Zoledronic Acid Significantly Reduces Skeletal Complications Compared With Placebo in Japanese Women With Bone Metastases From Breast Cancer
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《临床肿瘤学》
the Hyogo Medical Center for Adults, Akashi
National Hospital Organization Shikoku Cancer Center, Matsuyama
National Cancer Center Hospital E, Kashiwa
St Luke’s International Hospital
Sanno Medical Plaza Oncology Center
University of Tokyo, Tokyo
Kanagawa Cancer Center, Yokohama
Gunma University, Maebashi, Japan
Novartis Pharmaceuticals Corporation, E Hanover, NJ
ABSTRACT
PURPOSE: To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer.
PATIENTS AND METHODS: Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis.
RESULTS: The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase.
CONCLUSION: Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.
INTRODUCTION
Bone metastases from breast cancer result in significant skeletal morbidity. Annually, approximately 800,000 women are diagnosed with breast cancer worldwide,1 and an estimated 65% to 75% of patients with advanced metastatic breast cancer will develop bone metastases during the course of their disease.1,2 Bone lesions can result in skeletal complications, including pathologic fractures, severe bone pain requiring palliative radiotherapy, spinal cord compression, and potentially life-threatening hypercalcemia of malignancy (HCM).2,3 Long bone, hip, and vertebral fractures can be extremely painful, often require orthopedic surgery, and can result in impaired mobility and function. Median survival for patients with breast cancer is approximately 18 to 26 months after the initial diagnosis of bone metastases.4,5 Therefore, patients with bone metastases are at continued risk for developing skeletal complications. In randomized, controlled, clinical trials evaluating bisphosphonate therapy in patients with bone metastases from breast cancer, nearly 70% of patients in the placebo group developed at least one skeletal complication within 2 years, and the annual incidence of skeletal complications was approximately four events per year.6 Thus, skeletal complications are a significant clinical concern in breast cancer patients with bone metastases, and preventing or delaying the occurrence of these events is an important objective of treatment.
Intravenous (IV) bisphosphonates are the standard of care for the prevention of skeletal complications in breast cancer patients with bone metastases, and treatment guidelines from the American Society of Clinical Oncology recommend either IV pamidronate (90 mg) or IV zoledronic acid (4 mg) every 3 to 4 weeks for patients with radiologic evidence of bone destruction.7 IV pamidronate (90 mg) has been shown to significantly reduce the incidence and delay the onset of skeletal complications in randomized, placebo-controlled trials in patients with predominantly osteolytic lesions.6,8,9 Subsequently, IV zoledronic acid (4 mg) was shown to be significantly more effective than pamidronate (90 mg) for reducing the risk of skeletal complications, based on a multiple-event analysis in a large comparative trial of these two active agents in patients with all types of bone lesions.10
Zoledronic acid is a highly potent, new-generation bisphosphonate that has demonstrated greater potency compared with pamidronate in preclinical testing and can be safely administered via a 15-minute infusion.11,12 Zoledronic acid is superior to pamidronate for the treatment of HCM13 and is the first bisphosphonate to demonstrate efficacy in patients with bone metastases from solid tumors other than breast cancer, including prostate cancer, non–small-cell lung cancer, and a variety of other tumor types.14,15
This randomized trial was conducted as a registration trial in Japan to determine the clinical benefit of 4 mg zoledronic acid versus placebo in Japanese breast cancer patients with bone metastases. Placebo was an appropriate comparator in this trial because, unlike in Western countries, no bisphosphonate has been approved in Japan for the treatment of bone metastases. Consequently, there exists a high unmet medical need for women with bone metastases from breast cancer in Japan. This trial represents the first randomized, placebo-controlled trial of zoledronic acid in this patient population and provides important confirmatory data on the clinical benefit of zoledronic acid.
PATIENTS AND METHODS
Patients
The study enrolled adult patients (age 20 years) with at least one osteolytic bone metastasis (confirmed by diagnostic imaging with x-ray or computed tomography) secondary to stage IV breast cancer. For patients with only one osteolytic lesion, that lesion was not to have been treated with radiation therapy within 90 days of enrolling onto the study. Ambulatory patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2; however, patients with an ECOG performance status of 3, because their activity was restricted by bone lesions, were allowed to participate. Eligible patients were required to have corrected serum calcium 8.0 mg/dL and 11.5 mg/dL, serum creatinine 2 mg/dL (177 μmol/L), and total bilirubin 1.5 mg/dL (26 μmol/L). Patients were not eligible if they had received prior treatment with a bisphosphonate within 12 months of enrollment or calcitonin within 14 days of study drug administration, were pregnant or lactating, or had clinically symptomatic brain metastases. Ongoing antineoplastic therapy or hormonal therapy was permitted for all patients at the time of randomization. Antineoplastic therapy or hormonal therapy could be changed or discontinued during the study at the discretion of the treating physician. The study design, including ethical aspects, was reviewed and approved by the Institutional Review Boards of all centers, and all patients provided informed written consent. This trial was conducted in accordance with good clinical practice and the Declaration of Helsinki.
Treatment
Patients were randomly assigned in a double-blind fashion to treatment with zoledronic acid (4 mg) or placebo via 15-minute infusion. Infusions were administered every 4 weeks for 12 months. Serum creatinine was monitored before each dose of study drug. In contrast to the international studies,10,14,15 patients in this study did not receive calcium or vitamin D supplements.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled study involving 51 centers in Japan. Patients were registered by facsimile and their eligibility was verified in the central registration office. Randomization to treatment groups was done by the dynamic balancing method (a modified minimization method with biased coin technique) using age (< 50 years or 50 years), use of chemotherapy (none, primary treatment, or secondary treatment), use of hormonal agents (none, medroxyprogesterone acetate [MPA], or hormonal agents other than MPA), metastases to other sites excluding bones (yes or no), performance status (0-1 or 2) and study center as stratification variables.
