Skip Navigation


Annals of Oncology Advance Access originally published online on March 11, 2008
Annals of Oncology 2008 19(7):1266-1270; doi:10.1093/annonc/mdn038
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
19/7/1266    most recent
mdn038v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by von Moos, R.
Right arrow Articles by Pecherstorfer, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by von Moos, R.
Right arrow Articles by Pecherstorfer, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

breast cancer

Renal safety profiles of ibandronate 6 mg infused over 15 and 60 min: a randomized, open-label study

R. von Moos1,*, C. B. Caspar2, B. Thürlimann3, R. Angst3, R. Inauen1, R. Greil4, B. Bergstrom5, K. Schmieding6 and M. Pecherstorfer7

1 Kantonsspital Graubünden, Chur, Switzerland
2 Kantonsspital Baden, Baden, Switzerland
3 Kantonsspital St Gallen, St Gallen, Switzerland
4 University Hospital, Salzburg, Austria
5 Hoffmann-La Roche Inc., Nutley, NJ, USA
6 Roche Pharma (Schweiz) AG, Reinach, Switzerland
7 Wilhelminenspital, Vienna, Austria

* Correspondence to: Dr R. von Moos, Medizinische Onkologie, Kantonsspital Graubünden, Loëstrasse 170, 7000 Chur, Switzerland. Tel: +41-812-566-646; Fax: +41812566640; E-mail: roger.vonmoos{at}onkologie.li


   Abstract
Top
 Abstract
introduction
 methods
 results
 discussion
 conclusions
 funding
 References
 
Background: Clinical data show that a single, 15-min i.v. infusion of ibandronate 6 mg does not significantly alter renal function. We evaluated the effect on renal function of repeated 15-min infusions of ibandronate 6 mg in women with breast cancer and bone metastases.

Patients and methods: Patients were randomly assigned to i.v. ibandronate 6 mg every 3–4 weeks for ≤6 months, infusion over 15 min (n = 102) or 60 min (n = 28). The primary end point was the percentage of patients with increased serum creatinine of ≥44.2 µmol/l. Blood chemistry was assessed at each visit.

Results: Two per cent [2/101; 95% confidence interval (CI) 0.2–7.0] of patients in the 15-min infusion arm and no patients (0/26; 95% CI 0.0–13.2) in the 60-min infusion arm had increased serum creatinine that met the primary end point. There were no clinically relevant changes in serum creatinine, creatinine clearance, or N-acetyl-β-d-glucosaminidase, {alpha}1-microglobulin, or microalbuminuria. Most adverse events were mild or moderate. No clinically relevant changes were observed in vital signs, hematology, blood chemistry, or urine analysis.

Conclusions: Ibandronate 6 mg by 15-min infusion every 3–4 weeks appear to be consistent with those renal safety profiles of 60-min infusion.

Key words: bisphosphonates, bone metastases, breast cancer, ibandronate, randomized clinical trial, renal function


   introduction
Top
 Abstract
 introduction
methods
 results
 discussion
 conclusions
 funding
 References
 
Bone metastases are common in breast cancer and frequently lead to skeletal-related complications, including bone pain, pathologic fractures, hypercalcemia of malignancy, and spinal cord compression [1]. Bisphosphonates are potent inhibitors of bone resorption and are standard treatment for preventing skeletal complications of bone metastases [2, 3].

Ibandronate is a nitrogen-containing bisphosphonate available as i.v. and oral formulations for the prevention of skeletal-related events in patients with breast cancer and bone metastases. In a phase 3 clinical trial, i.v. ibandronate 6 mg significantly reduced the skeletal morbidity period rate (the number of 12-week periods with new bone events) by 20% compared with placebo [4]. Furthermore, a decrease was seen in both bone pain scores and analgesic use and improved quality of life [4–6].

Case reports and clinical trials suggest a risk of renal toxicity with some i.v. bisphosphonates [7–9]. In a phase 3 trial, ibandronate 6 mg (infused every 3–4 weeks over 1–2 h) had a renal tolerability profile comparable to placebo [4, 10, 11]. After 96 weeks, 6% of patients treated with ibandronate 6 mg had defined serum creatinine increases compared with 12% of patients receiving placebo, and there were no withdrawals due to renal events [11].

