- Email: [email protected]
The role of bisphosphonates in breast cancer
ARTICLE IN PRESS The Breast (2004) 13, S19–S28
THE
BREAST www.elsevier.com/locate/breast
The role of bisphosphonates in breast cancer Robert E. Coleman Cancer Research Centre, YCR Academic Unit of Oncology, Weston Park Hospital, Sheffield, S10 2SJ, UK
KEYWORDS Skeletal complications; Long-term continuing benefit; Zoledronic acid
Summary Patients with bone metastases from breast cancer are at high risk for debilitating skeletal complications. Bisphosphonates are effective inhibitors of tumour-induced bone resorption and significantly reduce the risk of skeletal complications in these patients. Several bisphosphonates have been investigated for the treatment of bone metastases in patients with breast cancer, including clodronate, pamidronate, ibandronate, and zoledronic acid. Among these agents, intravenous pamidronate and zoledronic acid have demonstrated the greatest clinical benefit based on conservative endpoints. Zoledronic acid is the only agent to be compared with another active bisphosphonate and has been shown to significantly reduce the risk of skeletal complications compared with pamidronate. On the basis of these results, zoledronic acid has rapidly become the new international standard of care for patients with bone metastases from breast cancer. & 2004 Elsevier Ltd. All rights reserved.
Introduction Annually, approximately 1 million women worldwide are diagnosed with breast cancer,1 and among the patients who progress to advanced disease, 65–75% will develop bone metastases.2,3 Tumourinduced bone resorption in these patients increases their risk of developing pathologic fractures and other skeletal complications, including debilitating bone pain, spinal cord compression, and hypercalcaemia of malignancy (HCM).3 Without bisphosphonate therapy, the vast majority (nearly 70%) of patients with bone metastases from breast cancer will experience 1 or more of these skeletal complications during the course of their disease, Tel.: +44 114 2265213; Fax: +44 114 2265678
E-mail address: [email protected] (R.E. Coleman).
with approximately 50% developing pathologic fractures and 40% requiring palliative radiation therapy (Fig. 1).4 Furthermore, because these patients have a long median survival after diagnosis of bone metastasis (approximately 2–3 years), they often suffer from clinically significant cumulative skeletal complications over a long period of time, resulting in dramatic effects on quality of life.2,3 Bisphosphonates are effective inhibitors of tumour-induced bone resorption and significantly reduce the incidence of skeletal complications in patients with bone metastases from breast cancer.4,5 Consequently, bisphosphonate therapy is the standard of care for the treatment of such patients. A variety of clinical trial endpoints have been used to assess skeletal complications and the treatment effects of bisphosphonates. The majority of trials have used a composite endpoint, defined as a
0960-9776/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2004.09.004
ARTICLE IN PRESS S20
R.E. Coleman
Figure 1 Percentage of patients with at least 1 skeletal-related event in the placebo group of 2 pooled pamidronate trials after 2 years of follow-up. SRE, Skeletal-related event; HCM, Hypercalcaemia of malignancy. Data from Lipton et al.4
skeletal-related event (SRE) or bone event, which includes complications such as pathologic fracture, radiation to bone to palliate bone pain or prevent impending fractures, surgery to bone to prevent or treat fractures, spinal cord compression, or HCM.6 Analysis of SREs provides an objective measure of bisphosphonate treatment effects. Trials have used a variety of analytical methods for evaluating SREs that range from the conservative first-event analysis (i.e. percentage of patients with an SRE or time to first SRE) recommended by the United States Food and Drug Administration7,8 to a variety of analyses that take into account multiple events. Several bisphosphonates, both oral and intravenous (i.v.) have been investigated for the treatment of bone metastases in patients with advanced breast cancer, and some of them have been approved for this indication. These agents vary in terms of their relative potency, dose, and schedule (Table 1).9–12 Oral clodronate, a first-generation bisphosphonate, has demonstrated clinical benefit for the treatment of bone metastases compared with placebo, but this agent has low potency compared with that of newer bisphosphonates and must be administered at high daily doses that may cause gastrointestinal toxicity. Intravenous pamidronate, a second-generation, nitrogen-containing bisphosphonate, became the standard of care worldwide in the mid 1990s on the basis of results from 2 large, randomised trials demonstrating statistically significant reductions in the incidence of SREs and delay in time to first SRE compared with placebo.13,14 Subsequently, zoledronic acid, a newgeneration bisphosphonate, was shown to significantly reduce the risk of skeletal complications by an additional 20% compared with pamidronate and is the only modern bisphosphonate to be directly compared with an active agent.5 On the basis of these data, zoledronic acid, which can be adminis-
tered via 15-min infusion, has become the new standard of care for the treatment of bone metastases in patients with breast cancer. In addition, both i.v. and oral ibandronate were recently approved outside the United States for use in patients with breast cancer on the basis of results from placebo-controlled trials similar to the original trials of pamidronate.11,12
Bisphosphonate clinical trial endpoints Clinical trials investigating the treatment effects of bisphosphonates in patients with bone metastases from breast cancer have employed a variety of clinical endpoints. Unlike subjective measurements such as pain scores and quality-of-life assessments, measurement of SREs as a composite endpoint provides an unbiased and clinically relevant determination of skeletal complications, thereby allowing a clear assessment of the multifaceted clinical benefit of bisphosphonate therapy.6 The skeletal events that define SREs have a negative effect on quality of life and clinical outcome, and any treatment that prevents or delays these events would be beneficial. Evaluation of SREs can be accomplished through conservative or comprehensive analyses (Fig. 2).6 Statistically conservative analyses include such first-event analyses as proportion of patients with at least 1 SRE and time to first SRE. These endpoints are preferred by regulatory authorities, but do not provide a complete picture of skeletal morbidity because they do not take into account events that occur after the first event. Patients with breast cancer typically experience multiple events over time, and patients’ risk (and thus the rate of events) commonly increases with time as their
ARTICLE IN PRESS The role of bisphosphonates in breast cancer Table 1
S21
Bisphosphonates approved for patients with bone metastases from breast cancer.*
Bisphosphonate First generation Clodronate Second generation Pamidronate Ibandronatez,y New generation Zoledronic acid
Relative potencyy
Dose, mg
Schedule
Infusion time
1
1600–3200
Daily
Oral
20 857
90 6 50
Every 3–4 weeks Every 3–4 weeks Daily
2h 1–2 h Oral
16,700
4
Every 3–4 weeks
15 min
Note: Clodronate and ibandronate are not approved in the United States for the treatment of bone metastases. * Data from Lipton.9 y Data from Green et al.10 z y
Data from Body et al.11
Data from Body et al.12
Figure 2 Statistical assessments of skeletal-related events. SMR=Skeletal morbidity rate; SMPR=Skeletal morbidity period rate. Adapted with permission from Major PP, Cook R. Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 2002; 25(suppl 6): S10–S18.6
disease progresses. Therefore, analytical methods that capture skeletal events over time and thus provide a more comprehensive assessment of treatment effects have been employed to evaluate skeletal morbidity. These methods include skeletal morbidity rate (SMR; number of events per patient per year) or skeletal morbidity period rate (SMPR; number of periods with new skeletal complications per person divided by time on study), Poisson regression analysis, and multiple event analysis. Each of these analyses considers all events that occur throughout the study period. However, only multiple event analysis is able to account for the changing event rate over time. Analyses of SMR, SMPR, and Poisson regression assume a constant event rate and thus may not accurately reflect the true risk of skeletal complications over time, resulting potentially in overestimation of treat-
ment effects.15 Because these methods do not consider the timing of events, they are less robust analyses compared with multiple event methods such as those described by Andersen and Gill16 in a population of patients with varying lengths of follow-up and varying event rates. These analyses also do not account for the clustering of events in individual patients; therefore, outcomes are affected to a greater extent by outliers (e.g. patients with a large number of events relative to the mean). In contrast, multiple event analysis is a statistically robust method that accounts for all skeletal events and the timing of events throughout the course of the disease and provides the most sensitive measure of skeletal complications. Methods for multiple event analysis have been described by Andersen and Gill,16 Ghosh and Lin,17 Cook and Lawless,18 Prentice, Williams, and Peterson,19 and
ARTICLE IN PRESS S22 Wei, Lin, and Weissfeld.20 To further reduce potential bias by overcounting dependent events in individual patients, a time window during which each event is counted only once can be implemented in these analyses.5,21 Beginning in the early 1990s, clodronate trials in patients with bone metastases from breast cancer began to use composite endpoints. In these trials, skeletal events were defined as HCM, pathologic fracture, and radiation therapy for bone pain.22,23 Analyses used in these trials included SMR, percentage of patients with a skeletal event, and time to first skeletal event. Subsequently, the pamidronate and zoledronic acid trials used the formalised SRE endpoint, which was defined as pathologic fracture, spinal cord compression, radiation or surgery to bone, and HCM, for some analyses.4,5,13,14,24,25 The primary analysis used in these trials was percentage of patients with an SRE (not including HCM). Secondary analyses included time to first SRE and SMR (including HCM). However, the zoledronic acid trials were the only ones to use prospectively planned Andersen-Gill multiple event analysis.5,25 The ibandronate trials defined a bone event as pathologic fracture and radiation or surgery to bone.11,12 The primary endpoint in these trials was SMPR, and secondary endpoints were percentage of patients with a bone event, time to first bone event, and number of periods with a new bone event. A Poisson regression analysis was also applied to the ibandronate data.