Before the first study treatment, bone scan, bone survey (x-ray of thoracic and lumbar vertebrae, ribs, and pelvis), and physical examination were performed, and a medical history was taken. At baseline, pain was assessed using the Brief Pain Inventory (BPI) 0 to 10 point scale,16 and analgesic use was scored on a scale of 0 to 4 as follows: 0, none; 1, minor analgesics (eg, aspirin or acetaminophen); 2, tranquilizers, antidepressants, muscle relaxants, or steroids; 3, mild narcotics (eg, oxycodone); 4, strong narcotics (eg, morphine). Bone surveys and ECOG performance status were evaluated at 3, 6, 9, and 13 months, and BPI pain scores and analgesic scores were assessed at 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 weeks. Bone resorption markers, tumor markers, serum chemistry, urinalysis, and hematology were assessed at baseline and at 2, 4, 8, 12, 24, 36, and 52 weeks. Follow-up bone scans were repeated at 6 and 13 months, and fractures were assessed radiographically at 3, 6, 9, and 13 months.
Skeletal-related events (SREs) were assessed at 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 weeks and were defined as a pathologic fracture, spinal cord compression, surgery to bone, radiation therapy to bone, and HCM (secondary efficacy analyses only). New vertebral compression fractures were diagnosed if there was a decrease in total, anterior, or posterior vertebral height of 25% from baseline. All radiologic assessments, including vertebral fractures, were conducted by a blinded radiographic assessment committee. Surgery to bone included procedures performed to set or stabilize pathologic fractures or areas of spinal cord compression and procedures performed to prevent an imminent fracture or cord compression. Radiation therapy to bone included radiation for pain relief, radiation to treat or prevent pathologic fractures, or radiation to treat or prevent spinal cord compression.
The primary efficacy variable was the ratio of the SRE rate (defined as the total number of SREs divided by the total years on study) for patients treated with zoledronic acid divided by the SRE rate for the placebo group. For the primary efficacy analysis, HCM was not included in the definition of SREs because zoledronic acid had already demonstrated efficacy in treating HCM.13 However, HCM is a clinically important event that can be life threatening, and efficacy in terms of treating HCM does not necessarily mean efficacy in terms of preventing HCM. Therefore, all secondary efficacy analyses considered HCM as part of the composite SRE end point. Hypercalcemia of malignancy was defined as corrected serum calcium 12 mg/dL or the upper limit of normal (ULN) with clinical symptoms requiring therapy. Secondary efficacy variables included the proportion of patients experiencing at least one SRE, time to first SRE, and multiple-event analysis by the Andersen-Gill method.17 Change from baseline BPI composite pain scores and bone resorption markers were also assessed. The BPI composite pain score consisted of four parameters: worst, least, average pain over the last 7 days, and pain right now.
Adverse events were graded according to National Cancer Institute Common Toxicity Criteria version 2.0. A serious adverse event was defined as follows: death, disability, any event possibly leading to death or disability, any event requiring hospitalization or prolonging hospitalization, or any congenital disease or anomaly in the offspring of a treated patient. Decreased renal function (ie, notable serum creatinine increase) was defined as a serum creatinine increase 0.5 mg/dL from baseline for patients with baseline serum creatinine less than the ULN (0.8 to 1.3 mg/dL), an increase 1.0 mg/dL from baseline for patients with baseline serum creatinine greater than the ULN, or any increase 2 x the baseline value.
Statistical Analysis
A sample size of 200 patients (100 patients per treatment group) was determined by the Freedman equation,18 based on the assumption that the percentage of patients with at least one SRE at 12 months would be approximately 55% in the placebo group and 35% in the zoledronic acid group. This would allow detection of between-group differences with a one-sided log-rank test at the 2.5% level with 80% power. All patients who received 1 infusion of the study drug were analyzed for efficacy and safety. Because blinded review of the data suggested that patients with a pathologic fracture before study entry were at higher risk of developing SREs on study compared with patients without a pathologic fracture before study entry, a statistical amendment to the protocol stipulated that the primary end point would be the stratified SRE rate ratio (defined above), which would be adjusted based on whether patients had or had not experienced a pathologic fracture before study entry. A stratified permutation test19 was conducted with the combined ratio for patients with and without a prior pathologic fracture. The Cochran-Mantel-Haenszel (CMH) test, stratified by whether patients had or had not experienced a pathologic fracture before study entry, was used to compare the proportion of patients with one SRE between treatment groups. The Kaplan-Meier method and a stratified Cox regression analysis were used to compare time to first SRE. Multiple-event analysis was performed using the stratified Andersen-Gill method, and the robust estimate of variance was used.17 The robust estimate of variance was used to minimize the impact of correlations between events that occurred closely in time or in clusters. Adverse events and laboratory data were summarized by treatment group.
RESULTS
Patients
A total of 228 Japanese patients with bone metastases from breast cancer were randomly assigned to treatment with 4 mg zoledronic acid (n = 114) or placebo (n = 114) for 12 months, and 227 patients were treated between May 2000 and May 2003. One patient in the placebo group did not receive study treatment and was excluded (per protocol) from efficacy and safety analyses. Overall, 67% of patients in the zoledronic acid group and 64% of patients in the placebo group completed the study. Demographics and baseline disease characteristics are listed in Table 1. The median age was 53 years, and the majority of patients had an ECOG performance status of 0. Treatment groups were well balanced with respect to patient and baseline disease characteristics. However, before study entry, 34% of patients in the zoledronic acid group versus 42% in the placebo group had experienced one or more SREs (excluding HCM), and 25% of patients in the zoledronic acid group versus 29% of patients in the placebo group had experienced a pathologic fracture; neither of these differences was statistically significant. Median time from initial diagnosis of cancer to first administration of study drug was approximately 40 months in both treatment groups, and median time from diagnosis of bone metastases to first administration of study drug was 4 months in both treatment groups. Mean baseline serum creatinine was 0.8 mg/dL, and more than 95% patients had normal serum creatinine (< 1.3 mg/dL) at study entry. Mean baseline BPI pain and analgesic scores were the same in both treatment groups.
Skeletal-Related Events
The adjusted SRE rate ratio, based on whether patients had or had not experienced a pathologic fracture before study entry, was 0.61 (P = .027), indicating that zoledronic acid reduced the rate of SREs by 39% (Table 2). Among patients with a pathologic fracture before study entry, the SRE rate was substantially higher than in patients with no prior fractures. However, treatment with zoledronic acid reduced the SRE rate in both groups of patients. The SRE rate was 0.63 events/yr in the zoledronic acid group versus 1.10 events/yr in the placebo group (SRE rate ratio, 0.57; P = .016) without adjustment for prior fracture.