Patients receiving bisphosphonates prefer shorter infusion times because they cause less disruption to their day [12]. Studies in healthy volunteers and patients with metastatic bone disease suggest that a single, 15-min i.v. infusion of ibandronate 6 mg does not significantly alter renal function [13–15]. The objective of the study reported here was to estimate the effect on renal function of ibandronate 6 mg infusion over 15 min every 3–4 weeks for ≤6 months in women with breast cancer and bone metastases.


   methods
Top
 Abstract
 introduction
 methods
results
 discussion
 conclusions
 funding
 References
 
study design
For this randomized, open-label, parallel group, multicenter, phase 2 trial (ML17632), patients were recruited from 10 centers in Austria, 7 centers in Switzerland, and 1 center in Germany.

inclusion and exclusion criteria
Eligible patients were women aged ≥18 years with histologically- or cytologically confirmed breast cancer and one or more osteolytic, mixed, or blastic bone metastasis confirmed by X-ray, computed tomography (CT), or magnetic resonance imaging. Patients had a World Health Organization performance status of two or less than two; had not received a bisphosphonate within the 3 weeks before study entry and had adequate renal function [serum creatinine within normal limits (44.2–120 µmol/l) and calculated creatinine clearance ≥50 ml/min (Cockcroft–Gault method) [16]]. Chemotherapies, hormone therapies, and trastuzumab were allowed if they had been initiated before starting study medication. The use of diuretics and nonsteroidal antirheumatic medications was allowed. Aminoglycoside antibiotics or antifungal agents, concurrent cisplatin and methotrexate chemotherapy, or high-dose chemotherapy were not permitted. Patients were excluded if they had a life expectancy of ≤6 months, were pregnant, had uncontrolled hypercalcemia or hypocalcemia (albumin-corrected serum calcium ≥3.0 mmol/l or ≤1.8 mmol/l), and had abdominal metastases with renal involvement and radiotherapy during the previous 5 weeks. The study was conducted in accordance with the Declaration of Helsinki (1996), with ethical approval from local ethics committees and patients’ written informed consent.

treatment
Patients were randomized to ibandronate 6 mg in 100 ml NaCl 0.9% over 15 min or in 500 ml NaCl 0.9% >60 min infused every 3–4 weeks for ≤6 months (six scheduled infusions). Before randomization, patients were stratified by previous treatment (chemotherapy versus other therapy) and the presence or absence of visceral metastases. Patients were randomly assigned centrally in a ratio of 9 : 2 (15-min arm : 60-mi arm), using blocks of 5 (4 : 1) and 6 (5 : 1).

assessments
A physical examination, dipstick urine analysis, assessments of blood chemistry, and vital parameters were carried out at each visit before administering study medication. Pathologic values from dipstick measurement led to microscopic analysis of the urine sample. A 24-h urine sample was collected at baseline and at the final visit to measure creatinine clearance and levels of N-acetyl-β-d-glucosaminidase, {alpha}1-microglobulin, and microalbuminuria. Adverse events were graded using the National Cancer Institute—Common Toxicity Criteria version 2.0.

end points
The primary end point was the percentage of patients with an increase in serum creatinine from baseline of ≥44.2 µmol/l (= 0.5 mg/dl) at any point in the study (central laboratory analysis). Secondary end points were changes from baseline to last visit in serum creatinine, calculated and measured creatinine clearance, and levels of tubular and glomerular markers of renal function (i.e. N-acetyl-β-d-glucosaminidase, {alpha}1-microglobulin, and microalbuminuria).

statistical analysis and sample size
For the primary end point, a 95% confidence interval (CI) was calculated. Other end points were analyzed using descriptive statistics. A sample size of 90 assessable patients (from 102 enrolled in the 15-min infusion arm) was considered sufficient to estimate the percentage of patients meeting primary end point within a 95% CI 0% to 3.3%. Because the 60-min infusion arm served as a control arm only, no formal statistical analysis was planned to compare treatment effects between both infusion arms. The last-observation-carried-forward method was used for missing values.


