Oncologist. The. Symptom Management and Supportive Care. Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid

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1 The Oncologist Symptom Management and Supportive Care Safety and Convenience of a 15-Minute Infusion of Zoledronic Acid JAMES BERENSON, a RAIMUND HIRSCHBERG b a Cedars-Sinai Medical Center, Los Angeles, California, USA; b Harbor-UCLA Medical Center, Torrance, California, USA Key Words. Alendronate Bone diseases Bone resorption Diphosphonates Hypercalcemia Neoplasm metastasis Palliative care LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Describe the effects of bisphosphonates on bone metabolism in patients with metastatic bone disease. 2. Explain the ability of intravenous bisphosphonates to reduce skeletal complications in patients with metastatic bone disease. 3. Identify differences among the different bisphosphonates in their efficacies at reversing hypercalcemia of malignancy. CME Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com ABSTRACT Skeletal morbidity, including hypercalcemia of malignancy (HCM), places a severe burden on patients with advanced cancers. Bisphosphonates effectively correct HCM and reduce skeletal morbidity in patients with bone metastases. However, with the widespread use of bisphosphonates, the safety and convenience of therapy are emerging concerns. The delivery of effective doses of early bisphosphonates required a lengthy 24-hour i.v. infusion protocol because of renal tolerability issues. The introduction of more potent bisphosphonates with superior tolerability profiles has allowed therapy to be safely delivered via shorter i.v. infusions. Intravenous therapy with etidronate, clodronate, pamidronate, ibandronate, and zoledronic acid has been used to treat HCM and skeletal complications in cancer patients. Of these therapies, zoledronic acid (which can be safely administered via a 15-minute i.v. infusion) is the most convenient and effective and has demonstrated an excellent safety profile with long-term use. Zoledronic acid has also received the broadest regulatory approval of any bisphosphonate and can be used to treat HCM or bone lesions secondary to multiple myeloma and a wide variety of solid tumors, including breast, prostate, and lung cancers. In addition to the patient preference for shorter infusion times, the 15-minute i.v. infusion protocol of zoledronic acid can provide benefits for infusion centers by potentially increasing patient throughput. The Oncologist 2004;9: Correspondence: James Berenson, M.D., Institute for Myeloma and Bone Cancer Research, 1875 Century Park East, Suite 300, Los Angeles, California 90067, USA. Telephone: ; Fax: ; jberenson@myelomasource.org Received July 31, 2003; accepted for publication November 24, AlphaMed Press /2004/$12.00/0 The Oncologist 2004;9:

2 320 Convenience of Zoledronic Acid INTRODUCTION Intravenous bisphosphonates have become an important adjunct to standard anticancer therapy for patients with malignant bone disease. Bisphosphonates are highly effective inhibitors of osteoclast-mediated bone resorption and the resultant calcium release from bone. Intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy (HCM) and the management of skeletal morbidity in cancer patients with bone involvement. During the long-term treatment of patients with cancer, the efficacy, safety, and convenience of therapy are important factors. Pamidronate (90 mg via a 2- or 4-hour i.v. infusion) was the previous standard of care for managing HCM and other complications in patients with osteolytic bone lesions associated with breast cancer or multiple myeloma. Oral clodronate and i.v. ibandronate have also been approved for the treatment of HCM in Europe. However, recent clinical trials have established that zoledronic acid (4 mg via a 15-minute i.v. infusion) is superior to pamidronate for the treatment of HCM [1] and is at least as effective as 90 mg pamidronate in reducing skeletal complications in patients with bone lesions from multiple myeloma or breast cancer [2]. In the subset of patients with breast cancer, a predefined multiple event analysis showed the superiority of 4 mg zoledronic acid over 90 mg pamidronate, as evidenced by a 20% risk reduction in developing a skeletal-related event (SRE) [3]. Zoledronic acid is also the only bisphosphonate to have demonstrated broad clinical efficacy in patients with a wide variety of solid tumors [4, 5] and is administered via a short 15-minute i.v. infusion. Zoledronic acid received approval from the U.S. Food and Drug Administration (FDA) for the treatment of HCM (August 2001) and from both the FDA (February 2002) and the European Agency for the Evaluation of Medicinal Products (July 2002) for the prevention of skeletal complications in patients with multiple myeloma or bone metastases secondary to any solid tumors, including breast, prostate, and lung cancers. SAFETY AND EFFICACY OF I.V. BISPHOSPHONATE INFUSIONS Although oral bisphosphonate therapy might seem more convenient than i.v. administration, daily oral bisphosphonate therapy is