The results of secondary efficacy analyses, both excluding and including HCM in the analysis of SREs, are summarized in Table 3. The proportion of patients with 1 SRE (excluding HCM) at 1 year was 29.8% in the zoledronic acid group versus 49.6% in the placebo group (stratified CMH test; P = .003). This represents a 40% relative reduction in the percentage of patients with an SRE. In addition, zoledronic acid consistently reduced the incidence of all types of SREs (Fig 1). The most common SREs were pathologic fractures and radiation to bone. Zoledronic acid also significantly delayed SREs compared with placebo. The median time to first SRE (excluding HCM) was not reached in the zoledronic acid group versus 364 days in the placebo group (stratified Cox regression; P = .007). Finally, multiple-event analysis demonstrated that treatment with 4 mg zoledronic acid significantly reduced the risk of developing a skeletal complication (excluding HCM) by 41% compared with placebo (risk ratio, 0.59; P = .019). Results of these analyses including HCM in the analysis of SREs were similar.
An analysis was also performed to determine the percentage of patients with zero, one, two, or more SREs during the study period (Table 4). This analysis showed that the majority of patients in this trial had at least one event during the course of the study.
Pain and Analgesic Scores
Zoledronic acid also consistently reduced BPI composite pain scores from baseline and compared with the placebo group throughout the study (Fig 2). At every time point, patients in the placebo group had either no change or an increase from baseline in their mean pain score, whereas patients in the zoledronic acid group had a statistically significant decrease from baseline in their mean pain score at every time point throughout the study, except for week 2. There were no clinically significant differences between treatment groups with regard to analgesic scores.
Safety
Zoledronic acid was well tolerated. The most frequently reported adverse events in both treatment groups (regardless of relationship to study drug) were pyrexia, nausea, fatigue, nasopharyngitis, vomiting, and bone pain (Table 5). The majority of these events were mild to moderate in severity. Pyrexia, fatigue, and abdominal pain were reported more frequently in the zoledronic acid group, whereas bone pain was reported by a substantially greater proportion of the patients in the placebo group (45% v 32%). In particular, 23 patients (20%) in the placebo group reported grade 3 or 4 bone pain compared with seven patients (6%) in the zoledronic acid group reporting grade 3 bone pain. Similar to other bisphosphonates studies, the most frequent adverse events suspected to be study drug–related were pyrexia, nausea, and fatigue. There was also a higher incidence of grade 1 hypocalcemia (39% v 7%) and hypophosphatemia (grades 1 to 3) in the zoledronic acid group. There was no grade 2 or 3 hypocalcemia in the zoledronic acid group, and one patient in each treatment group had grade 4 hypocalcemia.
Renal adverse events and increases in serum creatinine were reviewed in greater detail. There was no evidence of decreased renal function among patients treated with zoledronic acid compared with placebo. In the zoledronic acid group, mean serum creatinine was 0.79 mg/dL at baseline and 0.78 mg/dL at end of study. In the placebo group, mean serum creatinine was 0.79 mg/dL at baseline and 0.85 mg/dL at study end. Only one patient in the zoledronic acid group had a notable serum creatinine increase (2.0 mg/dL) from a baseline of 1.3 mg/dL compared with seven patients in the placebo group. Moreover, no patient treated with zoledronic acid developed a National Cancer Institute Common Toxicity Criteria grade 3 or 4 serum creatinine increase, whereas one patient in the placebo group had a grade 3 serum creatinine elevation. Renal adverse events were infrequent, and there was no difference between treatment groups. At study end, 2 microglobulin levels were higher in the zoledronic acid group (mean change, 1.6 ± 5.9 mg/L v 0.2 ± 1.6 mg/L). However, the clinical significance of this finding is not clear because increases in 2 microglobulin did not correlate with any increases in serum creatinine.
DISCUSSION
Although IV bisphosphonate therapy has been established as the standard of care in Western patients with bone metastases from breast cancer,20 no approved treatment options are available for such patients in Japan. The current study was conducted to address this unmet medical need and to demonstrate the efficacy of zoledronic acid in Japanese patients. In Western patients, zoledronic acid has demonstrated clinical benefit not only for patients with multiple myeloma and bone metastases from breast cancer, but also for patients with prostate cancer and other solid tumors.14,15 Such broad efficacy across tumor types has not been shown with other bisphosphonates, including pamidronate.
Zoledronic acid has been previously compared with pamidronate in patients with malignant bone lesions from breast cancer or multiple myeloma in a large, international, randomized trial reported by Rosen et al.10 Andersen-Gill multiple-event analysis of the stratified subset of patients with breast cancer in the Rosen et al trial demonstrated that zoledronic acid significantly reduced the risk of SREs by an additional 20%, compared with pamidronate (risk ratio, 0.8; P = .025). The trial reported in this article represents the first randomized, placebo-controlled trial of zoledronic acid for the treatment of bone metastases in patients with breast cancer, and it is the first randomized trial of zoledronic acid specifically for the indication of bone metastases in Japanese patients. At the time the pivotal trial of zoledronic acid was conducted in Western countries, 90 mg pamidronate was the standard of care in patients with bone metastases from breast cancer. Therefore, zoledronic acid was prospectively compared with pamidronate in Western patients. The current trial was placebo controlled because no bisphosphonate has been approved in Japan for treating patients with bone metastases.
The pattern and natural history of skeletal complications observed in the placebo arm of this trial were consistent with those observed in the placebo arm of previous trials of pamidronate in Western women with bone metastases from advanced breast cancer.6,8-10 Therefore, the efficacy of zoledronic acid compared with placebo in this trial is not unexpected. However, the magnitude of the therapeutic benefit after 1 year was striking. Among patients treated with zoledronic acid, there was an absolute 20% and a relative 40% reduction in the percentage of patients with at least one SRE compared with the placebo group. In comparison, the pamidronate trials, which also enrolled patients with osteolytic lesions, demonstrated an absolute 10% to 13% reduction and a relative 18% to 23% reduction in the percentage of patients with an SRE after 1 year.9,21 This is consistent with the findings from the randomized trial, which showed that zoledronic acid is superior to pamidronate, particularly among patients with predominantly osteolytic lesions.22
In addition to zoledronic acid and pamidronate, IV ibandronate (6 mg) and oral ibandronate (50 mg) have also been studied in Western patients with bone metastases from breast cancer.23,24 Both oral and IV ibandronate significantly reduced the skeletal morbidity period rate (SMPR, defined as the number of 12-week periods with new bone events) by approximately 20% compared with placebo (P = .004). However, both oral and IV ibandronate failed to significantly reduce the percentage of patients with at least one new bone event,23 and oral ibandronate did not significantly prolong time to first new bone event.24 Therefore, the clinical benefit of ibandronate in patients with bone metastases remains to be established in additional randomized trials.
