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Recommendations for Zoledronic Acid Treatment of Patients with Bone Metastases

On behalf of the Monterey Zoledronic Acid Advisory Board; Institute for Myeloma & Bone Cancer Research, West Hollywood, California, USA

Correspondence: James R. Berenson, M.D., Institute for Myeloma & Bone Cancer Research, 9201 W. Sunset Boulevard, Suite 300, West Hollywood, California 90069, USA. Telephone: 310-623-1214; Fax: 310-623-1120; e-mail: jberenson{at}myelomasource.org

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
After completing this course, the reader will be able to:

1. Describe new indications for the use of i.v. bisphosphonates in patients with metastatic bone disease.
   
2. Explain the importance of infusion time on potential adverse renal events from bisphosphonates.
   
3. List the types of adverse events that are associated with i.v. bisphosphonate therapy.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
The introduction of zoledronic acid, a new-generation bisphosphonate, has greatly extended the use of bisphosphonates in the treatment of patients with bone metastases. On the basis of results from three large, randomized, phase III clinical trials enrolling more than 3,000 patients, zoledronic acid (4 mg via 15-minute infusion) was approved in the United States for the treatment of patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy and patients with multiple myeloma. Zoledronic acid is also approved in Europe for the prevention of skeletal-related events in patients with advanced malignancies involving bone. Current treatment guidelines published by the American Society of Clinical Oncology recommend the use of intravenous bisphosphonates at first radiographic evidence of osteopenia in patients with multiple myeloma or osteolytic bone lesions in patients with breast cancer to significantly reduce the occurrence and delay the onset of skeletal complications. Zoledronic acid has also demonstrated efficacy in the treatment of bone metastases in patients with prostate cancer, lung cancer, and other solid tumors. Bisphosphonate therapy is generally well tolerated but can be associated with increases in serum creatinine. Therefore, monitoring renal function is required for all patients receiving bisphosphonate therapy. Serum creatinine should be monitored before each dose and treatment withheld until any serum creatinine elevations have resolved to baseline levels. Caution should be exercised when treating patients who are receiving other potentially nephrotoxic therapies. With these simple precautions, intravenous bisphosphonate therapy is safe for long-term use and provides durable treatment benefits.

Key Words. Bisphosphonate • Guidelines • Pamidronate • Renal safety • Zoledronic acid

	INTRODUCTION

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
Skeletal complications contribute substantially to the burden of disease in patients with bone metastases from solid tumors and in patients with multiple myeloma. Bone metastases are the most common cause of cancer-related pain [1] and often require palliative radiotherapy. Patients with advanced cancer involving bone frequently develop painful and debilitating pathologic fractures and spinal cord compression that can seriously limit mobility and may require surgical intervention. These and other skeletal complications contribute to the deterioration in quality of life and independence of many cancer patients [2]. Median survival after the development of bone metastases ranges from 6–48 months, depending on tumor type [2]. Malignant bone disease can result in chronic morbidity that often requires repeated interventions over several years.

Approximately half of all patients with solid tumors that metastasize to bone experience one or more skeletal events (including pathologic fractures, spinal cord compression, radiotherapy or surgery to bone, and hypercalcemia) during the course of their disease [3, 4]. The incidence of these skeletal events varies depending on the type of primary cancer. For example, patients with predominantly osteolytic bone metastases secondary to advanced breast cancer are at high risk. Without bisphosphonate therapy, these patients will experience an average of four skeletal events, including two pathologic fractures, each year [4]. Patients with multiple myeloma, or bone metastases from prostate cancer, lung cancer, or renal cell carcinoma (RCC) are also at high risk of skeletal complications. Patients with multiple myeloma experience an average of two skeletal events per year [5, 6], and patients with prostate cancer have a mean annual incidence of 1.5 events per year [7]. Notably, approximately 80% of patients with bone metastases from RCC will develop a skeletal complication without bisphosphonate therapy [8].

Currently available palliative therapies for patients with malignant bone disease include radiation, chemotherapy, hormone therapy, orthopedic surgery, and i.v. bisphosphonates. Bisphosphonate therapy has emerged as an important component of the overall management strategy for malignant bone disease. Randomized, placebo-controlled trials have shown that when i.v. bisphosphonates are administered in conjunction with standard anticancer therapy, the incidence of skeletal complications is significantly reduced. Pamidronate has been widely used as palliative therapy in patients with osteolytic lesions from multiple myeloma or metastatic breast cancer, based on evidence that 90 mg pamidronate every 3–4 weeks significantly reduced the incidence and delayed the onset of skeletal complications in these patients compared with placebo [3, 4, 6, 9]. Moreover, bisphosphonates have been shown in a variety of studies to have analgesic effects on bone pain in patients with bone metastases [10]. Until recently, other than in breast cancer or multiple myeloma, no bisphosphonate has demonstrated significant clinical benefits for cancer patients whose cancer has metastasized to bone (e.g., prostate, lung, and renal cancers).