R.E. Coleman
Clodronate Oral clodronate (1600 mg/day) has demonstrated significant clinical benefits compared with placebo or controls in patients with bone metastases from breast cancer in 2 randomised trials.22,23 In the first trial, 173 patients receiving clodronate for 18 months had significant reductions in SMR, incidence of vertebral fractures, and rate of vertebral deformity compared with patients receiving placebo (Po0.025).22 In addition, updated data analysis demonstrated that clodronate significantly delayed the time to first skeletal event compared with placebo (9.9 months versus 4.9 months for placebo; P=0.022).28 However, no first-event analysis was reported. In the second trial, 100 patients received either clodronate or no therapy for 2 years.23 This study demonstrated that in patients receiving clodronate, the time to first skeletal event was significantly delayed (P=0.015) and the incidence of fractures was significantly reduced (P=0.023) compared with controls. However, the effectiveness of clodronate was temporary; after 15 months, the need for radiation therapy for bone pain increased in the clodronate group compared with that in the control group. Studies have also demonstrated that treatment with daily oral clodronate (1600 mg) may inhibit the development of bone metastases in patients with early and advanced breast cancer without bone metastases.31–33 However, the data from these studies have not been adequately confirmed; therefore, oral bisphosphonates are not currently recommended for use in the preventive setting.
Analysis of clinical trials of bisphosphonates
Pamidronate
The significant clinical benefit of bisphosphonates in patients with bone metastases from breast cancer has been demonstrated in large, randomised trials using composite endpoints to capture objective data on skeletal complications (Table 24,5,11,21,26,27 and Table 312,22,23,28,29). The clinical benefits of bisphosphonate therapy include reduction in the incidence of skeletal complications, delay in the time to first SRE, and reduction of bone pain. Both i.v. and oral bisphosphonates have demonstrated significant clinical benefit in patients with bone metastases from breast cancer and are approved for this indication; however, studies of oral bisphosphonates have not demonstrated consistent, statistically significant improvements in the proportion of patients with skeletal complications.9 Furthermore, the use of oral bisphosphonates is complicated by poor gastrointestinal tolerability.30
In the mid-1990s, i.v. pamidronate (90 mg via 2-h infusion) was the international standard for the treatment of bone metastases in patients with breast cancer. Two long-term, randomised, placebo-controlled trials in this patient population have demonstrated that pamidronate significantly reduced the incidence of SREs and delayed the onset of SREs.4,13,14,24 Bone pain was also measured quantitatively in these studies. Both pamidronate trials enrolled patients with breast cancer who had at least 1 osteolytic bone lesion and were receiving either chemotherapy13 (protocol 19) or hormonal therapy14 (protocol 18). Patients in each study were treated with 90 mg pamidronate or placebo every 3–4 weeks for up to 24 months. In the group of patients receiving chemotherapy (N=382), pamidronate significantly reduced the percentage of patients with any SRE
ARTICLE IN PRESS The role of bisphosphonates in breast cancer Table 2 cancer.
S23
Clinical trial results for i.v. bisphosphonates in patients with bone metastases secondary to breast
Trial/Endpoint Rosen et al. 2003
Key clinical comparison 5
Patients with an SRE (%) Median time to first SRE (months) SMR (SREs/year) Multiple event analysis (risk ratio) Conte et al. 199626 Time to progressive disease in bone (days) Patients with marked pain reduction (%) Median time to first complication of bone metastases (days) Hultborn et al. 199927 Cumulative incidence of skeletal events Median time to first SRE (months) Lipton et al. 2000
4
Patients with an SRE (%) Median time to first SRE (months) SMR (SREs/year) Body et al. 200311 Patients with an SRE (%) Median time to first SRE (months) SMPR (intervals/year)
P-value
Zoledronic acid 4 mg (n=378*) 46 NR 0.91 0.799
Pamidronate 90 mg (n=388*) 49 NR 1.57 —
NS NS 0.102 0.025
Pamidronate 45 mg (n=143) 249
No bisphosphonate (n=152) 168
0.02
44
30
0.025
533
490
NS
Pamidronate 60 mg (n=201) 200
Placebo (n=203) 278
0.004
11.8
8.4
0.006
Pamidronate 90 mg (n=367) 51 12.7 2.4
Placebo (n=384) 64 7.0 3.7
o 0.001 o 0.001 o 0.001
Ibandronate 6 mg (n=154) 51 12.7 1.19
Placebo (n=158) 62 8.3 1.48
NS 0.018 0.004
i.v., Intravenous; SRE, Skeletal-related event; NS, Not significant; NR, Not reported; SMR, Skeletal morbidity rate; SMPR, Skeletal morbidity period rate. * Intent-to-treat population based on Rosen et al. 2004.21
compared with placebo at 15, 18, 21, and 24 months (Po0.001).13 Significant reductions were observed for each type of SRE, including nonvertebral pathologic fractures, radiation or surgery to bone, and HCM. Furthermore, the median time to first SRE was significantly prolonged in the pamidronate group (13.9 versus 7.0 months for placebo; Pp0.001). Pain scores were also significantly better in patients receiving pamidronate compared with placebo. After 2 years, significantly fewer patients in the pamidronate group reported an increased pain score from baseline (41% versus 55% for placebo; P=0.015). Similarly, in the group of patients receiving hormonal therapy (N=372), pamidronate significantly reduced the SMR at 12, 18, and 24 months.14 After 2 years of treatment, the
percentage of patients experiencing any SRE was significantly reduced in the pamidronate group compared with placebo (56% versus 67% for placebo; P=0.027). Pathologic fractures, radiation therapy for bone pain, and HCM were all significantly reduced. In addition, pamidronate significantly delayed the time to first SRE (median, 10.4 versus 6.9 months for the placebo group; P=0.049). This study also demonstrated a significant decrease in SMR for patients treated with pamidronate (2.4 versus 3.8 events/year; P=0.008) after 2 years of follow-up. Furthermore, significant improvement in mean pain scores was reported in patients receiving pamidronate compared with placebo. During the first year of therapy, there was a significant difference between the 2 treatment groups, with
ARTICLE IN PRESS S24
R.E. Coleman
Table 3 cancer.