In the current trial, zoledronic acid also significantly reduced bone pain, as indicated by the change from baseline BPI composite pain scores. Bisphosphonates are known to have analgesic effects in patients with malignant bone disease. For example, pamidronate was shown to significantly reduce mean pain and analgesic scores compared with placebo throughout the 2-year follow-up period.6 Consequently, patients required less radiation to bone for pain palliation. The reduced incidence of fractures may also contribute to improved outcomes with respect to pain.
The safety analysis of this trial provides further evidence that zoledronic acid (4 mg via 15-minute infusion every 4 weeks) is well tolerated, with overall and renal safety profiles similar to placebo. As expected, patients treated with zoledronic acid reported more fever and fatigue, which are typically associated with the acute-phase reaction that often accompanies the first infusion of an IV bisphosphonate.25 This is a class effect. However, these adverse events are nearly always mild to moderate in severity and occur infrequently with subsequent infusions. In contrast, bone pain, particularly severe bone pain, was reported more frequently in the placebo group. A notable increase from baseline serum creatinine also occurred more frequently in the placebo group. Only one patient in the zoledronic acid group had a notable serum creatinine increase, and no patient treated with zoledronic acid developed a grade 3 or 4 serum creatinine increase. The incidence of asymptomatic grade 1 hypocalcemia was higher in the zoledronic acid group as a result of the inhibition of bone resorption, but mild hypocalcemia may have been largely prevented with the use of daily calcium and vitamin D supplements, as was done in the international trials. Nevertheless, only one patient (0.9%) in each treatment group had grade 3 or 4 hypocalcemia.
In summary, this placebo-controlled trial has confirmed the significant clinical benefits of zoledronic acid in patients with bone metastases from breast cancer. Given the demonstrated efficacy of zoledronic acid compared with both placebo and pamidronate, plus the greater convenience of the 15-minute infusion, zoledronic acid is rapidly becoming the new standard of care worldwide for patients with bone metastases from advanced breast cancer. Zoledronic acid has also demonstrated statistically significant reductions in skeletal complications among patients with bone metastases from solid tumors other than breast cancer, including prostate cancer, non–small-cell lung cancer, and a variety of other tumor types.14,15,26
Authors’ Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Carsten Goessl, Novartis. Leadership Position: Carsten Goessl, Novartis. Consultant/Advisory Role: Hironobu Minami, Novartis; Yasuo Ohashi, Novartis. Honoraria: Yasuo Ohashi, Novartis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Acknowledgment
The authors gratefully acknowledge the participation of the following investigators: Motoshi Tamura, Miki Morimoto, Naohiro Nomura, Koji Ohnuki, Seiichi Takenoshita, Tadashi Nomizu, Hiroshi Nagaoka, Toru Yokota, Ei Ueno, Kenichi Inoue, Hirofumi Fujii, Kenji Ogawa, Masakazu Toi, Toshio Shimizu, Tsunehiro Nishi, Kiyoshi Kubochi, Tomoo Tajima, Kazuo Ishida, Kiyoshi Nishiyama, Satoru Shimizu, Mamoru Fukuda, Hiroshi Nakagomi, Osamu Senga, Kazunari Tohyama, Keigo Goto, Atsushi Takenaka, Tetsuya Taguchi, Hideo Inaji, Eisei Shin, Ken Morimoto, Shoji Oura, Hidefumi Nishikawa, Keisuke Miyauchi, Hiroshi Sonoo, Kazuya Miyoshi, Masato Koseki, Akihiko Ohsaki, Kenji Higaki, Shoshu Mitsuyama, Shinji Ohno, Noriaki Itoyanagi, Shigeto Maeda, Shinichi Tsutsui, and Reiki Nishimura.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Parkin DM, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 49:33-64, 1999
Coleman RE: Skeletal complications of malignancy. Cancer 80:1588-1594, 1997 (suppl)
Mercadante S: Malignant bone pain: Pathophysiology and treatment. Pain 69:1-18, 1997
Ries LAG, Eisner MP, Kosary CL, et al: SEER Cancer Statistics Review, 1975-2000. National Cancer Institute, Bethesda, MD. Available at http://seer.cancer.gov/csr/1975_2000. Accessed February 3, 2005
Domchek SM, Younger J, Finkelstein DM, et al: Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 89:363-368, 2000
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 88:1082-1090, 2000
Hilner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003. Published erratum in: J Clin Oncol 22:1351, 2004
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 16:2038-2044, 1998
Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial: Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846-854, 1999
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 98:1735-1744, 2003
Green JR, Müller K, Jaeggi KA: Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 9:745-751, 1994
Maxwell C, Swift R, Noonan K: Convenience of a 15-minute infusion of zoledronic acid. Presented at: Presented at the 3rd European Oncology Nursing Symposium Spring Convention, Venice, Italy, April 12-14, 2002
Major P, Lortholary A, Hon J, et al: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 19:558-567, 2001
Rosen LS, Gordon D, Tchekmedyian S, et al: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150-3157, 2003
Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma: For the Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst 94:1458-1468, 2002
Cleeland CS, Ryan KM: Pain assessment: Global use of the Brief Pain Inventory. Ann Acad Med Singapore 23:129-138, 1994
Andersen PK, Gill RD: Cox’s regression model for counting processes: A large sample study. Ann Stat 10:1100-1120, 1982
Freedman LS: Tables of the number of patients required in clinical trails using the logrank test. Stat Med 1:121-129, 1982
Westfall PH, Young SS: Resampling-based multiple testing: Examples and methods for P-value adjustment. New York, NY, Wiley, 1993
Hilner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer: American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 18:1378-1391, 2000
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 335:1785-1791, 1996
Rosen LS, Gordon DH, Dugan W Jr., et al: Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36-43, 2004
Body JJ, Diel IJ, Lichinitser MR, et al: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14:1399-1405, 2003. Corrigendum published in Ann Oncol 15:180, 2004
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 90:1133-1137, 2004
Zojer N, Keck AV, Pecherstorfer M: Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 21:389-406, 1999
Lipton A, Zheng M, Seaman J: Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 98:962-969, 2003(Norio Kohno, Kenjiro Aogi)
National Hospital Organization Shikoku Cancer Center, Matsuyama
National Cancer Center Hospital E, Kashiwa
St Luke’s International Hospital
Sanno Medical Plaza Oncology Center
University of Tokyo, Tokyo
Kanagawa Cancer Center, Yokohama
Gunma University, Maebashi, Japan
Novartis Pharmaceuticals Corporation, E Hanover, NJ
ABSTRACT
PURPOSE: To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer.
