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a Cancer Research Network, Plantation, Florida, USA; b Gilroy Private Practice, Gilroy, California, USA; c Cancer Specialist of South Texas, Corpus Christi, Texas, USA; d Central Georgia Hematology Oncology Associates, Macon, Georgia, USA; e Peachtree Hematology/Oncology Associates, Atlanta, Georgia, USA; f Queens Medical Associates, Fresh Meadows, New York, USA; g Hematology Oncology Associates of Albuquerque, Albuquerque, New Mexico, USA; h Northwestern Carolina Hematology/Oncology, Hickory, North Carolina, USA; i Novartis Oncology, Florham Park, New Jersey, USA
Correspondence: Charles L. Vogel, M.D., Cancer Research Network, 350 NW 84th Avenue, Suite 305, Plantation, Florida 33324, USA. Telephone: 954-473-6776; Fax: 954-473-4552; e-mail: drcvogel{at}aol.com
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ABSTRACT |
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Key Words. Zoledronic acid • Pamidronate • Bisphosphonate • Bone metastases
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INTRODUCTION |
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In clinical trials of zoledronic acid, the most common bisphosphonate-related adverse events (AEs) were bone pain, nausea, and fatigue [7]. The incidence of renal dysfunction was similar in patients receiving zoledronic acid 4 mg over 15 minutes and patients receiving pamidronate 90 mg over 2 hours; the incidence was higher in patients receiving zoledronic acid 4 mg or 8 mg over 5 minutes [1, 3, 7]. Therefore, adhering to current zoledronic acid administration guidelines (i.e., administration of 4 mg by i.v. infusion over no less than 15 minutes) is important to minimize the development of renal dysfunction [7].
Before Food and Drug Administration (FDA) approval of zoledronic acid, many cancer patients with bone metastases received pamidronate. Many of these patients are now treated with zoledronic acid. Approximately one-third of patients treated with i.v. bisphosphonates still receive pamidronate, although many may be candidates for conversion to zoledronic acid. Data regarding the safety of zoledronic acid in patients with a history of significant exposure to bisphosphonate therapy are limited; phase III trials evaluating zoledronic acid in cancer patients with bone metastases excluded this patient population [1, 3–5]. Therefore, an evaluation of the safety of zoledronic acid in patients who received prior i.v. bisphosphonate therapy is warranted and will support the clinical rationale for converting appropriate patients to zoledronic acid.
This article reports the results of a community-based study of zoledronic acid (4 mg through a 15-minute infusion) in patients with breast cancer, prostate cancer, or multiple myeloma and bone metastases; most of these patients received prior bisphosphonate therapy. The objectives of the study were to assess: A) overall and renal safety; B) changes in pain scores from baseline; C) quality of life (QOL); and D) infusion duration. Results were analyzed according to tumor type and history of bisphosphonate therapy.
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MATERIALS AND METHODS |
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18 years of age) with at least one cancer-related bone lesion detected by conventional radiography or bone scan and either Durie-Salmon stage III multiple myeloma or biopsy-proven breast or prostate cancer were enrolled in the study. The study protocol required all patients to have an FDA-approved indication for treatment with zoledronic acid; therefore, patients with prostate cancer were included only if their disease had progressed after receiving one or more hormone therapy regimens. All patients had a baseline Eastern Cooperative Oncology Group performance status of 
2.
Patients were excluded if they had abnormal renal function defined as either a serum creatinine (SCr) level that was at least 1.5 times above the upper limit of normal or a calculated creatinine clearance value of 60 ml/min, a corrected serum calcium level <8.0 mg/dl (i.e., 2.0 mmol/l), or symptomatic brain metastases. Previous bisphosphonate treatment was permitted.
Planned enrollment was approximately 500 patients to allow sufficient statistical power for analyses of pain, QOL, and safety parameters. The study was approved by the institutional review boards of the participating institutions and conducted in compliance with international guidelines regulating patient safety. Informed consent was obtained from each patient before enrollment.
Study Design and Treatment
This open-label, prospective, multicenter study was conducted at 90 community-based medical centers in the United States. Patients received an infusion of zoledronic acid 4 mg i.v. over 15 minutes every 3–4 weeks for six doses. The study included no control group. Administration delays were required for notable changes in SCr level, defined as an increase of 0.5 mg/dl for patients with a normal baseline SCr level (i.e., <1.4 mg/dl), an increase of 1.0 mg/dl in patients with an abnormal baseline SCr level (i.e., 1.4 mg/dl), or a doubling of any SCr level. For patients with a notable increase in SCr, the next dose was withheld until the SCr level returned to within 10% of the baseline SCr level.