Clinical trial results for oral bisphosphonates in patients with bone metastases secondary to breast
Trial/Endpoint
Key clinical comparison
Paterson et al. 199322
Clodronate 1600 mg (n=85) 218.6 84 168 9.9
Placebo (n=88) 304.8 124 252 4.9
o0.001 o0.025 o0.001 0.022
Clodronate 1600 mg (n=49) 28.6 NR
No drug (n=51) 41.2 NR
NS 0.015
Clodronate 1600 mg (n=69) 244
Placebo (n=68) 180
0.05
Ibandronate 50 mg (n=287) 45.3 22.5 0.95 0.62
Placebo (n=277) 52.2 16.2 1.18 —
NS NS 0.004 o0.0001
Mean SMR (events/100 patient years) Vertebral fractures/100 patient years Vertebral deformity/100 patient years Median time to first skeletal event* (months)28 Kristensen et al. 199923 Patients with a skeletal event (%) Time to first skeletal event Tubiana-Hulin et al. 200129 Median time to first bone event (days) Body et al. 2004
12
Patients with new bone event (%) Median time to new bone event (months) Mean SMPR Poisson regression (risk ratio)
P-value
SMR, Skeletal morbidity rate; NS, Not significant; NR, Not reported; SMPR, Skeletal morbidity period rate. * Updated analysis based on 185 patients (intent to treat).
pain scores improving from baseline in the pamidronate group and worsening in the placebo group (P=0.002). In the second year, pain scores worsened in both treatment groups, but patients in the pamidronate group had significantly less pain compared with the placebo group (P=0.007). A pooled analysis of these 2 trials confirmed the statistically significant treatment benefits of pamidronate patients with bone metastases from breast cancer.4 Pamidronate significantly reduced the SMR, percentage of patients experiencing an SRE, and time to first SRE; significant differences were demonstrated for any SRE, pathologic fracture, and radiation therapy (Po0.005). Moreover, analysis of bone lesion response demonstrated that a higher percentage of patients treated with pamidronate had either a complete or partial response in bone compared with patients in the placebo group (32% versus 22%; P=0.002).
Zoledronic acid The efficacy of i.v. zoledronic acid for the treatment of breast cancer patients with bone metastases was investigated in a large, randomised, controlled, phase III trial.5,25 This was a noninferiority trial directly comparing zoledronic acid with
pamidronate, and included patients with bone lesions associated with breast cancer or multiple myeloma. The same conservative clinical endpoints used to demonstrate the clinical activity of pamidronate were also employed in the zoledronic acid trial. However, a preplanned multiple event analysis using the Andersen-Gill method16 was also included to provide a comprehensive assessment of skeletal complications based on all SREs and the timing of events. This trial demonstrated that 4 mg zoledronic acid was at least as effective as 90 mg pamidronate in the overall patient population.5,25 In addition, zoledronic acid demonstrated evidence of superiority over pamidronate in the breast cancer subset and is now considered the gold standard.5,21 Breast cancer subset A total of 766 breast cancer patients with bone metastases were randomised to zoledronic acid (4 mg via 15-min infusion) or pamidronate (90 mg via 2-h infusion) every 3–4 weeks for 12 months with analysis of SREs over 13 months.5,21,25 Patients could then elect to continue study treatment for an additional 12-month extension phase. Approximately equal proportions of patients were being treated with chemotherapy and hormonal therapy. Importantly, the majority of patients (60%) had
ARTICLE IN PRESS The role of bisphosphonates in breast cancer
S25
Figure 3 Percentage of patients with at least 1 skeletal-related event (excluding hypercalcaemia of malignancy) in breast cancer patients treated with either 4 mg zoledronic acid versus 90 mg pamidronate or 90 mg pamidronate versus placebo. Intent-to-treat population. Data from Lipton et al.4 and Rosen et al.5 Used with permission from Allan Lipton, MD.34
experienced an SRE before study entry and were therefore at high risk for subsequent SREs. After 25 months of follow-up, the percentage of patients with breast cancer who experienced at least 1 SRE (not including HCM) in the zoledronic acid and pamidronate treatment groups was similar (46% versus 49%, respectively). These results correspond closely to the results of the original placebocontrolled trials of pamidronate in which 51% of patients receiving pamidronate had an SRE (not including HCM) compared with 64% of patients in the placebo group (Fig. 3).4,5,34 Zoledronic acid consistently reduced the percentage of patients with each type of SRE, and zoledronic acid significantly reduced the percentage of patients requiring radiation to bone compared with patients receiving pamidronate (19% versus 27% for pamidronate; P=0.011).35 Zoledronic acid also reduced the annual incidence of SREs by 42% compared with pamidronate (0.91 versus 1.57 events/year, respectively; P=0.102). Multiple event analysis showed that zoledronic acid significantly reduced the risk of SREs by an additional 20% of the reduction achieved with pamidronate (P=0.025), and by an additional 30% in the subsets of patients with breast cancer receiving hormonal therapy (P=0.009) and those with at least 1 osteolytic lesion (P=0.01).5,21 Furthermore, results from a survivaladjusted multiple event analysis that accounts for patient mortality demonstrated that zoledronic acid consistently reduced the cumulative incidence of SREs compared with pamidronate throughout the course of the trial (P=0.046).36 Therefore, zoledronic acid has been shown to reduce skeletal
complications more effectively than pamidronate in the only direct comparison of 2 clinically active i.v. bisphosphonates in patients with breast cancer. Safety In this trial, the overall safety profile of zoledronic acid was similar to that of pamidronate.5,21 In the breast cancer subset, the most commonly reported adverse events were bone pain, nausea, and fatigue, and the occurrence of these events was similar between treatment groups. Zoledronic acid (4 mg via 15-min infusion) also demonstrated a renal safety profile similar to that of pamidronate (90 mg via 2-h infusion); 9.4% of breast cancer patients receiving zoledronic acid and 6.5% of breast cancer patients receiving pamidronate had a notable increase in serum creatinine (defined as an increase X0.5 mg/dl for patients with normal baseline serum creatinine [o1.4 mg/dL], an increase X1.0 mg/dl for patients with abnormal baseline serum creatinine [X1.4 mg/dl], or X2 times baseline value).37 In addition, the time to first notable increase in serum creatinine was not significantly different between treatment groups, and only 1 patient (in the pamidronate group) developed National Cancer Institute Common Toxicity Criteria grade 3 or 4 serum creatinine over 24 months of therapy.
