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Renal Safety and Efficacy of i.v. Bisphosphonates in Patients with Skeletal Metastases Treated for up to 10 Years

^a Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy; ^b Division of Medical Oncology, St. Chiara University Hospital, Pisa, Italy

Key Words. Bone metastases • Bisphosphonates • Renal safety • Jaw osteonecrosis

Correspondence: Valentina Guarneri, M.D., Department of Oncology and Hematology, University of Modena University Hospital, Policlinico-Via Del Pozzo 71, Modena, 41100 Italy. Telephone: 39-059-4223033; Fax: 39-059-4224429; e-mail: guarneri.valentina{at}unimore.it

Received June 3, 2005; accepted for publication September 13, 2005.

	ABSTRACT

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Introduction. Bisphosphonates (BPs) delay the onset or reduce the incidence of skeletal complications in patients with bone metastases. However, there are few data on the renal safety and activity of i.v. BPs beyond 2 years of administration.

Materials and Methods. We retrospectively analyzed serum creatinine (SCr) levels and skeletal-related events (SREs) in cancer patients receiving i.v. BPs for 24 months. All patients received 90 mg pamidronate every 3–4 weeks. Pre- and post-treatment SCr levels and the peak levels attained were recorded. A notable SCr increase was defined as: an increase >0.5 mg/dl for patients with baseline SCr <1.4 mg/dl; an increase >1 mg/dl for patients with baseline SCr >1.4 mg/dl; or doubling over baseline. The following parameters were also analyzed: the proportion of patients with at least one SRE, the distribution of each type of SRE, the time to first SRE, and the skeletal morbidity rate (SMR).

Results. Fifty-seven patients with bone metastases resulting from breast cancer (BC) (n = 48), multiple myeloma (n = 7), renal cell carcinoma (n = 1), and prostate cancer (n = 1) were evaluated. The median age at the start of treatment was 57 years (range, 27–81); 25% of the patients were >70 years old. Forty-three patients received pamidronate then switched to zoledronic acid. The median overall duration of BP administration was 34 months (range, 24+ to 131+), with a median duration of zoledronic acid therapy of 25 months (range, 2–40). Twenty-seven of 48 BC patients received different chemotherapy regimens (median number of lines, 2; range, 1–6). The median SCr levels were: baseline, 0.82 mg/dl (range, 0.4–1.4); time of analysis, 0.89 mg/dl (0.4–2); highest level, 1.0 mg/dl (0.5–2). A notable SCr increase was observed in seven patients (12.2%; all grade 1). Twenty-six patients (45.6%) experienced SREs after starting BP treatment. The median time to first SRE was 911 days (95% confidence interval, 731; 1,023). The SMR was 0.20 events per year. Ten patients ceased treatment because of: an SCr level of 2 mg/dl (n = 1) physician decision (n = 6) and jaw osteonecrosis (n = 3). Ten patients died of progressive disease.

Conclusion. i.v. BPs are safe and active during prolonged treatment administration, and renal function is maintained in patients receiving multiple cytotoxic therapies. Jaw osteonecrosis occurred in 5% of the study population, and its causal relationship with BP treatment requires further observation and study.

	INTRODUCTION

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The onset of skeletal metastasis is common for many tumor types and leads to a variety of complications, including severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), as well as the need for surgery or radiation therapy (RT) [1–3]. The associated morbidity can thus severely impact healthcare resources and patient quality of life, particularly for those experiencing prolonged survival.

Bisphosphonates (BPs) represent the current standard of care for the treatment of HCM and prevention of skeletal complications in patients with bone metastases. In particular, the American Society of Clinical Oncology (ASCO) recommends pamidronate disodium (Aredia^®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com) and zoledronic acid (Zometa^®; Novartis Pharmaceuticals Corporation) for treating skeletal metastases in breast cancer and multiple myeloma (MM) patients [4]. Furthermore, zoledronic acid is the first BP with proven efficacy in the treatment of bone metastases from solid tumors other than breast carcinoma [5].

Overall, i.v. BP treatment is generally well tolerated, with transient side effects such as mild-to-moderate flulike symptoms following the initial infusion. However, all BPs have the potential for adversely affecting renal function; indeed, sporadic episodes of acute and subacute renal failure have been described for several i.v. BPs [6–13]. However, this toxicity is extremely rare when the agents are administered at their recommended doses and infusion rates. Nevertheless, accurate renal function monitoring is recommended for the use of i.v. BPs. Four large, randomized trials have investigated the long-term renal safety of both pamidronate disodium and zoledronic acid. In more than 3,200 patients, the data demonstrated that the renal safety profiles were similar for these compounds after 24 months of treatment, and, more notably, the renal safety profile of zoledronic acid was similar to that observed in patients receiving placebo [14–17]. A similar renal safety profile was reported for i.v. ibandronate (Boniva^®; Hoffmann-La Roche Inc., Nutley, NJ, http://www.rocheusa.com) in the treatment of breast cancer [18, 19].