Recently, the clinical benefits of a new-generation bisphosphonate, i.e., zoledronic acid, have been extended to patients with bone metastases secondary to a broad range of solid tumors including prostate cancer, lung cancer, and RCC. Zoledronic acid recently received broad regulatory approval for the treatment of bone metastases secondary to all solid tumor types and bone lesions from multiple myeloma based on the results of three large, randomized, phase III clinical trials enrolling more than 3,000 patients. These trials demonstrated that zoledronic acid (4 mg via 15-minute i.v. infusion every 3–4 weeks) effectively reduced the incidence of skeletal complications associated with malignant bone disease for patients with breast cancer, multiple myeloma, prostate cancer, or solid tumors other than breast or prostate cancer [7, 11, 12]. The primary efficacy end point in all three trials was the proportion of patients who experienced at least one skeletal-related event (SRE), defined as a pathologic fracture, spinal cord compression, radiotherapy to bone, or surgery to bone. Change in antineoplastic therapy to palliate bone pain was also included as an SRE only in the trial evaluating patients with prostate cancer. Hypercalcemia of malignancy (HCM) was included as an SRE in the analysis of secondary end points, including time to first SRE, the mean annual incidence of SREs (i.e., skeletal morbidity rate), and a multiple event analysis using the Andersen-Gill method. Multiple event analysis takes into account all clinically relevant SREs and the time to each event over a period of time, thereby providing a rigorous and sensitive assessment of skeletal morbidity. These three international trials were the largest bisphosphonate trials ever conducted, and unlike the previous pamidronate trials, they included patients with all types of bone lesions (i.e., osteolytic, mixed, and osteoblastic based on their radiographic appearance).

In the first of these trials to be published, zoledronic acid was compared with pamidronate in 1,648 patients with stage IV breast cancer with at least one bone lesion or Durie-Salmon stage III multiple myeloma. The results from this trial at 13 months demonstrated that zoledronic acid (4 mg via 15-minute infusion) was at least as effective as pamidronate (90 mg via 2-hour infusion) in the overall efficacy analysis, with a similar safety profile [11]. In addition, zoledronic acid significantly reduced the incidence of radiotherapy to bone compared with pamidronate (15% versus 20%; p = 0.031). Most notably, multiple event analysis showed that zoledronic acid significantly reduced the risk of developing SREs by an additional 16% (p = 0.030) compared with pamidronate during the 24 months of treatment [13, 14].

Zoledronic acid was compared with placebo in 643 patients with bone metastases from prostate cancer that had progressed during hormone therapy [7]. These patients develop primarily osteoblastic lesions. Zoledronic acid (4 mg) significantly reduced the proportion of patients who experienced at least one SRE at 15 months compared with placebo (33% versus 44%; p = 0.021), and zoledronic acid displayed consistent efficacy across all secondary end points. The majority of SREs in this patient population were pathologic fractures and radiation to bone. Of note, 22% of patients in the placebo group had a fracture in the first 15 months compared with 13% of patients treated with 4 mg zoledronic acid (p = 0.015). Patients treated with zoledronic acid also had lower mean pain scores (Brief Pain Inventory composite score) compared with placebo at every time point, and these differences were statistically significant (p < 0.05) at the 3- and 9-month time points. This is the first randomized, placebo-controlled trial to demonstrate that a bisphosphonate can provide objective and durable clinical benefits to patients with prostate cancer with bone metastases.

In the most recently published of these phase III trials, zoledronic acid was compared with placebo in 773 patients with bone metastases secondary to solid tumors other than breast or prostate cancer (including lung, renal, and bladder cancers) [12]. Half of the patients enrolled in this study had non-small cell lung cancer (NSCLC), and median survival was only approximately 6 months for the entire patient population. Although the primary end point did not reach statistical significance when HCM was excluded from the analysis, 4 mg zoledronic acid significantly decreased the proportion of patients who experienced an SRE compared with placebo when HCM was included in the analysis (38% versus 47%; p = 0.039). Zoledronic acid also significantly prolonged time to first SRE; the median time was prolonged by more than 2 months (p = 0.007) [15], which may be a more meaningful assessment of treatment effect in this poor-prognosis patient population [12]. Furthermore, in the overall patient population and the NSCLC stratum, multiple event analysis demonstrated that treatment with 4 mg zoledronic acid significantly reduced the risk of developing SREs by 29% compared with placebo (p = 0 .036) [16].

