Treatment of Hypercalcemia of Malignancy
Hypercalcemia of malignancy affects approximately 10% to 20% of all cancer patients; if untreated, the condition is potentially fatal. The mechanism of hypercalcemia of malignancy involves osteoclast-mediated resorption via the action of parathyroid hormone-related protein. In some cancers, such as squamous cell carcinoma, hypercalcemia occurs in the absence of detectable skeletal metastases due to the release of parathyroid hormone-related protein into the circulation. The clinical symptoms of this disorder are nonspecific and include dehydration, weight loss, fatigue, loss of appetite, constipation, nausea, vomiting, and mental status changes. If unrecognized, it can cause seizures, renal failure, cardiac conduction abnormalities and arrhythmia, coma, and death.
Along with rehydration, effective inhibition of the osteoclast-mediated bone resorption will result in rapid control of hypercalcemia of malignancy; thus, bisphosphonates are standard treatment for this disorder. Pamidronate is active,[29,30] but zoledronate is more effective. Two randomized, concurrent, parallel phase III trials compared the safety and efficacy of IV zoledronate at 4 mg or 8 mg vs IV pamidronate at 90 mg for the treatment of hypercalcemia of malignancy. Zoledronate was more effective in returning serum calcium levels to normal and maintaining them as such for a longer period (Table 2).
Treatment of Established Bone Metastases
Bone is the initial site of relapse in 30% to 40% of women with breast cancer. Although the median survival of breast cancer patients with metastases confined only to the skeleton is longer than those with visceral metastases, the complications associated with bone metastases cause significant morbidity and impair quality of life. Pain develops in up to 75% of breast cancer patients with skeletal metastases, pathologic fracture in 16%, hypercalcemia in 17%, and spinal cord compression in 3%.
Studies demonstrating the beneficial effects of bisphosphonates are described in Table 3.[26,27,33-38] Two double-blind, randomized placebo- controlled trials of IV pamidronate (90 mg) in breast cancer patients who were receiving either chemotherapy or hormonal therapy showed significant reductions in skeletal- related events and pain.[26,33] Among patients receiving chemotherapy, the overall reduction in skeletalrelated events (hypercalcemia, pathologic fracture, spinal cord compression, or radiation for palliation) was 43% vs 56% (P = .008), and the median time to first skeletal event was 14 vs 7 months (P < .001) for the pamidronate- and placebo-treated groups, respectively.[26,38] Among patients receiving hormonal therapy, the overall reduction in skeletal-related events was 56% vs 67% (P = .03), and the median time to first skeletal event was 10 vs 7 months (P = .05) for the pamidronate- and placebotreated groups, respectively. Overall survival was similar in both groups in both of these trials.
In another double-blind randomized trial, researchers compared zoledronate at 4 or 8 mg IV to pamidronate at 90 mg IV. No statistically significant differences emerged between zoledronate- and pamidronate- treated breast cancer patients in terms of declines in skeletal-related events or time to first skeletal event. Zoledronate was associated with reversible elevations in serum creatinine, primarily at the 8-mg dose and with a 5-minute bolus infusion. With the recommended dose of 4 mg over 15 minutes, the incidence of elevated serum creatinine levels did not differ between zoledronate- and pamidronate- treated patients. The shorter infusion time of zoledronate (15 minutes vs 90 to 120 minutes for pamidronate) and equivalent therapeutic efficacy relative to pamidronate makes zoledronate more convenient for many patients.
• Treatment Controversies—Pamidronate, and more recently zoledronate, are considered part of standard therapy for breast cancer patients with predominantly lytic skeletal metastases. However, several questions remain unanswered.
The optimal duration of bisphosphonate therapy is undefined, but treatment in excess of 2 years appears to be well tolerated. The American Society of Clinical Oncology (ASCO) practice guidelines concluded that once bisphosphonates are initiated, they should be continued until the patient's performance status declines.[ 41] The question of whether every breast cancer patient with skeletal metastases benefits from bisphosphonates also has no firm answers. Many patients have only one or two skeletal metastases and are asymptomatic, or are likely to respond to systemic chemotherapy or hormonal therapy. The ASCO panel concluded that the use of bisphosphonates is a high priority in patients with multiple painful lytic metastases or metastases in weight-bearing bones.
Finally, questions about the costeffectiveness of bisphosphonate added to the cost of breast cancer treatment are relevant, with one analysis concluding that the cost of pamidronate in combination with chemotherapy was $110,000 in the United States and $19,000 in Canada per qualityadjusted life-year gained.[41,42] The former is beyond the range of other accepted medical interventions, whereas the latter is not. This wide disparity was attributed, in part, to the relatively higher cost of pamidronate in the United States.
Upwards of 85% to 100% of men who die of prostate cancer have skeletal metastases that cause pain, pathologic fracture, and spinal cord compression. Although skeletal metastases from prostate cancer primarily have increased osteoblastic activity, evidence also suggests increased osteoclast activation and bone resorption. This observation is the basis for testing bisphosphonates in these patients. Randomized placebo-controlled trials are described in Table 4.[44-48] Treatment with clodronate or pamidronate failed to produce any reductions in the number of skeletal-related events.[44-47] In contrast, a recently reported randomized, placebo-controlled trial in patients with hormonerefractory metastatic prostate cancer showed a significant reduction in skeletal- related events (44.2% vs 33.2%, P = .021) and an increase in the median time to first skeletal-related event (14+ vs 11 months, P = .011) for zoledronate (4 mg IV). The results of this trial are promising; at this time, however, zoledronate should not be considered standard treatment for skeletal metastases from prostate cancer.
Other Solid Tumors
Zoledronate is also effective in reducing skeletal-related events and increasing the median time to first skeletal event in patients with predominately non-small-cell lung cancer and other nonbreast cancers. In a double-blind placebo-controlled trial of IV zoledronate at 4 mg, skeletal- related events were reduced (37% vs 44%, P = .13), and the median time to first skeletal event was prolonged (8 vs 5 months, P = .02). This trial was the first to show a significant benefit of bisphosphonates in patients with skeletal metastases from solid tumors other than breast and prostate cancer.
Multiple myeloma is a common hematologic malignancy with nearly 15,000 cases reported annually. Nearly 80% of multiple myeloma patients present with lytic skeletal metastases at the time of diagnosis, with pain and pathologic fractures being common features of this disease. Randomizedplacebo controlled trials are outlined in Table 5.[27,51-55] In one trial of oral clodronate, the progression of skeletal metastases was reduced, and in another, the incidence of nonvertebral fractures was reduced. Oral pamidronate, however, did not produce a statistically significant effect on skeletal-related morbidity.
Berenson et al demonstrated the efficacy of IV pamidronate, 90 mg administered every 4 weeks, in patients with advanced multiple myeloma.[ 54] In pamidronate-treated patients, the incidence of skeletal-related events was reduced (28% vs 44%, P = .001), and the median time to first skeletal event was prolonged (21 vs 10 months, P = .008). Although no statistically significant difference in overall survival emerged between the pamidronate- and placebo-treated groups, survival was shown to improve in a planned subset analysis of patients who received second-line chemotherapy. As in breast cancer patients, the benefits of zoledronate and pamidronate in reducing skeletalrelated events were comparable to those seen in multiple myeloma patients.