to Dr. Ron McCormick, Oncologist at the Cape Breton Regional Hospital, in Sydney, Nova Scotia for reviewing the draft copy of this article.

1. Palliative Medicine, Third Edition 1999. Roger Woodruff
    
2. Williams Text Book of Endocrinology, 9th Edition.
    
3. Ablaff Chemical Oncology, 2nd Edition.

You can search for abstracts of the above references by following this link: PubMed