L. Bressler
November, 1997
Cancer Associated Hypercalcemia
OBJECTIVES
1. Describe, in brief, the pathophysiologic changes associated with cancer associated hypercalcemia.
2. Discuss the mechanism(s) of the various treatment modalities for cancer associated hypercalcemia.
3. Be able to discuss relative advantages and disadvantages of the various treatment modalities for cancer associated hypercalcemia, and to recommend treatment for specific patients.
REQUIRED READING
NONE
SUGGESTED READING
1. Bilezikian JP: Management of acute hypercalcemia; N Engl J Med 326:1196-1203,1992
2. Hall TG, Schaiff RAB: Update on the medical treatment of hypercalcemia of malignancy; Clin Pharm 12:117-125, 1993
CANCER ASSOCIATED HYPERCALCEMIA
Hypercalcemia is reported to occur in 10-20% of patients with malignancies. Malignancy is one of the most common causes of hypercalcemia. Certain cancers are more likely than others to cause hypercalcemia. The most common cancers that are associated with the development of hypercalcemia are SQUAMOUS CELL LUNG CANCER, SQUAMOUS CELL HEAD AND NECK CANCERS, BREAST CANCER, MULTIPLE MYELOMA, T-CELL LYMPHOMAS, RENAL CELL CANCER, AND OVARIAN CANCER.
Hypercalcemia may be associated with BONE METASTASES in patients with solid tumors eg. metastatic breast cancer. Increased BONE RESORPTION by OSTEOCLASTS leads to hypercalcemia. The increased bone resorption in this setting may be mediated by PROSTAGLANDINS or other factors. In addition, TUMOR CELLS may be able to RESORB BONE DIRECTLY.
Hypercalcemia is also associated with HEMATOLOGIC MALIGNANCIES like multiple myeloma or T-cell lymphomas. Again, hypercalcemia in these cases results from increased BONE RESORPTION by OSTEOCLASTS, mediated by lymphokines.
Most widely studied in recent years is hypercalcemia associated with SOLID TUMORS WITHOUT BONE METASTASES eg. squamous cell lung or head and neck cancers. Hypercalcemia in these cases is due to a systemic humoral factor(s) that is produced by the tumor, the so-called HUMORAL HYPERCALCEMIA OF MALIGNANCY (HHM). Recent investigations have identified parathyroid hormone-related protein (PTH-rP) as a probable mediator of HHM. PTH-rP may act in conjunction with other factors (eg. TRANSFORMING GROWTH FACTOR ALPHA, TUMOR NECROSIS FACTOR, INTERLEUKIN-1) to cause the effects seen in humoral hypercalcemia.
The proximal cause of hypercalcemia in all of these situations is increased bone resorption. However, the kidneys help to maintain calcium homeostasis by increasing urinary calcium excretion when bone resorption increases. Changes in renal handling of calcium, then, are important in precipitating hypercalcemia in patients with increased bone resorption. Normal calcium reabsorption in the proximal renal tubule is linked with sodium reabsorption and with volume status. Hypercalcemia is associated with a decreased effect of ADH on the renal tubules, leading to dehydration. Dehydration leads to a decrease in GFR, increasing sodium and thus calcium reabsorption, and worsening the hypercalcemia. Other factors like vomiting also may also contribute to precipitating or maintaining hypercalcemia.
Normal total serum calcium is about 8.5-10.5mg/dl. About 40% is bound to proteins, mainly albumin. Fifteen percent is complexed to anions, and 45% is the free, ionized, active form. Formulae are available for correcting calcium concentrations for changes in albumin. These are supposed to estimate ionized, active calcium, although the correlation with measured ionized calcium is questionable. However, ionized calcium is usually not measured, and the formulae, based on albumin, are frequently used (eg. corrected serum calcium = [(4 - albumin) X 0.8] + measured serum calcium)
Clinical manifestations of hypercalcemia include GI: nausea, vomiting, constipation; NEUROLOGIC: weakness, lethargy, confusion, coma; RENAL: polyuria, thirst. Symptoms may depend on the rate of rise of calcium eg. slow, gradual increases may be less symptomatic than abrupt increases. Progressive hypercalcemia can lead to death. Prompt treatment is initiated in patients who are symptomatic and/or whose calcium is very high (eg. > 13mg/dl). Other patients are treated, but perhaps less urgently. Remember also, that certain drugs can contribute to hypercalcemia (eg. thiazides, lithium).
TREATMENT:
The first line of treatment for cancer associated hypercalcemia is HYDRATION with SALINE. Hydration repletes volume, and increases calcium excretion. Promotion of sodium diuresis leads to calciuresis as noted above. Hydration over 2 days (2-8L/day, depending on hydration status, of 0.9% NaCl) can decrease serum calcium by approximately 2mg/dl. Note that unless other treatment is initiated, or the underlying malignancy treated, calcium will rise again.