less effective and may not be any more convenient than monthly infusions [6-8]. Most first- and second-generation bisphosphonates are marketed as both i.v. and oral formulations for treating benign indications, such as Paget s disease and osteoporosis, and oral clodronate (1,600-3,200 mg/day) is approved outside the U.S. for treating HCM. However, orally administered bisphosphonates have limited efficacy in the treatment of HCM and malignant bone disease compared with i.v. therapy [6, 7]. Further, their use is limited by poor bioavailability (<5%), and large doses must, therefore, be administered in strict accordance with established protocols to avoid gastrointestinal toxicities (primarily esophagitis) [6, 8, 9]. Intravenous bisphosphonates mediate a more rapid and sustained normalization of serum calcium than do oral bisphosphonates and have demonstrated efficacy in reducing skeletal morbidity in patients with malignant bone lesions [7, 10]. Therefore, i.v. bisphosphonates are preferred by most physicians. Indeed, only i.v. bisphosphonates (etidronate, pamidronate, and zoledronic acid) have been approved in both the U.S. and Europe for the treatment of bone metastases and HCM [6]. At the time of this publication, zoledronic acid was the most prescribed bisphosphonate. It had been administered to more than 300,000 patients worldwide [11] and had been approved for the treatment of bone metastases in more than 40 countries worldwide including the U.S. and Europe and for the treatment of HCM in more than 70 countries. In general, bisphosphonates are well tolerated with a predictable and manageable side-effect profile that may include acute-phase responses, fluctuations in serum ion levels (calcium, magnesium, and phosphorus), and occasional elevations in serum creatinine [12, 13]. Self-limiting and transient acute-phase responses (e.g., mild fever, anorexia, asthenia, fatigue, headache, and flu-like symptoms) occasionally occur after the initial i.v. administration of nitrogen-containing bisphosphonates. These symptoms occur with similar incidences and severities for pamidronate, alendronate, and zoledronic acid. Ibandronate, however, has also been associated with prominent muscle pain and lymphocytosis [12]. The incidences of hypocalcemia and hypophosphatemia have been low in recent clinical trials of pamidronate and zoledronic acid in patients with malignant bone disease, possibly because patients received daily vitamin D and calcium (500 mg/day) supplementation [2, 5]. Acute-phase symptoms are manageable and transient, and hypophosphatemia and hypocalcemia may be reduced by prophylactic daily supplements. Intravenous bisphosphonates can infrequently also have adverse effects on renal function that appear to be both dose and infusion-rate dependent [2, 5, 14, 15]. These adverse renal effects are largely related to the bisphosphonate backbone shared by all drugs in this class and do not appear to be affected by differences in the side chain that affects the antiresorptive potency of these agents. The incidence of detectible adverse effects on renal function is expected to increase with faster rates of infusion (mg/minute) for all bisphosphonates. Consequently, when administering large doses of the weak first-generation bisphosphonates, clodronate and etidronate, i.v. infusions of long duration (e.g., 24 hours) were

3 Berenson, Hirschberg 321 required to assure renal safety [12]. However, the newer, highly potent, nitrogen-containing bisphosphonates, including pamidronate and zoledronic acid, are effective when administered at much lower molar amounts than the firstgeneration compounds and, thus, can be administered via much shorter (and, therefore, more convenient) i.v. infusions [1, 16, 17]. For example, at the low dose required to achieve therapeutic effects on bone resorption, zoledronic acid (4 mg) can be safely administered via a relatively rapid 15-minute i.v. infusion, with minimal adverse affects on renal function [1, 16-18]. New long-term clinical results from phase III trials have revealed that 4 mg zoledronic acid infused over 15 minutes is as well tolerated as 90 mg pamidronate infused over 2 hours [3, 19]. The recommended infusion time for 90 mg pamidronate is 2-4 hours. Several studies suggest that 90 mg pamidronate can be safely infused over minutes; however, the authors of those studies did not recommend this for general use without further testing because the results were preliminary, the treatment durations were <1 year, or the studies were relatively small [20-22]. TREATMENT OF HYPERCALCEMIA OF MALIGNANCY Adequate hydration can transiently lower serum calcium, improve the rate of glomerular filtration, and inhibit the tubular reabsorption of calcium that typically occurs in patients with HCM [7]. Therefore, acute management of HCM begins with hydration therapy (including i.v. saline infusions), and urine output should be maintained at approximately 2 liters/day during treatment [13]. Intravenous bisphosphonates are the mainstay of treatment for severe HCM because they provide the most rapid and sustained