Ibandronate Ibandronate, both oral and i.v. formulations, has recently received approval only in Europe for the
ARTICLE IN PRESS S26 treatment of bone metastases in patients with breast cancer, based on results from randomised trials comparing oral ibandronate (50 mg) or i.v. ibandronate (2 or 6 mg) with placebo.11,12 Analysis of 2 pooled studies in 564 patients with bone metastases from breast cancer demonstrated that oral ibandronate (50 mg/day for up to 96 weeks) significantly reduced the time-adjusted SMPR (defined as the number of 12-week periods with a new bone event divided by time on study) compared with placebo (P=0.004), primarily because of significant reductions in the need for radiotherapy (Po0.001) or surgery (P=0.037).12 This analysis was complicated by a decision to exclude events in the first 3-month period and to include events after withdrawal from study. No significant differences between ibandronate and placebo were noted in the number of skeletal fractures. Poisson regression analysis demonstrated a significant reduction in the risk of developing a skeletal event with oral ibandronate therapy compared with placebo (Po0.0001). However, oral ibandronate did not significantly reduce the percentage of patients with a new bone event or delay the time to first bone event compared with placebo. Additional randomised trials are needed to establish the clinical benefit of oral ibandronate in comparison to other licensed bisphosphonates. The incidence of drugrelated adverse events was slightly higher with ibandronate (26.6%) than with placebo (17.7%). In addition, the incidence of treatment-related upper gastrointestinal adverse events (dyspepsia, nausea, and oesophagitis) was nearly 2-fold higher in the ibandronate group (12.5% versus 6.9% for placebo). The efficacy of i.v. ibandronate has also been investigated in a randomised, placebo-controlled trial. In this study, 466 patients with bone metastases from breast cancer received i.v. ibandronate (2 or 6 mg via 1- to 2-h infusion) or placebo every 3–4 weeks for up to 2 years. Ibandronate (6 mg) significantly reduced the SMPR (P=0.004) and number of new bone events per patient (P=0.032) and significantly increased mean time to first bone event (P=0.018) compared with placebo.11 The percentage of patients with a new bone event was reduced in the 6-mg ibandronate group compared with placebo, but this difference did not reach statistical significance. In contrast, the 2mg dose was not effective. Notably, however, neither i.v. nor oral ibandronate have been compared directly with either i.v. pamidronate or zoledronic acid in a randomised trial; therefore, it is not possible to make efficacy comparisons between these bisphosphonates. In this trial, i.v. ibandronate (6 mg via 1- to 2-h infusion) demonstrated a renal safety profile
R.E. Coleman similar to that of placebo. Over 2 years, the incidence of renal adverse events was similar between treatment groups (4.5% for ibandronate versus 4% for placebo).38 Notable serum creatinine increases (defined as an increase X0.5 mg/dl for patients if baseline serum creatinine waso1.4 mg/ dl, an increase X1.0 mg/dl if baseline serum creatinine was X1.4 mg/dl, or X2 times baseline value) were reported in 4% of patients after 1 year and in 6% after 2 years of ibandronate treatment compared with 6% for placebo at years 1 and 2.39
Conclusions The development of highly potent i.v. bisphosphonates has expanded the role of bisphosphonates in the management of malignant bone disease, increasing both efficacy and convenience over that of early generation oral bisphosphonates. Using SREs as composite endpoints in clinical trials has provided clinically relevant and objective measures of the effect of bisphosphonates in patients with bone metastases from cancer. Firstevent analysis of SREs provides statistically conservative evidence, whereas more robust methodology, such as multiple event analysis, considers that patients typically experience multiple skeletal complications over time. Several randomised trials have indicated that i.v. bisphosphonates are the most effective intervention for patients with bone metastases, and zoledronic acid is more effective and convenient than pamidronate in patients with breast cancer. Other bisphosphonates have not been compared with pamidronate; thus, their relative effectiveness is not known. The available evidence also indicates that long-term treatment with i.v. bisphosphonate therapy is well tolerated, with patients experiencing only mild adverse events and few instances of decreased renal function. Consequently, the American Society of Clinical Oncology has recommended i.v. bisphosphonate therapy with either 90 mg pamidronate or 4 mg zoledronic acid every 3–4 weeks for any patient with breast cancer and radiographic evidence of bone destruction.
References 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide, version 1.0. IARC CancerBase No. 5. Lyon: IARCPress; 2001: Accessed 2004.
ARTICLE IN PRESS The role of bisphosphonates in breast cancer 2. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165–76. 3. Coleman RE. Skeletal complications of malignancy. Cancer 1997;80(suppl):1588–94. 4. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082–90. 5. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735–44. 6. Major PP, Cook R. Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 2002; 25(suppl 1):S10–8. 7. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003;21:1404–11. 8. Williams G, Pazdur R, Temple R. Assessing tumor-related signs and symptoms to support cancer drug approval. J Biopharm Stat 2004;14:5–21. 9. Lipton A. Management of metastatic bone disease and hypercalcemia of malignancy. Am J Cancer 2003;2:427–38. 10. Green JR, Mu ¨ller K, Jaeggi KA. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994;9:745–51. 11. Body J-J, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399–405. 12. Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133–7. 13. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998;16:2038–44. 14. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebocontrolled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846–54. 15. Cook RJ, Major P. Methodology for treatment evaluation in patients with cancer metastatic to bone. J Natl Cancer Inst 2001;93:534–8. 16. Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. Ann Stat 1982;10:1100–20. 17. Ghosh D, Lin DY. Nonparametric analysis of recurrent events and death. Biometrics 2000;56:554–62. 18. Cook RJ, Lawless JF. Marginal analysis of recurrent events and a terminating event. Stat Med 1997;16:911–24. 19. Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika 1981;68:373–9. 20. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Amer Stat Assoc 1989;84:1065–73. 21. Rosen LS, Gordon DH, Dugan Jr W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone
S27
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36–43. Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59–65. Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H, Mouridsen HT. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999; 246:67–74. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:1785–91. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377–87. Conte PF, Latreille J, Mauriac L, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group. J Clin Oncol 1996;14: 2552–9. Hultborn R, Gundersen S, Ryden S, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebo-controlled multicenter study. Anticancer Res 1999;19:3383–92. Pavlakis N, Stockler M. Bisphosphonates for breast cancer (Cochrane Review). In: The Cochrane Library, Issue 1. Hoboken, NJ: Wiley, 2004. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al. [Double-blind controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases]. Bull Cancer 2001;88:701–7. Major PP, Lipton A, Berenson J, Hortobagyi G. Oral bisphosphonates: a review of clinical use in patients with bone metastases. Cancer 2000;88:6–14. Diel IJ, Solomayer E-F, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–63. Powles T, Paterson S, Kanis JA, et al. Randomized, placebocontrolled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–24. Kanis JA, Powles T, Paterson AH, McCloskey EV, Ashley S. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996;19:663–7. Lipton A. Bisphosphonate therapy for patients with osteolytic and osteoblastic bone metastases from breast or prostate cancer. Progress in Breast Cancer Research Hauppauge, NY: Nova Science Publishers, Inc; submitted. Rosen LS, Coleman RE, Gordon D, et al. Zoledronic acid is superior to pamidronate in patients with breast cancer and bone metastases. Presented at: St. Gallen Oncology Conferences: Primary Therapy of Early Breast Cancer 8th International Conference; March 12–15, 2003; St. Gallen, Switzerland (poster 100). Major PP, Cook RJ, Chen B-L, Zheng M. Multiple event analysis of zoledronic acid trials in patients with cancer metastatic to bone. Proc Am Soc Clin Oncol 2003;22:762 (abstract 3062). Lipton A, Dewar R, Conte PF, Zheng M. Long-term safety of zoledronic acid for the treatment of patients with breast cancer and bone metastases. Presented at: 4th European
ARTICLE IN PRESS S28 Breast Cancer Conference; March 16–19, 2004; Hamburg, Germany (poster 296). 38. Diel I, Body J-J, Bergstro ¨m B. Low nephrotoxicity of Ibandronate: evidence from clinical trials in metastatic bone disease. Bone 2004;34:S77 (abstract 53).
R.E. Coleman 39. Bell R, Body J-J, Tripathy D, Bergstro ¨m B. Ibandronate does not affect time to renal function deterioration over 2 years of treatment: phase III trial results. Bone 2004;34:S75 (abstract 49).