To date, there are few renal safety data compiled from studies encompassing >2 years of i.v. BP administration [20]. Because many cancer patients (particularly those with breast and prostate tumors) can experience prolonged survival durations, it may be useful to accumulate more data on the safety of i.v. BPs administered over a prolonged period, notably, in combination with anticancer agents. This unmet need is reinforced by ASCO guidelines that recommend the continuation of BP therapy until patient performance status (PS) deteriorates, even in the case of skeletal complications [4], that is, skeletal-related events (SREs). Notably again, there is a scarcity of data on both the incidence and types of SREs that occur in patients with metastatic bone disease treated with BPs for >24 months [21].

To assess the safety and the efficacy of long-term BP administration, we performed a retrospective analysis on patients with bone metastases undergoing treatment with i.v. BPs for a period 24 months. The primary objective was to determine long-term renal safety; a secondary aim was the analysis of SREs.

	MATERIALS AND METHODS

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Eligibility Criteria
Patients with documented skeletal metastases and who received i.v. BPs (pamidronate and/or zoledronic acid) for at least 24 months were eligible.

Treatment
Patients received either pamidronate disodium, 90 mg (2–3 hours), or zoledronic acid, 4 mg (15-minute infusion), every 3–4 weeks.

Renal Safety Assessment
According to the U.S. Food and Drug Administration–approved labeling, measurements of serum creatinine (SCr) were conducted prior to each BP administration. Measurements included the baseline level, the last-available value (either at the end of treatment or at the time of analysis for patients still receiving BPs), and the highest peak level observed during treatment. A significant increase in SCr level was defined as: an increase >0.5 mg/dl for patients with baseline levels <1.4 mg/dl; an increase >1.0 mg/dl for patients with baseline levels >1.4 mg/dl; or a doubling over baseline level. The renal toxicity was graduated according to National Cancer Institute-Common Toxicity Criteria, version 2.0 (NCI-CTC, v2.0): grade 1, SCr greater than the upper limit of normal (ULN) – 1.5 x ULN; grade 2, SCr >1.5–3.0 x ULN; grade 3, SCr >3.0–6.0 x ULN; grade 4, SCr >6.0 x ULN.

The Wilcoxon signed-rank test provided statistical comparisons among SCr values (i.e., baseline value, last value, and highest value).

SREs
SREs were assessed at each patient visit and were defined as: pathologic fractures, HCM, spinal-cord compression, surgery to the bone, and RT to the bone. The following parameters were analyzed in this study: (a) proportion of patients with at least one SRE, (b) distribution of each type of SRE, (c) time to first SRE, and (d) skeletal morbidity rate. A 21-day event window was used for counting SREs, thus ensuring that linked events (i.e., surgery or RT for pathologic fracture) were not counted as separate entities. The patients were stratified based on the occurrence of any SREs prior to the start of BP therapy.

The Kaplan-Meier method was used to analyze the time to first SRE. The proportions of patients with at least one SRE were compared between the two strata using the log-rank test. The number of SREs per year defined the skeletal morbidity rate.

	RESULTS

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Fifty-seven patients were eligible for this analysis, with primaries of: breast cancer (n = 48), MM (n = 7), renal cell carcinoma (RCC, n=1), and prostate cancer (n=1). The median age at the start of BP therapy was 57 years (range, 27–81). Twenty-four patients (42%) experienced an SRE prior to the start of BP therapy: pathologic fracture (n = 5), HCM (n = 1), and RT to the bone (n = 18). Four patients experienced a subsequent SRE prior to the start of BP therapy, requiring RT (n = 3) and vertebral stabilization surgery (n = 1).

Forty-three patients received pamidronate disodium, 90 mg i.v. every 3–4 weeks, then were switched to zoledronic acid, 4 mg i.v. Eleven patients started with zoledronic acid, 4 mg i.v. every 3–4 weeks, and three patients had pamidronate only. The median duration of BP therapy was 34 months (range, 24+ to 131+), with a median duration of pamidronate therapy of 18 months (range, 4–95) and a median duration of zoledronic acid therapy of 25 months (range, 2–40). All patients received concomitant anticancer therapy during the course of BP treatment. In particular, breast cancer patients received several combinations of hormonal, cytotoxic, and biologic agents. A total of 21 (43.7%) patients received hormonal therapy, and 27 (56.2%) received chemotherapy, with a median number of therapy lines of two (range, 1–6 lines). Ten patients (20.8%) received trastuzumab (Herceptin^®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) (Table 1).