normalization of serum calcium levels [10]. However, it is important to ensure adequate hydration before administering bisphosphonates to patients with HCM to minimize the risk of adverse effects during treatment. In the early 1980s, clinical trials of the first-generation bisphosphonates, etidronate and clodronate, established that bisphosphonates could be used to effectively treat HCM [23, 24]. The investigators of those small, early trials reported no serious acute or long-term side effects. However, in a letter to Lancet in 1983, Bounameaux et al. [14] reported three cases of fatal acute renal failure in patients receiving rapid infusions of i.v. etidronate or clodronate, which may have been caused by the precipitation of insoluble calcium-bisphosphonate complexes in the renal tubuli [12]. The authors of that letter concluded that i.v. bisphosphonates should be infused slowly and that renal function should be monitored continuously during therapy for HCM. Since the observations of Bounameaux et al., episodes of renal failure have become extremely rare during i.v. bisphosphonate therapy, although patients occasionally develop mild elevations of serum creatinine. The reason for this is likely twofold. First, because of these early reports of renal failure, subsequent trials of i.v. bisphosphonates in patients with HCM were designed conservatively, such that serum creatinine levels were closely monitored, and the agents were also administered slowly and in large volumes of infusate. Secondly, the introduction of the more potent second- and third-generation bisphosphonates, primarily pamidronate, alendronate, ibandronate, and zoledronic acid, has allowed for effective treatment at much lower molar doses than those required for the first-generation agents etidronate and clodronate. In a comparative analysis of various bisphosphonates used to treat HCM, Zojer et al. [12] found that the administration of first-generation bisphosphonates was associated with a higher incidence of elevated serum creatinine (8% for etidronate, 5% for clodronate) compared with the second- and third-generation bisphosphonates that were introduced later ( 2% each for pamidronate, alendronate, and ibandronate). CLODRONATE Intravenous clodronate has been studied at doses ranging from 300 mg/day for up to 7 days to a single 1,500-mg infusion over 4 hours and has been shown to normalize serum calcium in approximately 80% of patients (based on experience in approximately 200 patients) [12, 25]. However, in a randomized trial comparing 60 mg pamidronate with 1,500 mg clodronate (both via 4-hour i.v. infusions) for the treatment of patients with mild to moderate HCM, increased serum creatinine occurred in 5 of 21 (24%) patients treated with clodronate, compared with none of the pamidronatetreated patients [26]. Pamidronate was also more effective than clodronate in establishing normocalcemia (100% versus 80%, respectively), and the mean duration of normocalcemia was significantly longer in the pamidronate arm (28 versus 14 days; p < 0.01). PAMIDRONATE The efficacy and safety of i.v. pamidronate in the treatment of HCM have been established based on clinical trial experience in more than 500 patients. Early trials investigated single doses of pamidronate ranging from mg infused over 2-24 hours [12, 26-35]. In conjunction with rehydration, pamidronate effectively normalized serum calcium levels in approximately 80% of patients and was well tolerated when infused at doses up to 90 mg over 2-24 hours [12]. The primary adverse events were fever, infusion-site reactions, and hypocalcemia. Although there were transient increases in serum creatinine levels in some patients, there were no permanent effects on renal function when 60 mg pamidronate was administered via a 4- or 24-hour i.v.

4 322 Convenience of Zoledronic Acid infusion [12, 30, 31]. Subsequently, pamidronate was shown to be safe and effective for the treatment of HCM when administered as a 2-hour i.v. infusion [28]. Moreover, two randomized, comparative trials found that a single infusion of 60 mg pamidronate was more effective than multiple infusions of etidronate (7.5 mg/kg i.v. daily 3 days) [30] or clodronate (1,500 mg) [26] for the treatment of HCM. Based on these data, i.v. pamidronate (60 or 90 mg, depending on baseline serum calcium levels) became the preferred agent for the treatment of HCM. These studies established that bisphosphonate therapy could be safely administered as a 2-hour i.v. infusion in the outpatient setting, which has since become the standard in most countries because costs are lower and patients are less inconvenienced than with a 24-hour infusion. IBANDRONATE Intravenous ibandronate also has demonstrated efficacy in the treatment of HCM and has received regulatory approval in Europe for this indication. Single doses of ibandronate ranging from mg via 2- to 4-hour infusions have been investigated in trials involving more than 300 patients [12]. A dose of 4-6 mg ibandronate (via a 2-hour infusion) was required to effectively normalize serum calcium levels in 75%-80% of patients with