FUROSEMIDE may be used to prevent fluid overload from hydration eg. in patients with CHF. Furosemide also has a calciuric effect and has been suggested as a treatment in addition to, or following, hydration. Reports of successful lowering of calcium with furosemide involved very high doses along with large volumes of fluid, strict electrolyte monitoring and replacement, and intensive care monitoring. Outside of this setting, dehydration from furosemide can offset any calciuric benefit, and its use should probably be reserved for patients who can't tolerate hydration, as noted above.
BISPHOSPHONATES - Today, bisphosphonates are probably the most frequently used calcium-lowering agents. They (ETIDRONATE, PAMIDRONATE) prevent osteoclastic bone resorption, and they may directly inhibit osteoclasts. Etidronate can also impair bone formation. For prompt response, bisphosphonates are given IV. Pamidronate is more potent than etidronate, and is probably used more often, although its clear superiority is not well documented. The recommended dose of pamidronate is 60-90mg IV. With either bisphosphonate, calcium decreases in about 48 hours and over the next 2 to 3 days, may fall to normal. Although commonly recommended for administration over 24 hours, pamidronate has been safely administered by short infusion (eg. 0.5-3 hours), making it attractive for outpatient use. Bisphosphonates are relatively free of side effects. There are reports of elevations of serum creatinine with etidronate in large doses. The clinical importance of mild reversible elevations is not clear. Because of the reports, the recommendations are to avoid etidronate in patients with serum creatinine greater than 5, and to decrease the dose when creatinine is > 2.5. Clinically, however, bisphosphonates may be safe to use even before patients are completely rehydrated (eg. while their creatinine may still be elevated).
Oral etidronate has been recommended for maintenance of normocalcemia. Its efficacy is less well established than that of parenteral bisphosphonates. Doses up to 20mg/kg/day have been used. Although inhibition of bone formation is a potential concern, many patients with cancer associated hypercalcemia have a limited survival, and will be unlikely to suffer long-term consequences.
PLICAMYCIN (mithramycin) is commonly used to treat cancer associated hypercalcemia after hydration. The dose is 25mcg/kg and should be reduced in patients with renal dysfunction (eg. by 50%). Plicamycin may be given as an IV bolus or infusion. Most side effects of plicamycin are associated with higher or repeated doses (eg. 25-50mcg/kg/day x 5). These side effects include thrombocytopenia, coagulopathy, hepatitis. The 25mcg/kg dose given once and perhaps repeated in 48 to 72 hours if necessary is well tolerated. Although calcium is lowered to normal levels in a majority of patients, the duration of normocalcemia is variable. When plicamycin provides normocalcemia for 7 days or more, it can also be a useful agent for maintaining lowered calcium.
GALLIUM NITRATE is given as a continuous IV infusion (200mg/m2/day x 5 days). It appears to be effective in a large proportion of patients. In a comparative study with etidronate, the median duration of normocalcemia was 8 days. Overall, gallium was reported to be more effective than etidronate. Gallium should be used after rehydration. Higher doses have been associated with nephrotoxicity, and it is recommended that gallium not be used in patients with serum creatinine greater than 2.5. Its relative place in therapy is yet to be defined, keeping in mind factors such as cost, duration of effect and duration of treatment, potential for nephrotoxicity, etc.
CALCITONIN is also used to lower serum calcium. It works within several hours, and may be useful in lowering calcium acutely. Calcitonin may also be used in patients with renal insufficiency or before rehydration. Resistance develops quickly to calcitonin, and although some investigators suggest that steroids prolong the effectiveness, others have not found that to be the case. Calcitonin requires frequent parenteral administration (IV or SQ). These latter factors make calcitonin a less than optimal choice for maintenance of normocalcemia.
Finally, CISPLATIN has been used to treat hypercalcemia associated with certain malignancies. It may provide several weeks of normocalcemia. However, it should not be used in patients with renal insufficiency. Cisplatin should only be given to patients who have been well hydrated.
Maintenance of normocalcemia may be achieved with intermittent administration of some of the agents described above to lower calcium initially (eg. plicamycin, pamidronate). Maintenance with oral etidronate was discussed above. ORAL PHOSPHATE is also used to maintain normocalcemia, provided patients are not hyperphosphatemic. Neutral phosphate capsules should be emptied and mixed with liquid. The starting dose of phosphate is about 1gm/day in divided doses. Diarrhea frequently impairs dose escalation and/or compliance, thus minimizing effectiveness.
 Previous |
 Next |
 Syllabus |
| The College of Pharmacy | UICPHARM@uic.edu | |
| The University of Illinois at Chicago | Last modified: Dec 19, 1997 | |