On the basis of results from these trials, zoledronic acid is emerging as the new standard of care for managing skeletal morbidity in patients with advanced cancers involving bone. Zoledronic acid has also been shown to reduce skeletal morbidity in patients with both osteolytic and osteoblastic bone lesions [17]. Zoledronic acid can be safely administered via a 15-minute infusion, compared with the minimum recommended infusion time of 2 hours for pamidronate. Since receiving U.S. and European regulatory approval, zoledronic acid has been used to treat >800,000 patients with bone metastases. In the context of its widespread application, we have developed treatment recommendations for zoledronic acid therapy to ensure safety and efficacy, based on the available data.

	CONVENIENCE OF A 15-MINUTE INFUSION

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
The infusion protocol for zoledronic acid has been standardized and is now available online at http://www.us.zometa.com/hcp/productinfo/infusioninstructions.jsp. Preinfusion assessments include a physical examination, vital signs, and laboratory testing of serum creatinine levels and hydration status. Because all i.v. bisphosphonates have the potential to cause an increase in serum creatinine and patients with serum creatinine 3.0 mg/dl were excluded from the phase III zoledronic acid trials, patients must be adequately hydrated and have serum creatinine levels <3.0 mg/dl (<4.5 mg/dl in patients with HCM [18] if the benefits of treatment are considered to outweigh the risk) before receiving i.v. bisphosphonates. Patients should be encouraged to drink two glasses of water before receiving their bisphosphonate infusion, but i.v. hydration is not typically necessary. The maximum recommended dose of zoledronic acid for the treatment of bone metastases or hypercalcemia of malignancy is 4 mg infused over no less than 15 minutes. Zoledronic acid powder (4 mg) can easily be reconstituted in 5 ml sterile water for injection USP and diluted in no less than 100 ml of 0.9% sodium chloride USP or 5% dextrose injection USP [11]. A concentrated solution of zoledronic acid (4 mg in 5 ml sterile water) is also available, eliminating the need for reconstitution. A 5-ml aliquot of the concentrate (4 mg zoledronic acid) should be mixed with 100 ml of calcium-free diluent before infusion. If not used immediately, the diluted solution can be stored in the refrigerator and should be re-equilibrated to room temperature and infused within 24 hours [19]. A peripheral i.v. line should be inserted and the diluted zoledronic acid solution infused over 15 minutes. The patient’s vital signs and the i.v. site should be monitored periodically during the infusion and again after the infusion has been completed.

Zoledronic acid has the shortest infusion time of any i.v. bisphosphonate (Table 1) [18, 20, 21]. The recommended 15-minute infusion time for zoledronic acid is significantly shorter than the 2-hour infusion time recommended for 90 mg pamidronate (4 hours for patients with multiple myeloma) [21] and results in less time spent in the infusion center for the patient [22], which many patients prefer [23]. Additionally, the shorter infusion time will allow for increased throughput in busy infusion centers [24]. Indeed, a microcosting analysis of patients receiving bisphosphonate therapy determined that the average visit time required to receive zoledronic acid was 66 minutes, compared with 172 minutes for patients receiving pamidronate, and the shorter infusion time of zoledronic acid resulted in a savings of $47 in indirect costs per infusion [22]. Based on an average of eight patients treated each day with i.v. bisphosphonates and the average infusion chair occupancy time for each agent, a typical infusion center would open up 1.8 infusion chairs per day when infusing zoledronic acid compared with pamidronate [22]. Therefore, in addition to the potential quality-of-life benefits for the patient, the shorter infusion time for zoledronic acid compared with pamidronate may reduce the demand on health care resources in busy infusion centers and hospitals.

	PATIENT SELECTION AND TIMING FOR INITIATION OF THERAPY

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

Recommendations for zoledronic acid administration that are consistent with the above guidelines and the available clinical data are summarized in Table 2 [25, 26]. Once initiated, zoledronic acid therapy should be continued as long as the patient is able to tolerate therapy or until the patient has a substantial decline in performance status.

Caution should be exercised when starting bisphosphonate therapy or when switching from one bisphosphonate to another in patients who have other renal-related risk factors (refer to guidelines in Table 2) [25, 26]. Risk factors include a diagnosis of multiple myeloma, diabetes mellitus, hypertension, advanced age, and the use of concomitant medications that are known to affect renal function (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]). Therefore, zoledronic acid or i.v. bisphosphonates should be used with caution for patients receiving drugs that may have a deleterious effect on kidney function.