PATIENTS AND METHODS: Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis.
RESULTS: The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase.
CONCLUSION: Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.
INTRODUCTION
Bone metastases from breast cancer result in significant skeletal morbidity. Annually, approximately 800,000 women are diagnosed with breast cancer worldwide,1 and an estimated 65% to 75% of patients with advanced metastatic breast cancer will develop bone metastases during the course of their disease.1,2 Bone lesions can result in skeletal complications, including pathologic fractures, severe bone pain requiring palliative radiotherapy, spinal cord compression, and potentially life-threatening hypercalcemia of malignancy (HCM).2,3 Long bone, hip, and vertebral fractures can be extremely painful, often require orthopedic surgery, and can result in impaired mobility and function. Median survival for patients with breast cancer is approximately 18 to 26 months after the initial diagnosis of bone metastases.4,5 Therefore, patients with bone metastases are at continued risk for developing skeletal complications. In randomized, controlled, clinical trials evaluating bisphosphonate therapy in patients with bone metastases from breast cancer, nearly 70% of patients in the placebo group developed at least one skeletal complication within 2 years, and the annual incidence of skeletal complications was approximately four events per year.6 Thus, skeletal complications are a significant clinical concern in breast cancer patients with bone metastases, and preventing or delaying the occurrence of these events is an important objective of treatment.
Intravenous (IV) bisphosphonates are the standard of care for the prevention of skeletal complications in breast cancer patients with bone metastases, and treatment guidelines from the American Society of Clinical Oncology recommend either IV pamidronate (90 mg) or IV zoledronic acid (4 mg) every 3 to 4 weeks for patients with radiologic evidence of bone destruction.7 IV pamidronate (90 mg) has been shown to significantly reduce the incidence and delay the onset of skeletal complications in randomized, placebo-controlled trials in patients with predominantly osteolytic lesions.6,8,9 Subsequently, IV zoledronic acid (4 mg) was shown to be significantly more effective than pamidronate (90 mg) for reducing the risk of skeletal complications, based on a multiple-event analysis in a large comparative trial of these two active agents in patients with all types of bone lesions.10
Zoledronic acid is a highly potent, new-generation bisphosphonate that has demonstrated greater potency compared with pamidronate in preclinical testing and can be safely administered via a 15-minute infusion.11,12 Zoledronic acid is superior to pamidronate for the treatment of HCM13 and is the first bisphosphonate to demonstrate efficacy in patients with bone metastases from solid tumors other than breast cancer, including prostate cancer, non–small-cell lung cancer, and a variety of other tumor types.14,15
This randomized trial was conducted as a registration trial in Japan to determine the clinical benefit of 4 mg zoledronic acid versus placebo in Japanese breast cancer patients with bone metastases. Placebo was an appropriate comparator in this trial because, unlike in Western countries, no bisphosphonate has been approved in Japan for the treatment of bone metastases. Consequently, there exists a high unmet medical need for women with bone metastases from breast cancer in Japan. This trial represents the first randomized, placebo-controlled trial of zoledronic acid in this patient population and provides important confirmatory data on the clinical benefit of zoledronic acid.
PATIENTS AND METHODS
Patients
The study enrolled adult patients (age 20 years) with at least one osteolytic bone metastasis (confirmed by diagnostic imaging with x-ray or computed tomography) secondary to stage IV breast cancer. For patients with only one osteolytic lesion, that lesion was not to have been treated with radiation therapy within 90 days of enrolling onto the study. Ambulatory patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2; however, patients with an ECOG performance status of 3, because their activity was restricted by bone lesions, were allowed to participate. Eligible patients were required to have corrected serum calcium 8.0 mg/dL and 11.5 mg/dL, serum creatinine 2 mg/dL (177 μmol/L), and total bilirubin 1.5 mg/dL (26 μmol/L). Patients were not eligible if they had received prior treatment with a bisphosphonate within 12 months of enrollment or calcitonin within 14 days of study drug administration, were pregnant or lactating, or had clinically symptomatic brain metastases. Ongoing antineoplastic therapy or hormonal therapy was permitted for all patients at the time of randomization. Antineoplastic therapy or hormonal therapy could be changed or discontinued during the study at the discretion of the treating physician. The study design, including ethical aspects, was reviewed and approved by the Institutional Review Boards of all centers, and all patients provided informed written consent. This trial was conducted in accordance with good clinical practice and the Declaration of Helsinki.
Treatment
Patients were randomly assigned in a double-blind fashion to treatment with zoledronic acid (4 mg) or placebo via 15-minute infusion. Infusions were administered every 4 weeks for 12 months. Serum creatinine was monitored before each dose of study drug. In contrast to the international studies,10,14,15 patients in this study did not receive calcium or vitamin D supplements.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled study involving 51 centers in Japan. Patients were registered by facsimile and their eligibility was verified in the central registration office. Randomization to treatment groups was done by the dynamic balancing method (a modified minimization method with biased coin technique) using age (< 50 years or 50 years), use of chemotherapy (none, primary treatment, or secondary treatment), use of hormonal agents (none, medroxyprogesterone acetate [MPA], or hormonal agents other than MPA), metastases to other sites excluding bones (yes or no), performance status (0-1 or 2) and study center as stratification variables.
Before the first study treatment, bone scan, bone survey (x-ray of thoracic and lumbar vertebrae, ribs, and pelvis), and physical examination were performed, and a medical history was taken. At baseline, pain was assessed using the Brief Pain Inventory (BPI) 0 to 10 point scale,16 and analgesic use was scored on a scale of 0 to 4 as follows: 0, none; 1, minor analgesics (eg, aspirin or acetaminophen); 2, tranquilizers, antidepressants, muscle relaxants, or steroids; 3, mild narcotics (eg, oxycodone); 4, strong narcotics (eg, morphine). Bone surveys and ECOG performance status were evaluated at 3, 6, 9, and 13 months, and BPI pain scores and analgesic scores were assessed at 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 weeks. Bone resorption markers, tumor markers, serum chemistry, urinalysis, and hematology were assessed at baseline and at 2, 4, 8, 12, 24, 36, and 52 weeks. Follow-up bone scans were repeated at 6 and 13 months, and fractures were assessed radiographically at 3, 6, 9, and 13 months.