   results
Top
 Abstract
 introduction
 methods
 results
discussion
 conclusions
 funding
 References
 
patient demographics
There were 132 patients enrolled (March 2004–December 2005) (see Figure 2). Two patients were not randomized: one due to a screening failure (no osteolytic, mixed, or blastic bone metastasis) and one due to closure of randomization by the time of enrollment. Patients (n = 130) were randomized to i.v. ibandronate infusion over 15 min (n = 102) or 60 min (n = 28) every 3–4 weeks. One patient in the 15-min arm and two patients in the 60-min arm were excluded and received no study medication as they violated renal inclusion criteria at screening. There were 127 patients who received one or more dose of study medication and had one or more follow-up assessment included in the per protocol population (n = 101, 15-min infusion arm; n = 26, 60-min infusion arm) (Table 1).


Figure 2
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2. Study population and analysis.

 

View this table:
[in this window]
[in a new window]

  		Table 1. Demographic and baseline characteristics

 
In the per protocol population, 82% (83/101) of patients in the 15-min infusion arm and 77% (20/26) of patients in the 60-min infusion arm completed the treatment course. Five patients in the 15-min infusion arm and two in the 60-min infusion arm withdrew due to an adverse event (15-min arm: increased pain n = 1, osteomyelitis n = 1, chronic gastritis n = 1, elevated serum creatinine n = 2; 60-min arm: epilepsy n = 1, urinary infection n = 1). Three patients in the 15-min infusion arm (disease progression n = 2, multiple organ failure n = 1) and three patients in the 60-min infusion arm (muscular weakness with fall n = 1, subdural hematoma n = 1, disease progression n = 1) died during the study. Four patients in the 15-min arm and one patient in the 60-min arm withdrew consent, and four patients in the 15-min arm withdrew due to protocol violations/noncompliance.

Patient exposure to ibandronate was similar in both treatment arms. Nine patients (9%) in the 15-min infusion arm and one patient (4%) in the 60-min infusion arm received half or fewer of the scheduled number of infusions.

effect on renal function
Pooling results from central and local laboratories, three patients (A, B, and C) in the 15-min infusion arm and no patients in the 60-min infusion arm had a measurable increase in serum creatinine of ≥44.2 µmol/l from baseline (Table 2). For patient A, an abdominal CT scan revealed an extensive solid tumor with large cyst formation and hydronephrosis, most likely of ovarian origin. The investigator considered the serum creatinine increase to be possibly related to the hydronephrosis. Patient A had received ≥34 doses of zoledronic acid just before study treatment and continued zoledronic acid after the study. Serum creatinine remained elevated after the study. For patient B, the increase of serum creatinine was related to diarrhea and returned to normal levels when diarrhea had resolved. In patient C (measured by the local laboratory only), serum creatinine was possibly increased by study medication, concomitant treatment with gemcitabine, or preexisting illness (type 2 diabetes mellitus and hypertension), returning to normal after end of study.


View this table:
[in this window]
[in a new window]

  		Table 2. Summary of serum creatinine and creatinine clearance values in patients meeting the primary end point (15-min infusion arm)

 
In either treatment arm, no clinically relevant changes from baseline to last visit were seen in median serum creatinine and calculated creatinine clearance (Figure 1), measured creatinine clearance (Table 2), and median N-acetyl-β-d-glucosaminidase levels, {alpha}1-microglobulin, and microalbuminuria (Table 3).


Figure 1
View larger version (35K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1. (A) Box plot of serum creatinine over time. (B) Box plot of calculated creatinine clearance over time. Boxes stretch from the 25th to the 75th percentile. Bars show upper and lower adjacent values. Median values are joined, and outliers are indicated by an asterisk symbol.