moderate-to-severe HCM (serum calcium 12 mg/dl) [36]. Serum creatinine elevations were reported in <1% of patients treated with ibandronate in those studies [12]. The safety of a single i.v. bolus infusion of 3 mg ibandronate in patients with normocalcemic breast cancer has also been investigated in a small pilot study; however, transient proteinuria occurred in almost half the patients and was sometimes associated with leukocyturia and microhematuria [17]. Additionally, this regimen was associated with a high incidence of serum divalent ion depletion (67% hypocalcemia and 53% hypophosphatemia). The administration of i.v. bolus ibandronate at higher doses or in patients with HCM has not been investigated and is not recommended. Therefore, the use of 6 mg ibandronate to treat HCM requires an infusion time 1 hour [37]. ZOLEDRONIC ACID Zoledronic acid is a new-generation, highly potent, nitrogen-containing bisphosphonate that is at least 100-fold more potent than pamidronate in preclinical models of osteoclastmediated bone resorption [38] and roughly an order of magnitude more potent than ibandronate at inhibiting signal transduction pathways in osteoclasts [39]. Zoledronic acid has gained worldwide regulatory approval for the treatment of HCM based on data from two large, randomized trials demonstrating the safety and superior efficacy of 4 or 8 mg zoledronic acid, compared with 90 mg pamidronate [1]. Those trials enrolled 287 patients with moderate to severe HCM (serum calcium 12.0 mg/dl) who were randomized to receive a single infusion of zoledronic acid (4 or 8 mg via a 5-minute infusion) or pamidronate (90 mg via a 2-hour infusion). Patients received a total of 500 ml i.v. fluids over 4 hours, and the study drug could be administered after 250 ml of fluids had been delivered. In the pooled analysis of these two identical studies, both the 4- and 8-mg doses of zoledronic acid were significantly more effective than 90 mg pamidronate, normalizing serum calcium levels by day 10 in 88%, 87%, and 70% of patients, respectively, and the duration of response was significantly longer in patients treated with zoledronic acid [1]. Overall, the adverse-event profiles of zoledronic acid and pamidronate were similar. Serum creatinine levels were monitored throughout the trial and graded according to the Common Toxicity Criteria (CTC) of the National Cancer Institute, which rates mg/dl as grade 3 and >7.2 mg/dl as grade 4, using an upper limit of normal of 1.2 mg/dl [40]. In the pamidronate group (n = 103), three patients had grade 3 and one patient had grade 4 elevated serum creatinine levels (4% total). The 8-mg dose of zoledronic acid was associated with a slightly higher incidence of increased serum creatinine (3% grade 3 and 2% grade 4). In contrast, none of the 86 patients treated with 4 mg zoledronic acid developed CTC grade 4 serum creatinine levels and only two (2%) patients had transient grade 3 serum creatinine levels. Therefore, those trials showed that 4 mg zoledronic acid could be safely administered to most patients as a 5-minute infusion, with a renal safety profile comparable with that of 90 mg pamidronate delivered via a 2-hour infusion. However, based on the more extensive clinical experience with zoledronic acid in >3,000 patients with bone metastases (see below), it is recommended that 4 mg zoledronic acid be infused in 100 ml of infusate over no less than 15 minutes. Based on the data from the randomized, comparative trials of zoledronic acid versus pamidronate [1] and pamidronate versus clodronate [26] described above, zoledronic acid (4 mg) appears to be more effective and better tolerated than first- and second-generation bisphosphonates [41]. Further, in patients with moderate to severe HCM (corrected serum calcium level 12 mg/dl), 4 mg zoledronic acid normalized serum calcium levels in 88% of patients [1], a rate that is at least comparable with the efficacy of ibandronate (6 mg), which yielded a 77% response rate in a similar patient population [36]. Importantly, 4 mg zoledronic acid has been shown to be safe and well tolerated when administered via the shortest approved infusion time of any bisphosphonate therapy. DOSING RECOMMENDATIONS FOR HCM Body et al. [7] published recommendations for the dose and schedule of i.v. clodronate, pamidronate, and ibandronate