Skeletal-related events (SREs) were assessed at 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 weeks and were defined as a pathologic fracture, spinal cord compression, surgery to bone, radiation therapy to bone, and HCM (secondary efficacy analyses only). New vertebral compression fractures were diagnosed if there was a decrease in total, anterior, or posterior vertebral height of 25% from baseline. All radiologic assessments, including vertebral fractures, were conducted by a blinded radiographic assessment committee. Surgery to bone included procedures performed to set or stabilize pathologic fractures or areas of spinal cord compression and procedures performed to prevent an imminent fracture or cord compression. Radiation therapy to bone included radiation for pain relief, radiation to treat or prevent pathologic fractures, or radiation to treat or prevent spinal cord compression.
The primary efficacy variable was the ratio of the SRE rate (defined as the total number of SREs divided by the total years on study) for patients treated with zoledronic acid divided by the SRE rate for the placebo group. For the primary efficacy analysis, HCM was not included in the definition of SREs because zoledronic acid had already demonstrated efficacy in treating HCM.13 However, HCM is a clinically important event that can be life threatening, and efficacy in terms of treating HCM does not necessarily mean efficacy in terms of preventing HCM. Therefore, all secondary efficacy analyses considered HCM as part of the composite SRE end point. Hypercalcemia of malignancy was defined as corrected serum calcium 12 mg/dL or the upper limit of normal (ULN) with clinical symptoms requiring therapy. Secondary efficacy variables included the proportion of patients experiencing at least one SRE, time to first SRE, and multiple-event analysis by the Andersen-Gill method.17 Change from baseline BPI composite pain scores and bone resorption markers were also assessed. The BPI composite pain score consisted of four parameters: worst, least, average pain over the last 7 days, and pain right now.
Adverse events were graded according to National Cancer Institute Common Toxicity Criteria version 2.0. A serious adverse event was defined as follows: death, disability, any event possibly leading to death or disability, any event requiring hospitalization or prolonging hospitalization, or any congenital disease or anomaly in the offspring of a treated patient. Decreased renal function (ie, notable serum creatinine increase) was defined as a serum creatinine increase 0.5 mg/dL from baseline for patients with baseline serum creatinine less than the ULN (0.8 to 1.3 mg/dL), an increase 1.0 mg/dL from baseline for patients with baseline serum creatinine greater than the ULN, or any increase 2 x the baseline value.
Statistical Analysis
A sample size of 200 patients (100 patients per treatment group) was determined by the Freedman equation,18 based on the assumption that the percentage of patients with at least one SRE at 12 months would be approximately 55% in the placebo group and 35% in the zoledronic acid group. This would allow detection of between-group differences with a one-sided log-rank test at the 2.5% level with 80% power. All patients who received 1 infusion of the study drug were analyzed for efficacy and safety. Because blinded review of the data suggested that patients with a pathologic fracture before study entry were at higher risk of developing SREs on study compared with patients without a pathologic fracture before study entry, a statistical amendment to the protocol stipulated that the primary end point would be the stratified SRE rate ratio (defined above), which would be adjusted based on whether patients had or had not experienced a pathologic fracture before study entry. A stratified permutation test19 was conducted with the combined ratio for patients with and without a prior pathologic fracture. The Cochran-Mantel-Haenszel (CMH) test, stratified by whether patients had or had not experienced a pathologic fracture before study entry, was used to compare the proportion of patients with one SRE between treatment groups. The Kaplan-Meier method and a stratified Cox regression analysis were used to compare time to first SRE. Multiple-event analysis was performed using the stratified Andersen-Gill method, and the robust estimate of variance was used.17 The robust estimate of variance was used to minimize the impact of correlations between events that occurred closely in time or in clusters. Adverse events and laboratory data were summarized by treatment group.
RESULTS
Patients
A total of 228 Japanese patients with bone metastases from breast cancer were randomly assigned to treatment with 4 mg zoledronic acid (n = 114) or placebo (n = 114) for 12 months, and 227 patients were treated between May 2000 and May 2003. One patient in the placebo group did not receive study treatment and was excluded (per protocol) from efficacy and safety analyses. Overall, 67% of patients in the zoledronic acid group and 64% of patients in the placebo group completed the study. Demographics and baseline disease characteristics are listed in Table 1. The median age was 53 years, and the majority of patients had an ECOG performance status of 0. Treatment groups were well balanced with respect to patient and baseline disease characteristics. However, before study entry, 34% of patients in the zoledronic acid group versus 42% in the placebo group had experienced one or more SREs (excluding HCM), and 25% of patients in the zoledronic acid group versus 29% of patients in the placebo group had experienced a pathologic fracture; neither of these differences was statistically significant. Median time from initial diagnosis of cancer to first administration of study drug was approximately 40 months in both treatment groups, and median time from diagnosis of bone metastases to first administration of study drug was 4 months in both treatment groups. Mean baseline serum creatinine was 0.8 mg/dL, and more than 95% patients had normal serum creatinine (< 1.3 mg/dL) at study entry. Mean baseline BPI pain and analgesic scores were the same in both treatment groups.
Skeletal-Related Events
The adjusted SRE rate ratio, based on whether patients had or had not experienced a pathologic fracture before study entry, was 0.61 (P = .027), indicating that zoledronic acid reduced the rate of SREs by 39% (Table 2). Among patients with a pathologic fracture before study entry, the SRE rate was substantially higher than in patients with no prior fractures. However, treatment with zoledronic acid reduced the SRE rate in both groups of patients. The SRE rate was 0.63 events/yr in the zoledronic acid group versus 1.10 events/yr in the placebo group (SRE rate ratio, 0.57; P = .016) without adjustment for prior fracture.