Patients were instructed to take a calcium supplement (500 mg) and a multivitamin tablet containing vitamin D (400–500 IU) once daily for the study duration. The study allowed concomitant treatment with all standard antineoplastic therapies, radiation therapy for skeletal and nonskeletal tumor sites, use of standard cytokines or colony-stimulating factors for prevention or treatment of chemotherapy-induced cytopenias and corticosteroids for prevention or treatment of chemotherapy-induced nausea and vomiting, treatment of spinal cord compression or other recognized cancer syndromes, and administration of other marketed therapies. Therapies that affect osteoclast activity, such as calcitonin, mithramycin, gallium nitrate, or a bisphosphonate other than the study drug, were not permitted.
Assessments
Before each infusion, patients were assessed for any AE occurring since the last infusion. All AEs were monitored and graded by the investigator using the National Cancer Institute’s Common Toxicity Criteria, version 2.0. Serious AEs were defined as untoward events that: A) were fatal or life threatening; B) required inpatient hospitalization or prolongation of existing hospitalization; C) caused persistent or significant disability or incapacity; D) constituted a congenital anomaly or birth defect; or E) were medically significant because they jeopardized the patient or required medical or surgical intervention to prevent one of the previously listed serious AEs. SCr levels were evaluated at baseline, within 2 weeks of each infusion, and at the final study visit (i.e., 4 weeks after the last zoledronic acid infusion). Physical examinations, routine monitoring of hematology parameters and blood chemistries, and other laboratory tests were conducted according to the clinical practice at each institution.
Pain assessments were conducted at baseline, before each infusion, and at the final study visit using a 100-mm visual analog scale (VAS). QOL was assessed at baseline and before infusions at visits 2 and 6 using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire [8]. At each study visit, study personnel recorded the duration of infusion.
Statistical Analysis
Safety analyses of all patients who received at least one dose of study medication were summarized according to tumor type, prior exposure to bisphosphonate therapy, and duration of prior bisphosphonate therapy. Pain, QOL, and infusion-duration parameters were evaluated for the intent-to-treat (ITT) population, defined as all patients who received at least one dose of study medication and had at least one post-baseline pain score recorded. The change from baseline pain score was analyzed using paired t-tests. Kaplan-Meier estimates were used to assess time to development of pain for patients who reported no pain upon study entry. Chi-squared analysis was used to compare the incidences of notably increased SCr levels and treatment delays and discontinuations because of increased SCr levels.
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RESULTS |
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Overall, 77.4% of patients received all six infusions, including 78% of patients with breast cancer, 75.3% of patients with prostate cancer, and 78.3% of patients with multiple myeloma. Table 1
shows baseline demographic and disease characteristics. The mean baseline pain score was 28.1 mm (maximum score = 100 mm), with approximately 75% of patients reporting pain at study entry.
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Overall Safety
Fatigue, nausea, and arthralgia were the most common AEs (Table 2). The incidence of these events did not vary significantly among tumor types. Nausea was mild in most cases, with grade 1/2 nausea occurring in 12.5% of patients. No cases of osteonecrosis were reported. Of 225 serious AEs in 96 patients, only one was suspected to be related to zoledronic acid (described in Renal Safety section). Grade 3 AEs occurred in 169 patients (26.5%); 79 patients (12.4%) experienced grade 4 AEs. Only 12 (4.8%) of the grade 3 or 4 AEs were suspected to be related to zoledronic acid. One death, unrelated to zoledronic acid, caused by renal failure and disseminated intravascular coagulation occurred in an 81-year-old patient with prostate cancer with a history of coronary artery disease, deep vein thrombosis, and hydronephrosis. Renal failure in this patient was attributed to underlying disease, diuretics, and previous cisplatin therapy.
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Renal Safety
During the study, 6.6% of patients had one or more SCr levels that met protocol criteria for a notably increased SCr level from that of baseline (Table 3). Although the incidence of notable SCr level increases was slightly higher among patients with prior exposure to bisphosphonates compared with patients with no prior bisphosphonate exposure (7.7% and 4.5%, respectively), the difference was not statistically significant, p = 0.31 (Table 3). The development of a notable SCr level increase was slightly higher in patients receiving more than 6 months of prior bisphosphonate therapy compared with patients receiving 6 months or less of prior bisphosphonate therapy (Table 3). The maximum changes in SCr level were similar in patients with and without prior bisphosphonate exposure and in patients within each tumor type. Changes in SCr levels, from baseline to final visit, were not influenced by duration of prior bisphosphonate therapy. The timing of first notable SCr level increase was consistent across infusions 2 through 6 (5–7 patients per infusion); however, a higher number of patients (n = 13) first experienced a notable elevation in SCr level at the posttreatment final visit.