5 Berenson, Hirschberg 323 for the treatment of HCM (Table 1) [1, 2, 4, 5, 7, 42], which included the bisphosphonates available at that time. Zoledronic acid can now be added to this list with a recommended dose and schedule of 4 mg via a 15-minute infusion [43]. The recommended dose of pamidronate is mg infused over 2 hours for patients with solid tumors, and 4 hours for patients with multiple myeloma. Higher doses of pamidronate have been associated with a higher risk of nephrotoxicity [20, 44]. Although the approved infusion time for pamidronate is 2-4 hours in most countries, shorter infusion times (60-90 minutes) are widely used in clinical practice and appear to be safe for short-term treatment. However, caution must be exercised when treating patients long-term with pamidronate for bone metastases. There is limited clinical experience with long-term pamidronate therapy administered via shorter infusion times. The doses and schedules in Table 1 were recommended for treating all grades of HCM. Although i.v. etidronate is approved in some countries, the authors did not recommend it for the treatment of HCM, given its lower efficacy compared with these other agents. TREATMENT OF PATIENTS WITH BONE METASTASES Bisphosphonates are recommended for the treatment of malignant bone disease and for patients whose cancer-associated bone pain is not relieved by analgesics and radiotherapy, based on extensive clinical trial data demonstrating that bisphosphonates reduce the incidence of skeletal complications [2, 4, 5, 45-48]. Unlike HCM, which is an acute condition [49], the skeletal morbidity that occurs in patients with malignant bone disease is an ongoing chronic problem, requiring long-term therapy. For example, patients with multiple myeloma, breast cancer, or prostate cancer survive for a median of 2-3 years after the diagnosis of bone metastases [50]. Therefore, the durable efficacy, convenience, and long-term safety of bisphosphonate therapy are important considerations in those patient populations [50]. PAMIDRONATE Pamidronate (90 mg via 2- to 4-hour infusions) became widely used to reduce skeletal morbidity in patients with osteolytic bone lesions secondary to advanced multiple myeloma or metastatic breast cancer after it was shown to significantly reduce the incidence and delay the onset of skeletal complications in three phase III trials that enrolled more than 1,000 patients [47, 48, 51-53]. In those trials, and the subsequent trials of zoledronic acid, skeletal complications (i.e., SREs) were defined as pathologic fractures, spinal cord compression or collapse, and the requirement for palliative radiation therapy or surgery to bone. In the breast cancer trials, patients received 90 mg pamidronate as 2-hour Table 1. Recommended i.v. bisphosphonate treatment schedules for HCM Compound Dose a Infusion time Clodronate 1,500 mg 2+ hours Pamidronate 90 mg 2+ hours b Ibandronate 4-6 mg 2 hours Zoledronic acid 4 mg 15 minutes c a Bisphosphonates should be diluted in saline or 5% dextrose. b The approved infusion time for pamidronate is 4 hours for patients with multiple myeloma and 2 hours for patients with other cancers. However, infusion times of minutes are generally used in clinical practice in some countries and for some indications. c Although a 5-minute infusion time was found to be safe in most patients with hypercalcemia of malignancy who received a single infusion of zoledronic acid [1], a 15-minute infusion was associated with a lower incidence of reduced renal function in phase III trials in patients with bone metastases who received long-term therapy [4]. Therefore, the FDA-approved infusion time for the treatment of hypercalcemia is 15 minutes [2, 5]. Data from Major et al. [1] and Body et al. [7, 42]. infusions in 250 ml of 5% dextrose every 4 weeks for up to 24 months [47, 48, 53]. In the multiple myeloma trials, patients received 90 mg pamidronate via 4-hour infusions in 500 ml of 5% dextrose every 4 weeks for up to 21 months [51, 52]. Pamidronate therapy was well tolerated. The only adverse events that occurred with greater frequency in the pamidronate group than in the placebo group were fatigue, fever, and vomiting, all of which are characteristic of bisphosphonate-associated acute-phase responses. A few minor allergic responses to the study medication were reported during long-term therapy [46, 47, 51]. No renal adverse events were reported in the pamidronate treatment groups of either breast cancer trial [47, 48, 53]. Likewise, in patients with multiple myeloma, the renal safety profile of pamidronate was similar to that of placebo [51, 52]. These studies established the safety and efficacy of pamidronate (90 mg via a 2- to 4-hour infusion) for long-term palliative treatment of bone metastases associated with multiple myeloma or breast cancer. Recently, a peculiar renal complication associated with long-term pamidronate therapy was described in six patients with multiple myeloma and in one patient with breast cancer. These patients developed a severe nephrotic syndrome (renal insufficiency and proteinuria caused by collapsing focal segmental glomerulosclerosis [cfsgs]) after months of therapy with pamidronate [44]. Of note, five of those patients received monthly infusions of pamidronate at doses in excess of the recommended 90 mg, namely at 180 or 360 mg. Typically, cfsgs occurs as an idiopathic clinicopathologic entity or secondary to viral infections such as HIV or parvovirus B19. Pamidronate