Renal Safety
All patients had normal SCr levels ( 1.4 mg/dl) prior to the start of BP therapy. The median baseline SCr level was 0.82 mg/dl (range, 0.4–1.4); the median SCr value at the end of treatment (or at the time of this analysis for patients still on therapy) was 0.89 mg/dl (range, 0.4–2); and the median highest SCr level observed was 1.0 mg/dl (range, 0.5–2). Significant differences were detected between both the baseline and final values (p < .001) and the baseline and peak values observed (p < .00001) (Fig. 1).

View larger version (13K): [in this window] [in a new window]   Figure 1. (A): Baseline serum creatinine (SCr) values. (B): Final SCr values. (C): Highest SCr values.

SREs
Overall, 26 patients (45.6%) experienced at least one SRE following the beginning of BP therapy. An SRE occurred in 15 of 33 patients (45.5%) who did not present with skeletal events prior to the start of therapy, versus 11 of 24 (45.8%) patients with prior SREs. The distribution of SREs by type is summarized in Table 2.

View larger version (20K): [in this window] [in a new window]   Figure 2. Median time to first skeletal-related event (SRE). Patients with previous SREs, 957 days (95% CI, 566; 1,117); patients without previous SREs, 883 days (95% CI, 728; 1,014) (p = .97).

Patient 2 (63 years of age) developed jaw osteonecrosis following 30 months of zoledronic acid administration. She received several concomitant chemotherapy lines (including epirubicin [Ellence^®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com], the taxanes, vinca alkaloids, antimetabolites, platinum agents, and trastuzumab), as well as high-dose steroid treatment for brain metastases. She had no history of major dental procedures. Following a debridement of the lesion, the microscopic examination indicated necrotic bone with associated micotic debris and granulation tissue.

Patient 3 (55 years of age) received pamidronate (8 months) and zoledronic acid (23 months). Concomitant therapy included chemotherapy consisting of vinorelbine (Navelbine^®; GlaxoSmithKline, Philadelphia, http://www.gsk.com) and trastuzumab, as well as sporadic steroid therapy. This complication required surgical removal of necrotic bone, and microscopic examination revealed necrotic bone with associated micotic debris and granulation tissue. The outcome resulting from osteonecrosis in this (and the previous) patient is not yet available because of the conditions’ recent onset.

	DISCUSSION AND CONCLUSION

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In addition to analgesic therapy, RT, and stabilization surgery, BP therapy represents the standard of care for patients who present with bone metastases. The efficacy and safety of pamidronate disodium, zoledronic acid, and i.v. ibandronate for up to 2 years of treatment were demonstrated in large, randomized trials in patients with bone metastases from breast cancer, MM, and prostate cancer, and other tumors [14–19]. Because of the potential for nephrotoxicity of such agents, accurate monitoring of renal function is strictly recommended prior to BP administration. In the course of clinical trials, in patients with bone metastases, a clinically insignificant rise in SCr level was observed in <10% of patients, and grade 3–4 renal toxicities were extremely rare. The current ASCO guidelines recommend continuation of BP therapy until a substantial decline in the patient’s PS is observed, despite the occurrence of SREs. However, published data on the long-term safety and efficacy of BPs are scarce. Ali and coworkers published data from 22 breast cancer and MM patients treated with pamidronate (n = 18) or zoledronic acid (n = 4) for a mean duration of 3.6 years (range, 2.2–6.0). They reported an increase (albeit not clinically relevant) in SCr level [20].

In the retrospective analysis reported herein, 57 patients were treated for a median time of 34 months with BP therapy. There were notable increases in SCr levels in 12.2% of the study patients, but the toxicities were grade 1; there were no episodes of acute or subacute renal failure, and only one patient ceased BP therapy because of physician decision following mild renal toxicity (SCr = 2 mg/dl). In this study population, a clinically relevant decrease in renal function was not observed despite the many potential causes for nephrotoxicity: advanced age (25% of patients were >70 years of age), underlying disease (e.g., MM), multiple concomitant cytotoxic therapies, and diseases that primarily affect the urogenital tract (i.e., prostate cancer, RCC).

Another important issue in the management of patients with metastatic bone disease is patient treatment when or if they experience an SRE while on BP therapy. Despite improved imaging techniques, bone lesions are still considered "nonmeasurable," and in clinical trials, the efficacy of BPs is measured by the occurrence of SREs. However, other factors also determine the onset of SREs, including those not related to the activity of BPs, for example, the site/type of lesion (lytic, sclerotic, mixed), the tumor type, the aggressiveness of the disease, skeletal comorbidities (i.e., osteoporosis, arthrosis), and the efficacy of anticancer therapy. As a result, the onset of an SRE does not invariably translate into treatment failure; moreover, the consequence(s) of ceasing a potentially active treatment after an SRE is not known. (The current ASCO guidelines suggest a continuation of BP therapy in this event.)