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). Treatment delays because of a notable SCr level increase did not correlate with the duration of prior bisphosphonate therapy or vary among tumor types (Table 3). The overall rate of discontinuation due to SCr level increases was 3.1%. There was a trend toward more treatment discontinuations because of SCr level increases in patients with prior bisphosphonate exposure compared with patients with no prior bisphosphonate exposure (4.1% and 1.3%, respectively, p = 0.06) (Table 3). Fifteen of 17 patients (88.2%) with prior bisphosphonate exposure who discontinued zoledronic acid because of SCr level increases had received more than 6 months of bisphosphonate treatment. Of note, protocol violations occurred in 16 patients who should have undergone dose delay because of a notably increased SCr level. Only one serious renal AE was suspected to be related to the study drug. A 74-year-old patient with prostate cancer developed grade 2 renal failure, concomitant congestive heart failure, and pneumonia 42 days after beginning the study and subsequently discontinued study medication because of poor medical condition. This patient had no history of bisphosphonate therapy.
Pain Scores
Of the 613 patients in the ITT population, 461 (75%) reported pain at baseline (VAS pain score, 5 mm). At every visit, these patients experienced a statistically significant decrease in mean pain scores compared with baseline pain scores (Fig. 1). For each tumor type, patients experienced reductions in pain scores at every visit, with the change in pain scores from baseline statistically significant in one or more assessments for each tumor type (Table 4). Patients with multiple myeloma and breast cancer experienced a significant reduction in pain scores from baseline scores in at least four of the six visits, whereas patients with prostate cancer experienced a significant reduction in pain scores from baseline at visit 2 only (Table 4). In the ITT population, mean VAS pain scores decreased from baseline scores at all assessments after the second visit, with statistically significant reductions at visits 4 (p = 0.05) and 5 (p = 0.03). Of the 152 patients (25%) who were pain free at baseline, the median time to development of pain, using Kaplan-Meier analysis, was estimated to be 168 days.
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). Total mean FACT-G scores also remained constant for each cancer type. Of the four subscale scores that comprise the total FACT-G score (physical, functional, emotional, social well-being), mean physical well-being scores improved significantly from baseline to infusion visit 2 (p = 0.03) as did mean emotional well-being scores (p < 0.001). Emotional well-being scores also improved significantly from baseline to visit 6 (p = 0.02). Functional and social well-being scores decreased from baseline at both assessments; these differences were not statistically significant.
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14 minutes occurred during only 3% of the infusions, demonstrating strict adherence to the protocol and prescribing information for zoledronic acid (i.e., administration of 4 mg by i.v. infusion over no less than 15 minutes) [7]. |
DISCUSSION |
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Zoledronic acid was generally well tolerated in this study, with 77% of patients completing all six infusions. AEs reported were similar to AEs experienced by patients in other trials evaluating i.v. bisphosphonate therapy [1, 3–5, 7]. With the exception of a higher incidence of nausea in bisphosphonate-naïve patients, the incidence of AEs did not differ based on history of prior bisphosphonate treatment. The overall incidence of AEs in this trial was lower than the incidence noted in the integrated safety analysis presented in the zoledronic acid package insert [7]. Bone pain occurred in only 8.9%–11.2% of patients [7].
Zoledronic acid displayed renal safety, with 6.6% of patients developing a notable increase in their SCr level, and only 1.1% of patients requiring a treatment delay due to an increased SCr level. Furthermore, only 3.1% of patients discontinued therapy because of a change in SCr level. These very low rates of treatment delay and discontinuation, in patients receiving anticancer therapy, indicate that the overall SCr-level increases in this study were minor and manageable.
Patients with multiple myeloma experienced a slightly higher incidence of notable SCr-level increases compared with patients with breast or prostate cancer. This finding is not surprising given the underlying, disease-related renal dysfunction in many patients with multiple myeloma. Despite the higher incidence of notable SCr-level increases in patients with multiple myeloma, these patients did not experience substantially higher rates of treatment delay or discontinuation compared with patients with breast or prostate cancer. More patients who received prior bisphosphonate therapy had treatment discontinued because of increased SCr level than patients with no prior bisphosphonate exposure (Table 3). Even though this difference approached statistical significance (p = 0.06), the statistical power of the study to detect this difference was low given the small number of these events.