6 324 Convenience of Zoledronic Acid therapy may be another cause for this nephrotic syndrome. Pamidronate-associated cfsgs appears to occur independently of the underlying malignancy or chemotherapeutic regimen and seems to be a rare event with treatment at or below the recommended dose of 90 mg infused over at least 2 hours. Because the nephrotoxicity of pamidronate is associated with glomerular defects, patients may first develop albuminuria prior to rises in serum creatinine levels. ZOLEDRONIC ACID Zoledronic acid is the newest addition to the repertoire of bisphosphonates available to oncologists and, based on the results of the three large phase III trials outlined below, exhibits potency superior to and renal tolerability comparable with that of other commercially available bisphosphonates [41]. Zoledronic acid demonstrated promising activity in phase I trials, a predictable and manageable safety profile, and no serum creatinine elevations above CTC grade 2 following monthly 5-minute infusions of up to 8 mg for 3 months [15, 18]. In a multicenter, phase II trial, the safety and efficacy of zoledronic acid (0.4, 2.0, and 4.0 mg by 5-minute i.v. infusions) were compared with those of pamidronate (90 mg by a 2-hour i.v. infusion) during 9 months of therapy in 280 patients with breast cancer or multiple myeloma. The phase II results indicate that monthly 5-minute infusions of zoledronic acid have a safety profile comparable with that of 2-hour infusions of 90 mg pamidronate, and that 4 mg zoledronic acid appeared to be as effective as 90 mg pamidronate at reducing skeletal complications [16]. In addition, 4 mg zoledronic acid had a more profound impact than pamidronate on markers of bone resorption. Based on the promising results from these early clinical studies, an extensive phase III clinical trial program was initiated in 1998 and has recently reached completion. Three large, multicenter, randomized trials were conducted in patients with bone lesions from breast cancer or multiple myeloma (protocol 010), prostate cancer (protocol 039), or solid tumors other than breast or prostate cancers (protocol 011). Protocol 010 compared zoledronic acid with pamidronate, the former standard of care for managing skeletal morbidity in patients with breast cancer or multiple myeloma, whereas protocol 039 and protocol 011 were placebo controlled because no bisphosphonate had previously demonstrated efficacy in those patient populations. The trials enrolled patients with corrected serum calcium levels <12 mg/dl and serum creatinine levels 3 mg/dl at baseline. Based on the results from phase I and II testing, the initial dose and schedule of zoledronic acid was 4 or 8 mg in 50 ml of infusate (0.9% sodium chloride or 5% glucose solution) via a 5-minute infusion once every 3 or 4 weeks in all phase III trials. However, shortly after the phase III trials were initiated, the infusion time of zoledronic acid was amended to 15 minutes and the infusate volume was increased to 100 ml, because the renal safety board detected higher incidences of notable serum creatinine elevations in the zoledronic acid arms that used the 5-minute infusion protocol. After the infusion time amendment was introduced, the integrated safety analysis demonstrated the long-term safety of the 4 mg zoledronic acid 15-minute infusion: <2% of patients developed CTC grade 3 or 4 serum creatinine elevations, an incidence similar to that observed in patients treated with 90 mg pamidronate [2, 4, 12, 47, 48, 51-53]. However, because of ongoing concerns about renal safety, the 8-mg dose was amended to 4 mg (8/4 mg group). The proportions of patients in protocol 010 with elevated serum creatinine levels before and after the infusion amendment are shown in Figure 1 [2]. In this study, notable elevation of serum creatinine level was defined as an increase 0.5 mg/dl for patients with baseline serum creatinine levels 1.4 mg/dl, an increase 1.0 mg/dl for patients with baseline serum creatinine levels >1.4 mg/dl, or an increase that resulted in doubling of the baseline value. Following the protocol amendment, the proportions of patients who experienced notable increases in serum creatinine levels were 8.9% for 4 mg zoledronic acid and 8.2% for pamidronate [2]. The nephrotic syndrome that was recently described in association with pamidronate therapy [44] was not observed in this trial. These phase III trials demonstrated that zoledronic acid has broad clinical utility and is safe for extended use in patients with advanced cancers. In patients with bone lesions secondary to breast cancer or multiple myeloma (protocol 010), 4 mg zoledronic acid was at least as effective as 90 mg Patients with serum creatine increase (%) Zoledronic acid 4 mg Pamidronate 90 mg 6.7 Before 15-minute amendment After 15-minute amendment Figure 1. Proportion of patients with notable elevations in serum creatinine levels by treatment group before and after the protocol amendment increasing the infusion time for zoledronic acid from 5 to 15 minutes. In this study, a notable elevation of serum creatinine was defined as an increase 0.5 mg/dl for patients with baseline serum creatinine levels 1.4 mg/dl, an increase 1.0 mg/dl for patients with baseline serum creatinine levels >1.4 mg/dl, or an increase that resulted in doubling of the baseline value. Included in this analysis are patients with breast cancer and multiple myeloma treated in protocol 010. Data from Rosen et al. [2].