However, as for safety issues, data on extended, long-term activity of BPs are not currently available. Our investigative group, therefore, retrospectively analyzed the SREs in our study population of patients who received BP therapy exceeding 24 months. Forty-two percent had experienced a skeletal complication prior to the beginning of BP therapy and were thus at higher risk for subsequent SREs. Overall, 28 patients (49%) experienced at least one SRE during BP treatment, and the skeletal morbidity rate was 0.2 events per year. Compared with previously reported data, both the incidence of SREs and skeletal morbidity rate are thus very low. This is probably a result of selection bias: the primary aim of our analysis was to determine long-term renal safety (beyond 24 months). Consequently, patients with less aggressive disease and/or who were treated with more efficacious anticancer agents (and combinations) were accrued. However, in spite of these inherent limitations in study eligibility, the extremely low incidence of SREs in a patient population with bone metastases that was followed for up to 10 years is notable.

Although our primary objective was to assess renal safety, and indeed, long-term administration of BPs is feasible without compromising renal function, an interesting finding from the study presented herein is the occurrence of jaw osteonecrosis (n = 3). In the past few years, a growing number of cases of jaw osteonecrosis has been reported in patients undergoing BP therapy [22, 23]. This complication was, in general, observed in patients treated with RT for head and neck cancer; other risk factors for osteonecrosis are long-term steroid therapy, cytotoxic chemotherapy, dental or sinus infections, and trauma.

The hypothesized pathogenesis of such lesions is the imbalance in bone remodeling possibly induced by BPs in general (with a potential synergism with cytotoxic therapy), resulting in bone necrosis, as well as the potential for inhibition of angiogenesis [24–26].

The incidence of this complication ranges from 0.03% to 6.2%, and this wide variation mainly depends on the kind of analysis performed (spontaneous report, web-based survey, retrospective analyses), with intrinsic biases in patient selection, diagnostic criteria, and completeness of the data [22, 23, 27, 28]. In our study population, the incidence of this complication (histologically confirmed in two cases) is somewhat high (5.2%), albeit taken in a small population sample. In addition to long-term BP therapy (30, 31, and 56 months), these patients received concomitant chemotherapy and long-term steroid administration (n = 2; the third patient had sporadic steroid therapy). Indeed, both factors have been associated with the occurrence of osteonecrosis [29]. Furthermore, the majority of patients were still on therapy, and the issue of jaw osteonecrosis was well known at the time of the present analysis; therefore, the possibility of a missed or wrong diagnosis can be excluded. Interestingly, in our study population, jaw osteonecrosis occurred in three of nine breast cancer patients treated with chemotherapy plus trastuzumab, while none of 19 breast cancer patients treated with chemotherapy alone developed this complication. The biology of the disease that might be associated with the combination of BPs and a biologic agent (such as the humanized monoclonal antibody trastuzumab), as well as a potential role in jaw osteonecrosis, has not yet been described. Certainly, this putative association also deserves further attention. Indeed, assessing dental status and taking precautions when carrying out dental surgery procedures in patients on BP therapy may be prudent, that is, using strict aseptic techniques, performing atraumatic surgery, and achieving primary wound closure when possible. The occurrence of jaw osteonecrosis reminds clinicians and patients alike that BPs, when administered for prolonged periods alone or in combination with cytotoxic anticancer agents (and perhaps certain biologic agents), might be associated with unusual toxicities. A causal relationship between BP therapy and jaw osteonecrosis has not been proven. However, the increasing use of BPs as the standard of care for the prevention and treatment of bone metastases and the maintenance of bone health encourages further study in cancer patients on the pathogenesis, prevention, and management of osteonecrosis. Indeed, such at-risk patients might also receive appropriate prophylactic attention to maintain oral health.

In conclusion, extended, long-term administration of BPs is feasible without compromising renal function. However, the increase in SCr level observed in 12% of our patients (albeit not clinically meaningful) supports a recommendation for monitoring renal function. Notably, the extremely low incidence of SREs, even in a selected population, reinforces the ASCO recommendations to continue BP therapy even after the onset of an SRE.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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Dr. Conte has received research support from and has acted as a consultant for Novartis Pharmaceuticals Corporation.

	ACKNOWLEDGMENT

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These study data were presented in part at the 29th European Society for Medical Oncology (ESMO) Congress, October 29–November 2, 2004, in Vienna, Austria.

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