The duration of prior bisphosphonate therapy did not significantly affect the incidence of notable SCr level increases or treatment delays due to SCr level increases. Rates of treatment discontinuation due to SCr-level changes increased proportionally according to duration of prior bisphosphonate therapy (Table 3); however, the rate of discontinuation in the most heavily exposed patient population (i.e., >24 months of previous bisphosphonate therapy) was only 7.3%, suggesting that most patients with prior bisphosphonate exposure receiving zoledronic acid will not require therapy interruption from renal complications.
The rate of notable SCr-level increases in this study (8.2% for all patient subgroups) compares favorably with the rate of notable SCr-level increases in the phase III trials evaluating zoledronic acid in patients without exposure to prior bisphosphonates (8.8%–15.2% of patients with multiple myeloma, breast cancer, or prostate cancer) [7]. In previous clinical trials evaluating the use of zoledronic acid as treatment for bone metastases, the duration of infusion was changed from 5 minutes to 15 minutes because of a high incidence of SCr-level increase observed in patients receiving 5-minute infusions. The study protocol did not permit prolongation of the 15-minute infusion time in patients who experienced elevated SCr levels, although this will be the focus of a separate study. The current study represents the largest experience with zoledronic acid administered as a 15-minute infusion in a community setting. This study demonstrates that the safety profile of zoledronic acid is better or comparable to that observed previously and not influenced substantially by prior bisphosphonate exposure. The low overall incidence of renal AEs also demonstrates that, with proper SCr-level monitoring as recommended in the manufacturer’s prescribing information, zoledronic acid is safe in patients with or without a history of prior bisphosphonate treatment.
Both pamidronate and zoledronic acid have been shown to decrease the incidence and/or severity of bone pain in some patients with bone metastases, although a number of factors other than bisphosphonate therapy may have contributed to this decrease, such as a response to antitumor therapy or the use of pain medications and/or other supportive care therapies [1, 3, 5, 9–11]. In this study, pain scores in patients receiving zoledronic acid decreased from baseline at each assessment, suggesting that zoledronic acid may help manage pain resulting from osteoclastic bone destruction and does not increase the incidence or severity of bone pain in patients with bone metastases. Statistically significant, albeit modest, reductions in mean pain scores compared with baseline scores occurred more often in patients with multiple myeloma or breast cancer than patients with prostate cancer. Nonetheless, mean pain scores in patients with prostate cancer did not increase at any assessment. A more rigorous and comprehensive pain and opioid assessment may have provided greater insight into the role of zoledronic acid for the palliation of bone pain.
Several trials assessing the safety and efficacy of bisphosphonate therapy in cancer patients with bone metastases have also included an assessment of QOL [3, 5, 9–11]. Because many factors other than bisphosphonate therapy influence QOL in these patients (i.e., AEs associated with anticancer therapy, underlying disease progression), the results of these trials have been inconsistent [3, 5, 9–11]. In some trials, QOL scores were similar in patients receiving bisphosphonates or placebo; in other trials, bisphosphonate-treated patients had less of a reduction in QOL scores compared with placebo-treated patients [3, 5, 9–11]. In this study, overall QOL remained stable. Patient-reported measures of physical and emotional well-being improved, whereas measures of functional and social well-being declined. The decline in functional and social well-being may have been related to the course of the underlying disease, concomitant administration of chemotherapy or radiation therapy, or other comorbid medical conditions or life situations. Although a variety of factors influence QOL measurements at any given time, our study results suggest that zoledronic acid therapy does not adversely affect overall QOL.
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CONCLUSIONS |
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ACKNOWLEDGMENT |
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REFERENCES |
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  M. Aapro, P. A. Abrahamsson, J. J. Body, R. E. Coleman, R. Colomer, L. Costa, L. Crino, L. Dirix, M. Gnant, J. Gralow, et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel Ann. Onc., March 1, 2008; 19(3): 420 - 432. [Abstract] [Full Text] [PDF]
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R. Bell Efficacy of Ibandronate in Metastatic Bone Disease: Review of Clinical Data Oncologist, October 1, 2005; 10(suppl_1): 8 - 13. [Abstract] [Full Text] [PDF]
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