THE
BREAST www.elsevier.com/locate/breast
The role of bisphosphonates in breast cancer Robert E. Coleman Cancer Research Centre, YCR Academic Unit of Oncology, Weston Park Hospital, Sheffield, S10 2SJ, UK
KEYWORDS Skeletal complications; Long-term continuing benefit; Zoledronic acid
Summary Patients with bone metastases from breast cancer are at high risk for debilitating skeletal complications. Bisphosphonates are effective inhibitors of tumour-induced bone resorption and significantly reduce the risk of skeletal complications in these patients. Several bisphosphonates have been investigated for the treatment of bone metastases in patients with breast cancer, including clodronate, pamidronate, ibandronate, and zoledronic acid. Among these agents, intravenous pamidronate and zoledronic acid have demonstrated the greatest clinical benefit based on conservative endpoints. Zoledronic acid is the only agent to be compared with another active bisphosphonate and has been shown to significantly reduce the risk of skeletal complications compared with pamidronate. On the basis of these results, zoledronic acid has rapidly become the new international standard of care for patients with bone metastases from breast cancer. & 2004 Elsevier Ltd. All rights reserved.
Introduction Annually, approximately 1 million women worldwide are diagnosed with breast cancer,1 and among the patients who progress to advanced disease, 65–75% will develop bone metastases.2,3 Tumourinduced bone resorption in these patients increases their risk of developing pathologic fractures and other skeletal complications, including debilitating bone pain, spinal cord compression, and hypercalcaemia of malignancy (HCM).3 Without bisphosphonate therapy, the vast majority (nearly 70%) of patients with bone metastases from breast cancer will experience 1 or more of these skeletal complications during the course of their disease, Tel.: +44 114 2265213; Fax: +44 114 2265678
E-mail address: [email protected] (R.E. Coleman).
with approximately 50% developing pathologic fractures and 40% requiring palliative radiation therapy (Fig. 1).4 Furthermore, because these patients have a long median survival after diagnosis of bone metastasis (approximately 2–3 years), they often suffer from clinically significant cumulative skeletal complications over a long period of time, resulting in dramatic effects on quality of life.2,3 Bisphosphonates are effective inhibitors of tumour-induced bone resorption and significantly reduce the incidence of skeletal complications in patients with bone metastases from breast cancer.4,5 Consequently, bisphosphonate therapy is the standard of care for the treatment of such patients. A variety of clinical trial endpoints have been used to assess skeletal complications and the treatment effects of bisphosphonates. The majority of trials have used a composite endpoint, defined as a
0960-9776/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2004.09.004
ARTICLE IN PRESS S20
R.E. Coleman
Figure 1 Percentage of patients with at least 1 skeletal-related event in the placebo group of 2 pooled pamidronate trials after 2 years of follow-up. SRE, Skeletal-related event; HCM, Hypercalcaemia of malignancy. Data from Lipton et al.4
skeletal-related event (SRE) or bone event, which includes complications such as pathologic fracture, radiation to bone to palliate bone pain or prevent impending fractures, surgery to bone to prevent or treat fractures, spinal cord compression, or HCM.6 Analysis of SREs provides an objective measure of bisphosphonate treatment effects. Trials have used a variety of analytical methods for evaluating SREs that range from the conservative first-event analysis (i.e. percentage of patients with an SRE or time to first SRE) recommended by the United States Food and Drug Administration7,8 to a variety of analyses that take into account multiple events. Several bisphosphonates, both oral and intravenous (i.v.) have been investigated for the treatment of bone metastases in patients with advanced breast cancer, and some of them have been approved for this indication. These agents vary in terms of their relative potency, dose, and schedule (Table 1).9–12 Oral clodronate, a first-generation bisphosphonate, has demonstrated clinical benefit for the treatment of bone metastases compared with placebo, but this agent has low potency compared with that of newer bisphosphonates and must be administered at high daily doses that may cause gastrointestinal toxicity. Intravenous pamidronate, a second-generation, nitrogen-containing bisphosphonate, became the standard of care worldwide in the mid 1990s on the basis of results from 2 large, randomised trials demonstrating statistically significant reductions in the incidence of SREs and delay in time to first SRE compared with placebo.13,14 Subsequently, zoledronic acid, a newgeneration bisphosphonate, was shown to significantly reduce the risk of skeletal complications by an additional 20% compared with pamidronate and is the only modern bisphosphonate to be directly compared with an active agent.5 On the basis of these data, zoledronic acid, which can be adminis-
tered via 15-min infusion, has become the new standard of care for the treatment of bone metastases in patients with breast cancer. In addition, both i.v. and oral ibandronate were recently approved outside the United States for use in patients with breast cancer on the basis of results from placebo-controlled trials similar to the original trials of pamidronate.11,12
Bisphosphonate clinical trial endpoints Clinical trials investigating the treatment effects of bisphosphonates in patients with bone metastases from breast cancer have employed a variety of clinical endpoints. Unlike subjective measurements such as pain scores and quality-of-life assessments, measurement of SREs as a composite endpoint provides an unbiased and clinically relevant determination of skeletal complications, thereby allowing a clear assessment of the multifaceted clinical benefit of bisphosphonate therapy.6 The skeletal events that define SREs have a negative effect on quality of life and clinical outcome, and any treatment that prevents or delays these events would be beneficial. Evaluation of SREs can be accomplished through conservative or comprehensive analyses (Fig. 2).6 Statistically conservative analyses include such first-event analyses as proportion of patients with at least 1 SRE and time to first SRE. These endpoints are preferred by regulatory authorities, but do not provide a complete picture of skeletal morbidity because they do not take into account events that occur after the first event. Patients with breast cancer typically experience multiple events over time, and patients’ risk (and thus the rate of events) commonly increases with time as their
ARTICLE IN PRESS The role of bisphosphonates in breast cancer Table 1
S21
Bisphosphonates approved for patients with bone metastases from breast cancer.*
Bisphosphonate First generation Clodronate Second generation Pamidronate Ibandronatez,y New generation Zoledronic acid
Relative potencyy
Dose, mg
Schedule
Infusion time
1
1600–3200
Daily
Oral
20 857
90 6 50
Every 3–4 weeks Every 3–4 weeks Daily
2h 1–2 h Oral
16,700
4
Every 3–4 weeks
15 min
Note: Clodronate and ibandronate are not approved in the United States for the treatment of bone metastases. * Data from Lipton.9 y Data from Green et al.10 z y
Data from Body et al.11
Data from Body et al.12
Figure 2 Statistical assessments of skeletal-related events. SMR=Skeletal morbidity rate; SMPR=Skeletal morbidity period rate. Adapted with permission from Major PP, Cook R. Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 2002; 25(suppl 6): S10–S18.6
disease progresses. Therefore, analytical methods that capture skeletal events over time and thus provide a more comprehensive assessment of treatment effects have been employed to evaluate skeletal morbidity. These methods include skeletal morbidity rate (SMR; number of events per patient per year) or skeletal morbidity period rate (SMPR; number of periods with new skeletal complications per person divided by time on study), Poisson regression analysis, and multiple event analysis. Each of these analyses considers all events that occur throughout the study period. However, only multiple event analysis is able to account for the changing event rate over time. Analyses of SMR, SMPR, and Poisson regression assume a constant event rate and thus may not accurately reflect the true risk of skeletal complications over time, resulting potentially in overestimation of treat-
ment effects.15 Because these methods do not consider the timing of events, they are less robust analyses compared with multiple event methods such as those described by Andersen and Gill16 in a population of patients with varying lengths of follow-up and varying event rates. These analyses also do not account for the clustering of events in individual patients; therefore, outcomes are affected to a greater extent by outliers (e.g. patients with a large number of events relative to the mean). In contrast, multiple event analysis is a statistically robust method that accounts for all skeletal events and the timing of events throughout the course of the disease and provides the most sensitive measure of skeletal complications. Methods for multiple event analysis have been described by Andersen and Gill,16 Ghosh and Lin,17 Cook and Lawless,18 Prentice, Williams, and Peterson,19 and
ARTICLE IN PRESS S22 Wei, Lin, and Weissfeld.20 To further reduce potential bias by overcounting dependent events in individual patients, a time window during which each event is counted only once can be implemented in these analyses.5,21 Beginning in the early 1990s, clodronate trials in patients with bone metastases from breast cancer began to use composite endpoints. In these trials, skeletal events were defined as HCM, pathologic fracture, and radiation therapy for bone pain.22,23 Analyses used in these trials included SMR, percentage of patients with a skeletal event, and time to first skeletal event. Subsequently, the pamidronate and zoledronic acid trials used the formalised SRE endpoint, which was defined as pathologic fracture, spinal cord compression, radiation or surgery to bone, and HCM, for some analyses.4,5,13,14,24,25 The primary analysis used in these trials was percentage of patients with an SRE (not including HCM). Secondary analyses included time to first SRE and SMR (including HCM). However, the zoledronic acid trials were the only ones to use prospectively planned Andersen-Gill multiple event analysis.5,25 The ibandronate trials defined a bone event as pathologic fracture and radiation or surgery to bone.11,12 The primary endpoint in these trials was SMPR, and secondary endpoints were percentage of patients with a bone event, time to first bone event, and number of periods with a new bone event. A Poisson regression analysis was also applied to the ibandronate data.