The results of secondary efficacy analyses, both excluding and including HCM in the analysis of SREs, are summarized in Table 3. The proportion of patients with 1 SRE (excluding HCM) at 1 year was 29.8% in the zoledronic acid group versus 49.6% in the placebo group (stratified CMH test; P = .003). This represents a 40% relative reduction in the percentage of patients with an SRE. In addition, zoledronic acid consistently reduced the incidence of all types of SREs (Fig 1). The most common SREs were pathologic fractures and radiation to bone. Zoledronic acid also significantly delayed SREs compared with placebo. The median time to first SRE (excluding HCM) was not reached in the zoledronic acid group versus 364 days in the placebo group (stratified Cox regression; P = .007). Finally, multiple-event analysis demonstrated that treatment with 4 mg zoledronic acid significantly reduced the risk of developing a skeletal complication (excluding HCM) by 41% compared with placebo (risk ratio, 0.59; P = .019). Results of these analyses including HCM in the analysis of SREs were similar.
An analysis was also performed to determine the percentage of patients with zero, one, two, or more SREs during the study period (Table 4). This analysis showed that the majority of patients in this trial had at least one event during the course of the study.
Pain and Analgesic Scores
Zoledronic acid also consistently reduced BPI composite pain scores from baseline and compared with the placebo group throughout the study (Fig 2). At every time point, patients in the placebo group had either no change or an increase from baseline in their mean pain score, whereas patients in the zoledronic acid group had a statistically significant decrease from baseline in their mean pain score at every time point throughout the study, except for week 2. There were no clinically significant differences between treatment groups with regard to analgesic scores.
Safety
Zoledronic acid was well tolerated. The most frequently reported adverse events in both treatment groups (regardless of relationship to study drug) were pyrexia, nausea, fatigue, nasopharyngitis, vomiting, and bone pain (Table 5). The majority of these events were mild to moderate in severity. Pyrexia, fatigue, and abdominal pain were reported more frequently in the zoledronic acid group, whereas bone pain was reported by a substantially greater proportion of the patients in the placebo group (45% v 32%). In particular, 23 patients (20%) in the placebo group reported grade 3 or 4 bone pain compared with seven patients (6%) in the zoledronic acid group reporting grade 3 bone pain. Similar to other bisphosphonates studies, the most frequent adverse events suspected to be study drug–related were pyrexia, nausea, and fatigue. There was also a higher incidence of grade 1 hypocalcemia (39% v 7%) and hypophosphatemia (grades 1 to 3) in the zoledronic acid group. There was no grade 2 or 3 hypocalcemia in the zoledronic acid group, and one patient in each treatment group had grade 4 hypocalcemia.
Renal adverse events and increases in serum creatinine were reviewed in greater detail. There was no evidence of decreased renal function among patients treated with zoledronic acid compared with placebo. In the zoledronic acid group, mean serum creatinine was 0.79 mg/dL at baseline and 0.78 mg/dL at end of study. In the placebo group, mean serum creatinine was 0.79 mg/dL at baseline and 0.85 mg/dL at study end. Only one patient in the zoledronic acid group had a notable serum creatinine increase (2.0 mg/dL) from a baseline of 1.3 mg/dL compared with seven patients in the placebo group. Moreover, no patient treated with zoledronic acid developed a National Cancer Institute Common Toxicity Criteria grade 3 or 4 serum creatinine increase, whereas one patient in the placebo group had a grade 3 serum creatinine elevation. Renal adverse events were infrequent, and there was no difference between treatment groups. At study end, 2 microglobulin levels were higher in the zoledronic acid group (mean change, 1.6 ± 5.9 mg/L v 0.2 ± 1.6 mg/L). However, the clinical significance of this finding is not clear because increases in 2 microglobulin did not correlate with any increases in serum creatinine.
DISCUSSION
Although IV bisphosphonate therapy has been established as the standard of care in Western patients with bone metastases from breast cancer,20 no approved treatment options are available for such patients in Japan. The current study was conducted to address this unmet medical need and to demonstrate the efficacy of zoledronic acid in Japanese patients. In Western patients, zoledronic acid has demonstrated clinical benefit not only for patients with multiple myeloma and bone metastases from breast cancer, but also for patients with prostate cancer and other solid tumors.14,15 Such broad efficacy across tumor types has not been shown with other bisphosphonates, including pamidronate.
Zoledronic acid has been previously compared with pamidronate in patients with malignant bone lesions from breast cancer or multiple myeloma in a large, international, randomized trial reported by Rosen et al.10 Andersen-Gill multiple-event analysis of the stratified subset of patients with breast cancer in the Rosen et al trial demonstrated that zoledronic acid significantly reduced the risk of SREs by an additional 20%, compared with pamidronate (risk ratio, 0.8; P = .025). The trial reported in this article represents the first randomized, placebo-controlled trial of zoledronic acid for the treatment of bone metastases in patients with breast cancer, and it is the first randomized trial of zoledronic acid specifically for the indication of bone metastases in Japanese patients. At the time the pivotal trial of zoledronic acid was conducted in Western countries, 90 mg pamidronate was the standard of care in patients with bone metastases from breast cancer. Therefore, zoledronic acid was prospectively compared with pamidronate in Western patients. The current trial was placebo controlled because no bisphosphonate has been approved in Japan for treating patients with bone metastases.
The pattern and natural history of skeletal complications observed in the placebo arm of this trial were consistent with those observed in the placebo arm of previous trials of pamidronate in Western women with bone metastases from advanced breast cancer.6,8-10 Therefore, the efficacy of zoledronic acid compared with placebo in this trial is not unexpected. However, the magnitude of the therapeutic benefit after 1 year was striking. Among patients treated with zoledronic acid, there was an absolute 20% and a relative 40% reduction in the percentage of patients with at least one SRE compared with the placebo group. In comparison, the pamidronate trials, which also enrolled patients with osteolytic lesions, demonstrated an absolute 10% to 13% reduction and a relative 18% to 23% reduction in the percentage of patients with an SRE after 1 year.9,21 This is consistent with the findings from the randomized trial, which showed that zoledronic acid is superior to pamidronate, particularly among patients with predominantly osteolytic lesions.22
In addition to zoledronic acid and pamidronate, IV ibandronate (6 mg) and oral ibandronate (50 mg) have also been studied in Western patients with bone metastases from breast cancer.23,24 Both oral and IV ibandronate significantly reduced the skeletal morbidity period rate (SMPR, defined as the number of 12-week periods with new bone events) by approximately 20% compared with placebo (P = .004). However, both oral and IV ibandronate failed to significantly reduce the percentage of patients with at least one new bone event,23 and oral ibandronate did not significantly prolong time to first new bone event.24 Therefore, the clinical benefit of ibandronate in patients with bone metastases remains to be established in additional randomized trials.