7 Berenson, Hirschberg 325 pamidronate at every clinical end point and provided significant efficacy benefits over pamidronate in some secondary clinical end points and among patients with breast cancer [2, 3]. Specifically, a predefined multiple event analysis revealed that patients who received 4 mg zoledronic acid had a statistically significant 16% lower risk of developing SREs (including HCM) than patients who received pamidronate (90 mg; p = 0.03) during 2 years of treatment (core and extension studies) [3]. This multiple event analysis used Andersen- Gill methodology [54] to analyze the incidence and timing of all SREs in each patient throughout the course of the trial and provides a robust and comprehensive assessment of skeletal morbidity [55]. In addition to its prevalence in advanced breast cancer, metastasis to bone also occurs commonly in patients with other solid tumors [50]. Nevertheless, before the introduction of zoledronic acid, no bisphosphonate had demonstrated significant objective benefits in this sizable patient population [56-64]. Moreover, there was no previous study showing the efficacy of bisphosphonates in patients with osteoblastic metastases. In the phase III trial in patients with bone metastases (mostly osteoblastic lesions) from prostate cancer (protocol 039), treatment with zoledronic acid resulted in a significantly lower proportion of patients experiencing objectively measurable skeletal complications (p = 0.021), a significantly longer time to first skeletal complication (p = 0.011), and a significantly lower mean annual incidence of skeletal complications (p = 0.006) [5]. Zoledronic acid was well tolerated, and treatment-related adverse events were limited to transient fatigue, myalgia, fever, and lower-limb edema. In the 4-mg zoledronic acid group, only 2% of patients developed CTC grade 3 or 4 hypocalcemia, and 3% of patients had grade 3 serum creatinine increases. Most events were transient and manageable, and therapy was generally well tolerated. Similarly, among patients with solid tumors other than breast or prostate cancers (protocol 011), treatment with 4 mg zoledronic acid every 3-4 weeks resulted in a significantly longer time to first SRE (p = 0.023), significantly lower mean annual incidence of SREs and HCM (p = 0.017), and significantly lower risk of developing SREs including HCM (robust p = 0.006) by multiple event analysis [4]. The only adverse events that occurred with greater frequency, albeit only slightly, with 4-mg zoledronic acid treatment than with placebo were nausea, vomiting, and dyspnea, all of which were manageable and transient. Each of these trials was extended to investigate the efficacy and safety of zoledronic acid during long-term therapy (up to 24 months), and these results are soon to be released. These trials support the safety and broad clinical activity of zoledronic acid for patients with malignant bone disease from a variety of primary cancers, including patients with osteolytic, osteoblastic, or mixed bone lesions. Further, these trials demonstrate that effective bisphosphonate therapy can be delivered safely via a relatively short and convenient 15-minute i.v. infusion, which may have important implications with respect to patient preferences and infusion center patient throughput [65]. IBANDRONATE Ibandronate has also been evaluated for the palliative treatment of bone metastases in patients with breast cancer. In a multicenter, randomized, placebo-controlled trial, 462 patients received either ibandronate (2 mg via an i.v. bolus injection or 6 mg via a 1- or 2-hour infusion) or placebo monthly for up to 2 years [66]. The 6-mg dose resulted in a statistically significant 20% lower skeletal morbidity period rate (the number of 12-week periods in which new skeletal complications occurred; p = compared with placebo) and a significantly lower mean number of bone events per patient (2.65 versus 3.54 events/patients for placebo; p = 0.032). However, the 2-mg dose resulted in a nonsignificant 11% lower skeletal morbidity period rate (p = 0.152) and a mean number of bone events per patient that was actually higher than that of the placebo arm (4.24 versus 3.54 events/patient; p value not given). The difference between the proportions of patients who experienced no new bone events during the trial in the 6 mg ibandronate arm and in the placebo arm approached significance (49% versus 38% for placebo; p = 0.052); however, there was no difference in this end point between the 2 mg ibandronate and placebo arms (38% for both). Administration of 6 mg ibandronate via a 1- to 2-hour infusion each month was well tolerated; however, the incidence of clinically relevant serum creatinine increases was 2.6% for 6 mg ibandronate, 0.7% for 2 mg ibandronate, and 1.3% for placebo. Unfortunately, no specific definition of clinically relevant increases was provided. Nonetheless, this corresponds closely with the proportion of patients who developed grade 3 serum creatinine elevations during treatment with 4 mg zoledronic acid by a 15-minute infusion [2]. Therefore, based on the limited data available, it appears that 6 mg ibandronate has a renal safety profile similar to other i.v. bisphosphonates. Intravenous ibandronate (2-mg bolus injection monthly) has also been investigated in patients with osteolytic lesions from multiple myeloma, but failed to produce any significant effects on skeletal morbidity [67]. The efficacy of the 6-mg ibandronate dose outside the breast cancer setting is unknown. Daily oral ibandronate is also under investigation in patients with malignant bone disease. A preliminary report of a phase III, placebo-controlled trial of oral ibandronate (20 or 50 mg daily) in patients with bone-metastatic breast cancer reported that ibandronate produced significantly less

