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©2013 UpToDate ® Print Email Pivotal phase III trials of bisphosphonates in patients with bone metastases from breast cancer Bisphosphonate Comparator Sample size Results Pamidronate 90 mg IV three to four times weekly for 12 months [1] Placebo for 12 months 382; patients on chemotherapy with at least one lytic lesion Results favored pamidronate for: Time to first SRE: 13.1 vs. 7.0 months, p = 0.005 Proportion of patients with SRE 43 vs. 56 percent, p = 0.008 Bone pain: p = 0.046 Performance status: p = 0.027 Overall survival was not significantly affected by pamidronate (median survival 14.8 vs. 14.2 months) Pamidronate 90 mg IV three to four times weekly for 24 months [2] Placebo for 24 months 374; patients on endocrine therapy Results favored pamidronate for: Skeletal morbidity rate at 12, 18 and 24 cycles p = 0.028, 0.023, and 0.008, respectively Proportion of patients having SREs at 24 months: 56 vs. 67 percent at 24 cycles; p = 0.027 Time to first SRE: 10.4 vs. 6.9 months, p = 0.049 Bone pain: p = 0.002 Median survival was unchanged (37 months) Pamidronate 90 mg IV three to four times weekly; up to 24 months [3] (this report is a continuation of above study [1] ) Placebo up to 24 months 382; patients on chemotherapy with at least one lytic lesion Results favored pamidronate for: Proportion of patients with any SREs at 15, 18, 21 & 24 months; p<0.001 Long-term treatment did not result in any unexpected adverse events Survival did not differ between the two groups Zoledronic acid 4 or 8 mg [4] Pamidronate 90 mg 287 patients HCM Results favored zoledronic acid for: Complete response rate by day 10; p = 0.002 to 0.015 Normalization of corrected serum calcium by day 4 was superior in zoledronic acid (50 percent) compared to pamidronate (33 percent) Duration of complete response favored zoledronic acid: 32 to 43 vs. 18 days for pamidronate Zoledronic acid 4 (and 8) mg IV three to four times weekly for 13 months (8 mg arm dropped secondary to excessive renal toxicity) [5] Pamidronate 90 mg IV three to four times weekly for 13 months 1648 patients with multiple myeloma or breast cancer patients with lytic disease The proportion of patients with at least one SRE was similar in all treatment groups Median time to the first SRE was approximately one year in each treatment group Zoledronic acid (4 mg) and pamidronate were equally well tolerated

Pamidronate 90 mg IV three to four times weekly for 13 months 1648 patients with multiple myeloma or breast cancer patients with lytic disease The proportion of patients with at least one SRE was similar in all treatment groups Median time to the first SRE was approximately one year in each treatment group Zoledronic acid (4 mg) and pamidronate were equally well tolerated The incidence of renal impairment: zoledronic acid 4 mg over 15 minute infusion was similar to that among patients treated with pamidronate Zoledronic acid 4 (and 8) mg IV three to four times weekly for 24 months (8 mg arm dropped secondary to excessive renal toxicity) [6] (this report is a continuation of above study [5] ) Pamidronate 90 mg IV three to four times weekly for 24 months 1648 patients with multiple myeloma or breast cancer patients with lytic disease; 606 patients continued on extended study At 25 months, 47 percent of patients on zoledronic acid and 51 percent of patients on pamidronate experienced an SRE other HCM, although results favored zoledronic acid for: Decreasing the percent of patients undergoing radiation therapy to bone (10 vs. 24 percent, p = 0.037) Subset analysis demonstrated patients with MBC on endocrine therapy experienced an extended time to SRE (415 vs. 370 days, p = 0.047) Skeletal morbidity rate was decreased 25 percent with zoledronic acid (1.04 events per year for 4 mg zoledronic acid vs. 1.39 events per year for pamidronate; p = 0.084), but in MBC on endocrine therapy, there were 0.83 SREs per year vs. 1.37 SREs per year, respectively; p = 0.039 Multiple event analysis, including HCM, was in favor of zoledronic acid (95% CI), 0.719-0.983 The presentation of the data from the long term follow up of this study, and the multiple events analysis has been criticized Zoledronic acid 4 mg IV every four weeks for 12 months [7] Placebo IV every four weeks for 12 months 228 with at least one osteolytic metastases from breast cancer Results favored zoledronic acid for: Reducing SRE by 39 percent (p = 0.027). The SRE events per year was 0.63 for zoledronic acid vs. 1.10 events per year for placebo; p = 0.016 When including HCM into the SRE analysis, zoledronic acid provided a 40 percent relative reduction in the proportion of patients experiencing SREs Multiple event demonstrated zoledronic acid HR 0.59; p = 0.019 Zoledronic acid (4 mg) IV every four weeks [8] Denosumab (120 mg) SQ every four weeks

Reducing SRE by 39 percent (p = 0.027). The SRE events per year was 0.63 for zoledronic acid vs. 1.10 events per year for placebo; p = 0.016 When including HCM into the SRE analysis, zoledronic acid provided a 40 percent relative reduction in the proportion of patients experiencing SREs Multiple event demonstrated zoledronic acid HR 0.59; p = 0.019 Zoledronic acid (4 mg) IV every four weeks [8] Denosumab (120 mg) SQ every four weeks 2046 women, advanced breast cancer, with ≥1 bone metastasis Results favored denosumab for: Significant delay in time to first on-study skeletal related event (HR 0.82, 95% CI, 0.71-0.95) Significant decrease in the risk of developing multiple SREs (risk ratio 0.77, 95% CI, 0.66-0.89) Signficant reduction in the mean skeletal morbidity rate (0.45 versus 0.58 events per patient per year) HCM: hypercalcemia of malignancy; HR: hazard ratio; IV: intravenous; MBC: metastatic breast cancer; SRE: skeletal-related event. References: Hortobagyi GN, et al. N Engl J Med 1996; 335:1785. Theriault R, et al. J Clin Oncol 1999; 17:846. Hortobagyi GN, et al. J Clin Oncol 1998; 16:2038. Major P, et al. J Clin Oncol 2001; 19:558. Rosen LS, et al. Cancer J 2001; 7:377. Rosen LS, et al. Cancer 2003; 98:1735. Kohno N, et al. J Clin Oncol 2005; 23:3314. Stopek AT, et al. J Clin Oncol 2010; 28:5132.