R.E. Coleman
Clodronate Oral clodronate (1600 mg/day) has demonstrated significant clinical benefits compared with placebo or controls in patients with bone metastases from breast cancer in 2 randomised trials.22,23 In the first trial, 173 patients receiving clodronate for 18 months had significant reductions in SMR, incidence of vertebral fractures, and rate of vertebral deformity compared with patients receiving placebo (Po0.025).22 In addition, updated data analysis demonstrated that clodronate significantly delayed the time to first skeletal event compared with placebo (9.9 months versus 4.9 months for placebo; P=0.022).28 However, no first-event analysis was reported. In the second trial, 100 patients received either clodronate or no therapy for 2 years.23 This study demonstrated that in patients receiving clodronate, the time to first skeletal event was significantly delayed (P=0.015) and the incidence of fractures was significantly reduced (P=0.023) compared with controls. However, the effectiveness of clodronate was temporary; after 15 months, the need for radiation therapy for bone pain increased in the clodronate group compared with that in the control group. Studies have also demonstrated that treatment with daily oral clodronate (1600 mg) may inhibit the development of bone metastases in patients with early and advanced breast cancer without bone metastases.31–33 However, the data from these studies have not been adequately confirmed; therefore, oral bisphosphonates are not currently recommended for use in the preventive setting.
Analysis of clinical trials of bisphosphonates
Pamidronate
The significant clinical benefit of bisphosphonates in patients with bone metastases from breast cancer has been demonstrated in large, randomised trials using composite endpoints to capture objective data on skeletal complications (Table 24,5,11,21,26,27 and Table 312,22,23,28,29). The clinical benefits of bisphosphonate therapy include reduction in the incidence of skeletal complications, delay in the time to first SRE, and reduction of bone pain. Both i.v. and oral bisphosphonates have demonstrated significant clinical benefit in patients with bone metastases from breast cancer and are approved for this indication; however, studies of oral bisphosphonates have not demonstrated consistent, statistically significant improvements in the proportion of patients with skeletal complications.9 Furthermore, the use of oral bisphosphonates is complicated by poor gastrointestinal tolerability.30
In the mid-1990s, i.v. pamidronate (90 mg via 2-h infusion) was the international standard for the treatment of bone metastases in patients with breast cancer. Two long-term, randomised, placebo-controlled trials in this patient population have demonstrated that pamidronate significantly reduced the incidence of SREs and delayed the onset of SREs.4,13,14,24 Bone pain was also measured quantitatively in these studies. Both pamidronate trials enrolled patients with breast cancer who had at least 1 osteolytic bone lesion and were receiving either chemotherapy13 (protocol 19) or hormonal therapy14 (protocol 18). Patients in each study were treated with 90 mg pamidronate or placebo every 3–4 weeks for up to 24 months. In the group of patients receiving chemotherapy (N=382), pamidronate significantly reduced the percentage of patients with any SRE
ARTICLE IN PRESS The role of bisphosphonates in breast cancer Table 2 cancer.
S23
Clinical trial results for i.v. bisphosphonates in patients with bone metastases secondary to breast
Trial/Endpoint Rosen et al. 2003
Key clinical comparison 5
Patients with an SRE (%) Median time to first SRE (months) SMR (SREs/year) Multiple event analysis (risk ratio) Conte et al. 199626 Time to progressive disease in bone (days) Patients with marked pain reduction (%) Median time to first complication of bone metastases (days) Hultborn et al. 199927 Cumulative incidence of skeletal events Median time to first SRE (months) Lipton et al. 2000
4
Patients with an SRE (%) Median time to first SRE (months) SMR (SREs/year) Body et al. 200311 Patients with an SRE (%) Median time to first SRE (months) SMPR (intervals/year)
P-value
Zoledronic acid 4 mg (n=378*) 46 NR 0.91 0.799
Pamidronate 90 mg (n=388*) 49 NR 1.57 —
NS NS 0.102 0.025
Pamidronate 45 mg (n=143) 249
No bisphosphonate (n=152) 168
0.02
44
30
0.025
533
490
NS
Pamidronate 60 mg (n=201) 200
Placebo (n=203) 278
0.004
11.8
8.4
0.006
Pamidronate 90 mg (n=367) 51 12.7 2.4
Placebo (n=384) 64 7.0 3.7
o 0.001 o 0.001 o 0.001
Ibandronate 6 mg (n=154) 51 12.7 1.19
Placebo (n=158) 62 8.3 1.48
NS 0.018 0.004
i.v., Intravenous; SRE, Skeletal-related event; NS, Not significant; NR, Not reported; SMR, Skeletal morbidity rate; SMPR, Skeletal morbidity period rate. * Intent-to-treat population based on Rosen et al. 2004.21
compared with placebo at 15, 18, 21, and 24 months (Po0.001).13 Significant reductions were observed for each type of SRE, including nonvertebral pathologic fractures, radiation or surgery to bone, and HCM. Furthermore, the median time to first SRE was significantly prolonged in the pamidronate group (13.9 versus 7.0 months for placebo; Pp0.001). Pain scores were also significantly better in patients receiving pamidronate compared with placebo. After 2 years, significantly fewer patients in the pamidronate group reported an increased pain score from baseline (41% versus 55% for placebo; P=0.015). Similarly, in the group of patients receiving hormonal therapy (N=372), pamidronate significantly reduced the SMR at 12, 18, and 24 months.14 After 2 years of treatment, the
percentage of patients experiencing any SRE was significantly reduced in the pamidronate group compared with placebo (56% versus 67% for placebo; P=0.027). Pathologic fractures, radiation therapy for bone pain, and HCM were all significantly reduced. In addition, pamidronate significantly delayed the time to first SRE (median, 10.4 versus 6.9 months for the placebo group; P=0.049). This study also demonstrated a significant decrease in SMR for patients treated with pamidronate (2.4 versus 3.8 events/year; P=0.008) after 2 years of follow-up. Furthermore, significant improvement in mean pain scores was reported in patients receiving pamidronate compared with placebo. During the first year of therapy, there was a significant difference between the 2 treatment groups, with
ARTICLE IN PRESS S24
R.E. Coleman
Table 3 cancer.
