Treatment

Asymptomatic patients with mild to moderately elevated serum calcium (<3.25 mmol/l, < 14 mg/dl) do not require immediate treatment as an inpatient (Fojo 2005). Rather, medical therapy maybe instituted on an outpatient basis with periodic monitoring of serum calcium and renal function. Symptomatic patients, or those with a serum calcium level above 3.25 mmol/l (> 14 mg/dl) indicating severe hypercalcemia require hospital admission and immediate intervention. The traditional and most basic treatment for hypercalcemia is i.v. hydration with isotonic saline. By increasing urine calcium excretion, hydration results in a rapid, yet modest (0.5 mmol/l) reduction in serum calcium levels. Renal function can also be expected to improve as the prerenal component of dysfunction is corrected. Hydration is generallybegun with the infusion of1 — 2l of isotonic saline over 1-4 h (Flombaum 2000). Total volumes and rate of delivery will depend on the hydra-

Table 13.1. Treatment options for hypercalcemia of malignancy

Treatment

Dose

Route

Frequency

Normal saline hydration

1-21

IV

As necessary

Furosemide

20-40mg

IV

As necessary

5-15 min

IV

Every 4-6 weeks

Calcitonin

4-8 IU/kg

IM/SC

Every 6 - 8 h

Gallium nitrate

100-200 mg/ m2/day x 5 days

IV

Dialysis Nephrectomy

tion and cardiovascular status of the patient. Furose-mide, a loop diuretic that inhibits calcium reabsorption at the loop ofHenle, can be used to augment renal calcium excretion. Loop diuretics should only be used when rehydration has been completed.

Rehydration alone is often inadequate (Hosking et al. 1981). The majority of patients with hypercalcemia of malignancy will require additional medical therapy as outlined in Table 13.1. The cornerstone of such therapy is the bisphosphonate group of medications. As pyrophosphate analogs with a high affinity for hydroxyapa-tite, bisphosphonates concentrate in areas of high bone turnover where they become internalized into osteoclasts and inhibit bone resorption (Fleisch 1991; Lin 1996; Sato et al. 1991; Fojo 2005). Three generations of bisphosphonates are now available, each providing an incremental improvement in potency, response duration, and toxicity profile. Etidronate, the original bisphosphonate, corrects hypercalcemia in 50% of patients; however, this is achieved at the expense of significant demineralization (Singer and Minoofar 1995). The success rate of second- and third-generation bisphos-phonates exceeds 80 % (Purohit et al. 1995; Nussbaum et al. 1993). The current drug of choice is zoledronate, a third-generation bisphosphonate that achieves normo-calcemia in more than 90% of patients (Major et al. 2001). As with all bisphosphonates, this agent must be given intravenously because of poor oral absorption. Zoledronate usually corrects hypercalcemia within 4-10 days for a duration of 4 - 6 weeks. Bisphosphona-tes are more effective against hypercalcemia arising from focal bone destruction secondary to metastases than against HHM. Despite potent inhibition of focal and systemic bone resorption, bisphosphonates have no effect on renal calcium reabsorption, which plays a prominent role in HHM. Animal studies suggest that bisphosphonates may cause or exacerbate renal failure; therefore, these agents should be used with caution if the serum creatinine exceeds 3.0 mg/dl (Stewart 2005).

Calcitonin is another treatment option for hypercalcemia. Reduction in serum calcium occurs primarily through the inhibition of osteoclast-mediated bone resorption. However, supraphysiologic doses have also been shown to improve renal calcium excretion (Lin 1996; Sato et al. 1991). Tachyphylaxis occurs within 2-3 days of repeated calcitonin dosing; therefore long-term efficacy is not possible. The primary utility of calcitonin lies in the rapidity of its onset (2 - 6 h) (Warrell et al. 1988). As such, calcitonin is ideally used in combination with longer-acting medications with delayed-onset such as bisphosphonates. With the exception of rare allergic reactions, calcitonin is considered safe and nontoxic.

Gallium nitrate, originally developed as an anticancer drug, is a potent inhibitor of bone resorption (Warrell et al. 1991). In addition to osteoclast inhibition, gallium nitrate reduces serum calcium through the inhibition of both renal calcium reabsorption and PTH secretion (Warrell et al. 1984; Warrell 1997). A continuous 5-day i.v. infusion corrects hypercalcemia in approximately 80 % of patients for a median duration of 8 days (Warrell et al. 1991). Serum calcium begins to normalize within hours but maximal effect takes place after the infusion is complete. Ten percent of treated patients experience an elevation in serum creatinine; therefore, gallium nitrate should be used with caution in patients with baseline renal dysfunction (Zojer et al. 1999). Based on its lengthy administration protocol and potential for nephrotoxicity, gallium nitrate is rarely used today. It does, however, remain an important treatment option in cases of hypercalcemia refractory to bisphos-phonate therapy.

Dialysis is indicated in patients with severe hyper-calcemia complicated by significant mental changes. Patients with chronic renal failure or congestive heart failure often cannot tolerate i.v. hydration therapy; therefore, hemodialysis is frequently necessary in these cases as well.

Depending on the extent of disease and the oncologic prognosis, nephrectomy may also be a consideration. Hypercalcemia typically normalizes after nephrectomy in cases of localized RCC (Gold and Fefer 1996; Fahn et al. 1991). Persistence or relapse of hypercalcemia is often an indication oflocal recurrence or occult metastatic disease. Cytoreductive nephrectomy has been shown to correct hypercalcemia in two-thirds of patients with metastatic RCC; however, this effect is only temporary (Walther et al. 1997).

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