	MANAGING BISPHOSPHONATE-RELATED ADVERSE EVENTS

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
Bisphosphonate therapy is associated with mainly mild to moderate adverse events. The safety profile of zoledronic acid has been well established, based on randomized controlled trials and the collective experiences of more than 800,000 patients treated with zoledronic acid. Recommendations have been developed (Table 2) [25, 26] to ensure the safety and comfort of patients during bisphosphonate therapy. The renal monitoring guidelines and treatment interruption criteria detailed in the prescribing information are the same for zoledronic acid and pamidronate.

Acute-Phase Reactions
The most common adverse events associated with the administration of i.v. bisphosphonates are self-limiting flu-like symptoms related to an acute-phase reaction [28]. Patients may have low-grade fever, arthralgia/myalgia, and increased bone pain. The incidence of these symptoms ranges from 1%–18% of patients treated with zoledronic acid and is similar to the incidence in patients receiving pamidronate (Table 3) [11, 29]. The onset of these symptoms typically occurs within 24 hours after the first infusion, and symptoms generally persist for 48 hours [28]. Acute-phase reactions usually diminish and/or disappear following the second or third infusion. Patients who are switching from pamidronate to zoledronic acid may also experience acute-phase reactions, even if they did not experience them when receiving pamidronate. Patients should be advised of the possibility that they may experience these symptoms. However, because these reactions do not occur in the majority of patients, prophylactic pretreatment regimens are not recommended. Acetaminophen and oral fluids can be used to manage flu-like symptoms, and antiemetics are recommended for nausea. It is important to recognize that the flu-like syndrome is unlikely to persist after subsequent infusions. In patients with fatigue that is accompanied by anemia, erythropoietin or transfusion support is occasionally recommended. The recommendations for supportive care during zoledronic acid therapy are summarized in Table 2 [25, 26].

View larger version (11K): [in this window] [in a new window]   Figure 1. Time to first increase in serum creatinine. Kaplan-Meier estimates of time to first increase in serum creatinine in patients with breast cancer or multiple myeloma treated with pamidronate (90 mg via 2-hour infusion) or zoledronic acid (4 mg via 15-minute infusion) in a randomized, phase III trial. Data from the trial by Rosen et al. [13].

In patients who are receiving potentially nephrotoxic therapies or who have abnormal renal function at baseline, additional considerations must be made. At this time, there are insufficient clinical data to generate specific renal monitoring recommendations for zoledronic acid in patients receiving nephrotoxic drugs such as radiographic contrast media. If possible, zoledronic acid and nephrotoxic drugs should not be administered on the same day. Anecdotal evidence from clinical experience and a small open-label trial suggest that concomitant therapy with thalidomide may potentiate adverse renal effects [32]. However, in the phase III clinical trial setting, concomitant therapy with thalidomide was not identified as a risk factor in patients with multiple myeloma [11]. Drugs with the potential for renal toxicity, such as NSAIDs, should also be administered with caution to patients who are receiving zoledronic acid, and use of these chronically administered medications may need to be avoided around the time of i.v. bisphosphonate therapy. Waiting 24 hours after the administration of zoledronic acid before administering any drugs that are potentially nephrotoxic may minimize the risk of renal impairment. Further, clinical experiences suggest that increasing the infusion time for zoledronic acid from 15 to 30 minutes may possibly further reduce the risk of serum creatinine increases in these patients. However, this has not been confirmed in controlled studies.

Other Adverse Events
The most commonly reported adverse events among patients treated with zoledronic acid or pamidronate are shown in Table 4 [11]. Severe adverse events are rare. The majority of these adverse events can be managed with standard supportive care, as summarized in Table 2 [25, 26]. Serum ion fluctuations (e.g., hypocalcemia, hypophosphatemia, and hypermagnesemia) may occur during therapy with any bisphosphonate. Therefore, dietary vitamin D supplements are recommended to minimize these events. Occasional untoward effects on the eye (uveitis) have been reported with i.v. bisphosphonates.