In the current trial, zoledronic acid also significantly reduced bone pain, as indicated by the change from baseline BPI composite pain scores. Bisphosphonates are known to have analgesic effects in patients with malignant bone disease. For example, pamidronate was shown to significantly reduce mean pain and analgesic scores compared with placebo throughout the 2-year follow-up period.6 Consequently, patients required less radiation to bone for pain palliation. The reduced incidence of fractures may also contribute to improved outcomes with respect to pain.
The safety analysis of this trial provides further evidence that zoledronic acid (4 mg via 15-minute infusion every 4 weeks) is well tolerated, with overall and renal safety profiles similar to placebo. As expected, patients treated with zoledronic acid reported more fever and fatigue, which are typically associated with the acute-phase reaction that often accompanies the first infusion of an IV bisphosphonate.25 This is a class effect. However, these adverse events are nearly always mild to moderate in severity and occur infrequently with subsequent infusions. In contrast, bone pain, particularly severe bone pain, was reported more frequently in the placebo group. A notable increase from baseline serum creatinine also occurred more frequently in the placebo group. Only one patient in the zoledronic acid group had a notable serum creatinine increase, and no patient treated with zoledronic acid developed a grade 3 or 4 serum creatinine increase. The incidence of asymptomatic grade 1 hypocalcemia was higher in the zoledronic acid group as a result of the inhibition of bone resorption, but mild hypocalcemia may have been largely prevented with the use of daily calcium and vitamin D supplements, as was done in the international trials. Nevertheless, only one patient (0.9%) in each treatment group had grade 3 or 4 hypocalcemia.
In summary, this placebo-controlled trial has confirmed the significant clinical benefits of zoledronic acid in patients with bone metastases from breast cancer. Given the demonstrated efficacy of zoledronic acid compared with both placebo and pamidronate, plus the greater convenience of the 15-minute infusion, zoledronic acid is rapidly becoming the new standard of care worldwide for patients with bone metastases from advanced breast cancer. Zoledronic acid has also demonstrated statistically significant reductions in skeletal complications among patients with bone metastases from solid tumors other than breast cancer, including prostate cancer, non–small-cell lung cancer, and a variety of other tumor types.14,15,26
Authors’ Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Carsten Goessl, Novartis. Leadership Position: Carsten Goessl, Novartis. Consultant/Advisory Role: Hironobu Minami, Novartis; Yasuo Ohashi, Novartis. Honoraria: Yasuo Ohashi, Novartis. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
Acknowledgment
The authors gratefully acknowledge the participation of the following investigators: Motoshi Tamura, Miki Morimoto, Naohiro Nomura, Koji Ohnuki, Seiichi Takenoshita, Tadashi Nomizu, Hiroshi Nagaoka, Toru Yokota, Ei Ueno, Kenichi Inoue, Hirofumi Fujii, Kenji Ogawa, Masakazu Toi, Toshio Shimizu, Tsunehiro Nishi, Kiyoshi Kubochi, Tomoo Tajima, Kazuo Ishida, Kiyoshi Nishiyama, Satoru Shimizu, Mamoru Fukuda, Hiroshi Nakagomi, Osamu Senga, Kazunari Tohyama, Keigo Goto, Atsushi Takenaka, Tetsuya Taguchi, Hideo Inaji, Eisei Shin, Ken Morimoto, Shoji Oura, Hidefumi Nishikawa, Keisuke Miyauchi, Hiroshi Sonoo, Kazuya Miyoshi, Masato Koseki, Akihiko Ohsaki, Kenji Higaki, Shoshu Mitsuyama, Shinji Ohno, Noriaki Itoyanagi, Shigeto Maeda, Shinichi Tsutsui, and Reiki Nishimura.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Parkin DM, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 49:33-64, 1999
Coleman RE: Skeletal complications of malignancy. Cancer 80:1588-1594, 1997 (suppl)
Mercadante S: Malignant bone pain: Pathophysiology and treatment. Pain 69:1-18, 1997
Ries LAG, Eisner MP, Kosary CL, et al: SEER Cancer Statistics Review, 1975-2000. National Cancer Institute, Bethesda, MD. Available at http://seer.cancer.gov/csr/1975_2000. Accessed February 3, 2005
Domchek SM, Younger J, Finkelstein DM, et al: Predictors of skeletal complications in patients with metastatic breast carcinoma. Cancer 89:363-368, 2000
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 88:1082-1090, 2000
Hilner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003. Published erratum in: J Clin Oncol 22:1351, 2004
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 16:2038-2044, 1998
Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial: Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17:846-854, 1999
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 98:1735-1744, 2003
Green JR, Müller K, Jaeggi KA: Preclinical pharmacology of CGP 42'446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 9:745-751, 1994
Maxwell C, Swift R, Noonan K: Convenience of a 15-minute infusion of zoledronic acid. Presented at: Presented at the 3rd European Oncology Nursing Symposium Spring Convention, Venice, Italy, April 12-14, 2002
Major P, Lortholary A, Hon J, et al: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 19:558-567, 2001
Rosen LS, Gordon D, Tchekmedyian S, et al: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21:3150-3157, 2003
Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma: For the Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst 94:1458-1468, 2002
Cleeland CS, Ryan KM: Pain assessment: Global use of the Brief Pain Inventory. Ann Acad Med Singapore 23:129-138, 1994
Andersen PK, Gill RD: Cox’s regression model for counting processes: A large sample study. Ann Stat 10:1100-1120, 1982
Freedman LS: Tables of the number of patients required in clinical trails using the logrank test. Stat Med 1:121-129, 1982
Westfall PH, Young SS: Resampling-based multiple testing: Examples and methods for P-value adjustment. New York, NY, Wiley, 1993
Hilner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer: American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 18:1378-1391, 2000
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 335:1785-1791, 1996
Rosen LS, Gordon DH, Dugan W Jr., et al: Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36-43, 2004
Body JJ, Diel IJ, Lichinitser MR, et al: Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14:1399-1405, 2003. Corrigendum published in Ann Oncol 15:180, 2004
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 90:1133-1137, 2004
Zojer N, Keck AV, Pecherstorfer M: Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 21:389-406, 1999
Lipton A, Zheng M, Seaman J: Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 98:962-969, 2003(Norio Kohno, Kenjiro Aogi)