Clinical trial results for oral bisphosphonates in patients with bone metastases secondary to breast
Trial/Endpoint
Key clinical comparison
Paterson et al. 199322
Clodronate 1600 mg (n=85) 218.6 84 168 9.9
Placebo (n=88) 304.8 124 252 4.9
o0.001 o0.025 o0.001 0.022
Clodronate 1600 mg (n=49) 28.6 NR
No drug (n=51) 41.2 NR
NS 0.015
Clodronate 1600 mg (n=69) 244
Placebo (n=68) 180
0.05
Ibandronate 50 mg (n=287) 45.3 22.5 0.95 0.62
Placebo (n=277) 52.2 16.2 1.18 —
NS NS 0.004 o0.0001
Mean SMR (events/100 patient years) Vertebral fractures/100 patient years Vertebral deformity/100 patient years Median time to first skeletal event* (months)28 Kristensen et al. 199923 Patients with a skeletal event (%) Time to first skeletal event Tubiana-Hulin et al. 200129 Median time to first bone event (days) Body et al. 2004
12
Patients with new bone event (%) Median time to new bone event (months) Mean SMPR Poisson regression (risk ratio)
P-value
SMR, Skeletal morbidity rate; NS, Not significant; NR, Not reported; SMPR, Skeletal morbidity period rate. * Updated analysis based on 185 patients (intent to treat).
pain scores improving from baseline in the pamidronate group and worsening in the placebo group (P=0.002). In the second year, pain scores worsened in both treatment groups, but patients in the pamidronate group had significantly less pain compared with the placebo group (P=0.007). A pooled analysis of these 2 trials confirmed the statistically significant treatment benefits of pamidronate patients with bone metastases from breast cancer.4 Pamidronate significantly reduced the SMR, percentage of patients experiencing an SRE, and time to first SRE; significant differences were demonstrated for any SRE, pathologic fracture, and radiation therapy (Po0.005). Moreover, analysis of bone lesion response demonstrated that a higher percentage of patients treated with pamidronate had either a complete or partial response in bone compared with patients in the placebo group (32% versus 22%; P=0.002).
Zoledronic acid The efficacy of i.v. zoledronic acid for the treatment of breast cancer patients with bone metastases was investigated in a large, randomised, controlled, phase III trial.5,25 This was a noninferiority trial directly comparing zoledronic acid with
pamidronate, and included patients with bone lesions associated with breast cancer or multiple myeloma. The same conservative clinical endpoints used to demonstrate the clinical activity of pamidronate were also employed in the zoledronic acid trial. However, a preplanned multiple event analysis using the Andersen-Gill method16 was also included to provide a comprehensive assessment of skeletal complications based on all SREs and the timing of events. This trial demonstrated that 4 mg zoledronic acid was at least as effective as 90 mg pamidronate in the overall patient population.5,25 In addition, zoledronic acid demonstrated evidence of superiority over pamidronate in the breast cancer subset and is now considered the gold standard.5,21 Breast cancer subset A total of 766 breast cancer patients with bone metastases were randomised to zoledronic acid (4 mg via 15-min infusion) or pamidronate (90 mg via 2-h infusion) every 3–4 weeks for 12 months with analysis of SREs over 13 months.5,21,25 Patients could then elect to continue study treatment for an additional 12-month extension phase. Approximately equal proportions of patients were being treated with chemotherapy and hormonal therapy. Importantly, the majority of patients (60%) had
ARTICLE IN PRESS The role of bisphosphonates in breast cancer
S25
Figure 3 Percentage of patients with at least 1 skeletal-related event (excluding hypercalcaemia of malignancy) in breast cancer patients treated with either 4 mg zoledronic acid versus 90 mg pamidronate or 90 mg pamidronate versus placebo. Intent-to-treat population. Data from Lipton et al.4 and Rosen et al.5 Used with permission from Allan Lipton, MD.34
experienced an SRE before study entry and were therefore at high risk for subsequent SREs. After 25 months of follow-up, the percentage of patients with breast cancer who experienced at least 1 SRE (not including HCM) in the zoledronic acid and pamidronate treatment groups was similar (46% versus 49%, respectively). These results correspond closely to the results of the original placebocontrolled trials of pamidronate in which 51% of patients receiving pamidronate had an SRE (not including HCM) compared with 64% of patients in the placebo group (Fig. 3).4,5,34 Zoledronic acid consistently reduced the percentage of patients with each type of SRE, and zoledronic acid significantly reduced the percentage of patients requiring radiation to bone compared with patients receiving pamidronate (19% versus 27% for pamidronate; P=0.011).35 Zoledronic acid also reduced the annual incidence of SREs by 42% compared with pamidronate (0.91 versus 1.57 events/year, respectively; P=0.102). Multiple event analysis showed that zoledronic acid significantly reduced the risk of SREs by an additional 20% of the reduction achieved with pamidronate (P=0.025), and by an additional 30% in the subsets of patients with breast cancer receiving hormonal therapy (P=0.009) and those with at least 1 osteolytic lesion (P=0.01).5,21 Furthermore, results from a survivaladjusted multiple event analysis that accounts for patient mortality demonstrated that zoledronic acid consistently reduced the cumulative incidence of SREs compared with pamidronate throughout the course of the trial (P=0.046).36 Therefore, zoledronic acid has been shown to reduce skeletal
complications more effectively than pamidronate in the only direct comparison of 2 clinically active i.v. bisphosphonates in patients with breast cancer. Safety In this trial, the overall safety profile of zoledronic acid was similar to that of pamidronate.5,21 In the breast cancer subset, the most commonly reported adverse events were bone pain, nausea, and fatigue, and the occurrence of these events was similar between treatment groups. Zoledronic acid (4 mg via 15-min infusion) also demonstrated a renal safety profile similar to that of pamidronate (90 mg via 2-h infusion); 9.4% of breast cancer patients receiving zoledronic acid and 6.5% of breast cancer patients receiving pamidronate had a notable increase in serum creatinine (defined as an increase X0.5 mg/dl for patients with normal baseline serum creatinine [o1.4 mg/dL], an increase X1.0 mg/dl for patients with abnormal baseline serum creatinine [X1.4 mg/dl], or X2 times baseline value).37 In addition, the time to first notable increase in serum creatinine was not significantly different between treatment groups, and only 1 patient (in the pamidronate group) developed National Cancer Institute Common Toxicity Criteria grade 3 or 4 serum creatinine over 24 months of therapy.