8 326 Convenience of Zoledronic Acid skeletal morbidity than placebo. Oral ibandronate was also reported to be well tolerated; however, patients treated with the 50-mg dose of ibandronate (the recommended dose for further study) had a higher incidence of anemia and renal adverse events than did patients receiving the 20-mg dose or placebo [68]. Furthermore, long-term compliance with daily oral bisphosphonate therapy in patients outside structured clinical trials may be an issue because of epigastric pain, especially if patients fail to drink adequate volumes of water and remain upright after swallowing the tablets. In addition, decreased absorption of the medication can result if patients ingest food or beverages (other than water) for 30 minutes after taking their bisphosphonate tablets. Because of these issues, daily oral bisphosphonate therapy may be less convenient than a once-monthly i.v. infusion [6-9]. Although the efficacy of bisphosphonates for preventing skeletal complications in patients with bone metastases secondary to breast cancer was well established when the ibandronate trials were initiated, those trials compared ibandronate with a placebo control arm. No comparative trials of ibandronate with other bisphosphonates for the treatment of malignant bone disease have been reported. Therefore, the relative safety and efficacy of ibandronate compared with pamidronate or other bisphosphonates are not known. CONVENIENCE OF A 15-MINUTE VERSUS 2-HOUR INFUSION Recently, DesHarnais Castel et al. [69] conducted a time and motion study that compared the overall differences in the administration of zoledronic acid (approved infusion time of 15-minutes) and pamidronate (approved infusion time of 2 hours) in the clinical setting using data from three outpatient infusion sites. Patients treated with pamidronate had an average visit time of 2 hours, 52 minutes compared with 1 hour, 6 minutes for patients treated with zoledronic acid. Similar results were recently reported from a Canadian time and motion study and an Australian study of infusion chair occupancy time during bisphosphonate therapy [70, 71]. Although the quality-of-life benefits of the 15-minute infusion have not yet been formally quantified, the need to spend less time at outpatient clinics is likely to represent considerable benefit to the patient. A recent patient preference study compared the pamidronate with the zoledronic acid infusion protocols. After patients (n = 183) received alternating cycles of zoledronic acid and pamidronate therapy, they were asked to complete a questionnaire about their preferences. Zoledronic acid was preferred by 86% of the patients, whereas 14% of the patients preferred pamidronate (p < ). The main reason for this preference was the shorter infusion time of zoledronic acid [65, 72]. These analyses provide tangible support for the inference that shorter infusion times provide meaningful benefits to patients. CONCLUSIONS AND FUTURE DIRECTIONS The accumulated clinical experience with i.v. bisphosphonates has shown that these compounds can be safely administered for the treatment of HCM and as long-term palliative therapy to reduce the skeletal morbidity associated with malignant bone disease. Because bisphosphonates provide meaningful quality-of-life benefits to patients, they have been widely accepted as an important adjunct to standard anticancer therapies for patients with bone lesions. This, in turn, has led to increased pressure to improve patient convenience and ensure long-term safety. Before the introduction of more potent agents, the administration of high doses of bisphosphonates was required for clinical efficacy, and infusions of long duration (e.g., up to 24 hours) were needed to avoid serious renal complications. Further, first-generation bisphosphonates had demonstrated limited clinical activity. The introduction of highly potent, new-generation bisphosphonates that are effective at lower doses than were earlier bisphosphonates has enabled the use of shorter, more convenient infusion protocols. Notably, 4 mg zoledronic acid, which has a demonstrated greater efficacy and broader clinical activity than any other bisphosphonate, can be safely infused in just 15 minutes. Therefore, zoledronic acid offers a more effective, safe, and convenient option for bisphosphonate therapy in patients with advanced cancers. ACKNOWLEDGMENTS J.B. is on the advisory board and receives grant support and honoraria from Novartis. R.H. is a consultant for Novartis. 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