View this table: [in this window] [in a new window]   Table 4. Most common adverse eventsa occurring in 15% of patients with breast cancer or multiple myeloma receiving zoledronic acid (4 mg) or pamidronate (90 mg)

Duration of Bisphosphonate Therapy
There are limited data on the optimal duration of zoledronic acid therapy. Current guidelines suggest that, once initiated, bisphosphonate therapy should be continued as long as it is well tolerated or until there is a significant decrease in performance status in patients with bone metastases from breast cancer [36]. Although there are no consensus guidelines for the duration of bisphosphonate therapy in patients with prostate cancer, recently published recommendations from a multidisciplinary panel suggest that bisphosphonate treatment should be ongoing after bone metastases are diagnosed [37]. This is supported by recent reports that the efficacy of zoledronic acid does not appear to decrease during long-term use [38] or in patients who have already experienced SREs [39]. Moreover, zoledronic acid demonstrated early and sustained palliation of pain compared with placebo during a 24-month course of treatment [38]. In patients with bone metastases from solid tumors other than breast or prostate cancer, no formal recommendations have been published. However, zoledronic acid has demonstrated significant benefits in this setting in patients who have experienced prior SREs [40], so treatment should not be discontinued on the basis of SRE history.

	SUMMARY AND CONCLUSIONS

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
Zoledronic acid is the first bisphosphonate to demonstrate significant and durable clinical benefit in reducing skeletal complications for patients with malignant bone involvement from multiple myeloma and a variety of solid tumors, including breast cancer, prostate cancer, and lung cancer [7, 11, 12]. Treatment with zoledronic acid can prevent or delay debilitating skeletal complications, and therefore may slow the erosion of quality of life experienced by patients with advanced cancer involving the bone. Importantly, long-term treatment with zoledronic acid has been shown to be safe and well tolerated during its widespread use in clinical practice. Adherence to renal monitoring will ensure renal safety.

The development of an effective and safe i.v. bisphosphonate therapy that can be administered in only 15 minutes is an important therapeutic advance that provides a direct quality-of-life benefit to the patient. Furthermore, the 15-minute infusion protocol for zoledronic acid has renal and overall safety profiles similar to those of the 2-hour infusion of pamidronate, the former standard of care for patients with breast cancer or multiple myeloma [11]. In summary, with the proper dose, schedule, and patient monitoring, zoledronic acid represents an important advance in the management of patients with bone metastases.

	ACKNOWLEDGMENT

Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 
James Berenson receives research grants and honoraria and is on the advisory board for Novartis. The authors wish to thank all of the participants on the Monterey Zoledronic Acid Advisory Board for their insight and input: Dr. Per-Anders Abrahamsson, Malmo University Hospital, Sweden; Dr. Joan Albanell, Medical Oncology Service, Spain; Dr. Brent Blumenstein, Duke University Medical Center, USA; Dr. Pier Franco Conte, UO Oncologia Medica Ospedale, S. Chiara, Italy; Dr. Richard Cook, University of Waterloo, Canada; Dr. Ingo J. Diel, CCG-Klinik GmbH, Germany; Dr. Manuel Domine, Spain; Dr. Brent Eilersten, Denmark; Dr. Karim Fizaz, France; Dr. Gunther Gastl, Innsbruck University Hospital, Austria; Dr. Stephen J. Hartland, Middlesex Hospital, UK; Dr. Adrian Harnett, Norfolk and Norwich Hospital, UK; Dr. Alex Heidenreich, Germany; Dr. Celestia Higano, University of Washington Cancer Center, USA; Dr. David Joseph, Sir Charles Gairdner Hospital, Australia; Dr. S. Ming Lee, Middlesex Hospital, UK; Dr. Michael Lein, University Hospital Charite, Germany; Dr. Allan Lipton, Milton S. Hershey Medical Center, USA; Dr. Hironobu Minami, National Cancer Center Hospital East, Japan; Dr. Phillip Moreau, C.H.U. Hospital Hotel-Dieu, France; Professor Jean-Francois Morere, Service Domologie Medicale, France; Dr. Robin Murray, Peter MacCallum Cancer Institute, Australia; Dr. Emilio Palazzo, Cordoba Private Hospital, Argentina; Dr. Kishan Pandya, University of Rochester Medical Center, USA; Dr. G. David Roodman, University of Pittsburgh Cancer Institute, USA; Dr. Victoria Schaffer; Dr. Matthew Smith, Massachusetts General Hospital, USA; Dr. Andrew Spencer, Alfred Hospital, Australia; Dr. Maureen Trudeau, Toronto-Sunnybrook Regional Cancer Centre, Canada; Dr. Christine VandePol, Enpharma Consulting, USA; and Dr. Jefferson Vinholes, Brazil.

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Top Learning Objectives Abstract Introduction Convenience of a 15-Minute... Patient Selection and Timing... Managing Bisphosphonate-Related... Summary and Conclusions References

 

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