Ibandronate Ibandronate, both oral and i.v. formulations, has recently received approval only in Europe for the
ARTICLE IN PRESS S26 treatment of bone metastases in patients with breast cancer, based on results from randomised trials comparing oral ibandronate (50 mg) or i.v. ibandronate (2 or 6 mg) with placebo.11,12 Analysis of 2 pooled studies in 564 patients with bone metastases from breast cancer demonstrated that oral ibandronate (50 mg/day for up to 96 weeks) significantly reduced the time-adjusted SMPR (defined as the number of 12-week periods with a new bone event divided by time on study) compared with placebo (P=0.004), primarily because of significant reductions in the need for radiotherapy (Po0.001) or surgery (P=0.037).12 This analysis was complicated by a decision to exclude events in the first 3-month period and to include events after withdrawal from study. No significant differences between ibandronate and placebo were noted in the number of skeletal fractures. Poisson regression analysis demonstrated a significant reduction in the risk of developing a skeletal event with oral ibandronate therapy compared with placebo (Po0.0001). However, oral ibandronate did not significantly reduce the percentage of patients with a new bone event or delay the time to first bone event compared with placebo. Additional randomised trials are needed to establish the clinical benefit of oral ibandronate in comparison to other licensed bisphosphonates. The incidence of drugrelated adverse events was slightly higher with ibandronate (26.6%) than with placebo (17.7%). In addition, the incidence of treatment-related upper gastrointestinal adverse events (dyspepsia, nausea, and oesophagitis) was nearly 2-fold higher in the ibandronate group (12.5% versus 6.9% for placebo). The efficacy of i.v. ibandronate has also been investigated in a randomised, placebo-controlled trial. In this study, 466 patients with bone metastases from breast cancer received i.v. ibandronate (2 or 6 mg via 1- to 2-h infusion) or placebo every 3–4 weeks for up to 2 years. Ibandronate (6 mg) significantly reduced the SMPR (P=0.004) and number of new bone events per patient (P=0.032) and significantly increased mean time to first bone event (P=0.018) compared with placebo.11 The percentage of patients with a new bone event was reduced in the 6-mg ibandronate group compared with placebo, but this difference did not reach statistical significance. In contrast, the 2mg dose was not effective. Notably, however, neither i.v. nor oral ibandronate have been compared directly with either i.v. pamidronate or zoledronic acid in a randomised trial; therefore, it is not possible to make efficacy comparisons between these bisphosphonates. In this trial, i.v. ibandronate (6 mg via 1- to 2-h infusion) demonstrated a renal safety profile
R.E. Coleman similar to that of placebo. Over 2 years, the incidence of renal adverse events was similar between treatment groups (4.5% for ibandronate versus 4% for placebo).38 Notable serum creatinine increases (defined as an increase X0.5 mg/dl for patients if baseline serum creatinine waso1.4 mg/ dl, an increase X1.0 mg/dl if baseline serum creatinine was X1.4 mg/dl, or X2 times baseline value) were reported in 4% of patients after 1 year and in 6% after 2 years of ibandronate treatment compared with 6% for placebo at years 1 and 2.39
Conclusions The development of highly potent i.v. bisphosphonates has expanded the role of bisphosphonates in the management of malignant bone disease, increasing both efficacy and convenience over that of early generation oral bisphosphonates. Using SREs as composite endpoints in clinical trials has provided clinically relevant and objective measures of the effect of bisphosphonates in patients with bone metastases from cancer. Firstevent analysis of SREs provides statistically conservative evidence, whereas more robust methodology, such as multiple event analysis, considers that patients typically experience multiple skeletal complications over time. Several randomised trials have indicated that i.v. bisphosphonates are the most effective intervention for patients with bone metastases, and zoledronic acid is more effective and convenient than pamidronate in patients with breast cancer. Other bisphosphonates have not been compared with pamidronate; thus, their relative effectiveness is not known. The available evidence also indicates that long-term treatment with i.v. bisphosphonate therapy is well tolerated, with patients experiencing only mild adverse events and few instances of decreased renal function. Consequently, the American Society of Clinical Oncology has recommended i.v. bisphosphonate therapy with either 90 mg pamidronate or 4 mg zoledronic acid every 3–4 weeks for any patient with breast cancer and radiographic evidence of bone destruction.
References 1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide, version 1.0. IARC CancerBase No. 5. Lyon: IARCPress; 2001: Accessed 2004.
ARTICLE IN PRESS The role of bisphosphonates in breast cancer 2. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165–76. 3. Coleman RE. Skeletal complications of malignancy. Cancer 1997;80(suppl):1588–94. 4. Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082–90. 5. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735–44. 6. Major PP, Cook R. Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 2002; 25(suppl 1):S10–8. 7. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003;21:1404–11. 8. Williams G, Pazdur R, Temple R. Assessing tumor-related signs and symptoms to support cancer drug approval. J Biopharm Stat 2004;14:5–21. 9. Lipton A. Management of metastatic bone disease and hypercalcemia of malignancy. Am J Cancer 2003;2:427–38. 10. Green JR, Mu ¨ller K, Jaeggi KA. Preclinical pharmacology of CGP 42’446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994;9:745–51. 11. Body J-J, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399–405. 12. Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133–7. 13. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998;16:2038–44. 14. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebocontrolled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846–54. 15. Cook RJ, Major P. Methodology for treatment evaluation in patients with cancer metastatic to bone. J Natl Cancer Inst 2001;93:534–8. 16. Andersen PK, Gill RD. Cox’s regression model for counting processes: a large sample study. Ann Stat 1982;10:1100–20. 17. Ghosh D, Lin DY. Nonparametric analysis of recurrent events and death. Biometrics 2000;56:554–62. 18. Cook RJ, Lawless JF. Marginal analysis of recurrent events and a terminating event. Stat Med 1997;16:911–24. 19. Prentice RL, Williams BJ, Peterson AV. On the regression analysis of multivariate failure time data. Biometrika 1981;68:373–9. 20. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Amer Stat Assoc 1989;84:1065–73. 21. Rosen LS, Gordon DH, Dugan Jr W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone
S27
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36–43. Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59–65. Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H, Mouridsen HT. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999; 246:67–74. Hortobagyi GN, Theriault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 1996; 335:1785–91. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001;7:377–87. Conte PF, Latreille J, Mauriac L, et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group. J Clin Oncol 1996;14: 2552–9. Hultborn R, Gundersen S, Ryden S, et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebo-controlled multicenter study. Anticancer Res 1999;19:3383–92. Pavlakis N, Stockler M. Bisphosphonates for breast cancer (Cochrane Review). In: The Cochrane Library, Issue 1. Hoboken, NJ: Wiley, 2004. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al. [Double-blind controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases]. Bull Cancer 2001;88:701–7. Major PP, Lipton A, Berenson J, Hortobagyi G. Oral bisphosphonates: a review of clinical use in patients with bone metastases. Cancer 2000;88:6–14. Diel IJ, Solomayer E-F, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–63. Powles T, Paterson S, Kanis JA, et al. Randomized, placebocontrolled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–24. Kanis JA, Powles T, Paterson AH, McCloskey EV, Ashley S. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996;19:663–7. Lipton A. Bisphosphonate therapy for patients with osteolytic and osteoblastic bone metastases from breast or prostate cancer. Progress in Breast Cancer Research Hauppauge, NY: Nova Science Publishers, Inc; submitted. Rosen LS, Coleman RE, Gordon D, et al. Zoledronic acid is superior to pamidronate in patients with breast cancer and bone metastases. Presented at: St. Gallen Oncology Conferences: Primary Therapy of Early Breast Cancer 8th International Conference; March 12–15, 2003; St. Gallen, Switzerland (poster 100). Major PP, Cook RJ, Chen B-L, Zheng M. Multiple event analysis of zoledronic acid trials in patients with cancer metastatic to bone. Proc Am Soc Clin Oncol 2003;22:762 (abstract 3062). Lipton A, Dewar R, Conte PF, Zheng M. Long-term safety of zoledronic acid for the treatment of patients with breast cancer and bone metastases. Presented at: 4th European
ARTICLE IN PRESS S28 Breast Cancer Conference; March 16–19, 2004; Hamburg, Germany (poster 296). 38. Diel I, Body J-J, Bergstro ¨m B. Low nephrotoxicity of Ibandronate: evidence from clinical trials in metastatic bone disease. Bone 2004;34:S77 (abstract 53).
R.E. Coleman 39. Bell R, Body J-J, Tripathy D, Bergstro ¨m B. Ibandronate does not affect time to renal function deterioration over 2 years of treatment: phase III trial results. Bone 2004;34:S75 (abstract 49).