 

View this table:
[in this window]
[in a new window]

  		Table 3. Mean change from baseline to last visit in measured creatinine clearance, N-acetyl-β-d-glucosaminidase, {alpha}1-microglobulin, and microalbuminuria

 
adverse events
Seventy-seven per cent of patients in the 15-min infusion arm and 73% of patients in the 60-min infusion arm reported at least one adverse event. Adverse events are shown in Table 4. The majority were mild to moderate (grade 1/2) in intensity. There was no clinically relevant difference between treatment arms in the type and frequency of adverse events considered related to ibandronate.


View this table:
[in this window]
[in a new window]

  		Table 4. Summary of adverse events

 
One patient (15-min arm) experienced a serious adverse event, osteonecrosis of the jaw (ONJ), requiring antibiotics and dental surgery. ONJ was assessed as possibly related to ibandronate and resolved following treatment, and the patient completed the trial. There were no clinically relevant changes from baseline in vital signs or the laboratory parameters for hematology, blood chemistry, or urine analysis in either treatment arm.


   discussion
Top
 Abstract
 introduction
 methods
 results
 discussion
conclusions
 funding
 References
 
No adversely renal function was observed in this phase II study. Ibandronate 6 mg infused i.v. over 15 min every 3–4 weeks is well tolerated. Only two patients in the 15-min infusion arm met the primary end point of an increase in serum creatinine of ≥44.2 µmol/l from baseline in the central laboratory. The third patient who was considered to have an increase in serum creatinine possibly related to ibandronate only had a relevant increase of ≥44.2 µmol/l in the local laboratory that was not confirmed in the central laboratory. Levels of N-acetyl-β-d-glucosaminidase, {alpha}1-microglobulin, and microalbuminuria showed no clinically relevant changes over time in either treatment arm. This suggests that ibandronate does not cause renal tubular cell damage, interfere with renal tubular reabsorption, or affect glomerular filtration, supporting preclinical research [17].

As the sample size of the study was relatively small (n = 102), we are unable to exclude the possibility of rare renal dysfunction occurring with ibandronic acid infused over 15 min; however, the study was sufficiently powered to detect treatment-related renal events and has since supported the 2007 European approval of this treatment regimen [15]. Although the study was not powered for a direct statistical comparison of the 15-min and 60-min infusion arms, the safety results of this phase 2 study are consistent with previous trials of a single, rapid ibandronate infusion [13, 14]. The findings are also supported by preclinical data [18], which show no cumulative renal toxicity with ibandronate. The current use of the 15-min infusion of ibandronic acid in clinical practice will provide additional renal tolerability data from the real-life setting.

Treatment with i.v. ibandronate was generally well tolerated during this study. The most frequently reported adverse event was nausea. Patients in the 15-min infusion arm recorded a higher incidence of gastrointestinal disorders, such as vomiting and diarrhea than those in the 60-min infusion arm. One serious adverse event, ONJ, observed in a patient receiving the 15-min infusion, was considered by the investigator to be possibly related to study treatment. Retrospectively, the investigator considered the possibility that ONJ may have started before study entry since the patient had previously received pamidronate and zoledronic acid >42 months, had a history of dental surgery, and preexisting periodontal disease.


   conclusions
Top
 Abstract
 introduction
 methods
 results
 discussion
 conclusions
funding
 References
 
In conclusion, the renal function and overall adverse event profile of 15-min infusions of ibandronate every 3–4 weeks appear to be consistent with those of the 60-min infusion in patients with breast cancer and bone metastases [4]. The recent European approval of a 15-min infusion of ibandronate in patients with metastatic breast cancer should help increase the infusion capacity and the convenience of therapy for the patient [15, 19, 20]. Ibandronate has no mandatory requirement for renal function monitoring before each dose [15].


   funding
Top
 Abstract
 introduction
 methods
 results
 discussion
 conclusions
 funding
References
 
Roche.

Received for publication November 13, 2007. Revision received January 22, 2008. Accepted for publication January 24, 2008.


   References
Top
 Abstract
 introduction
 methods
 results
 discussion
 conclusions
 funding
 References
 
1. Theriault RL, Hortobagyi GN. Bone metastasis in breast cancer. Anticancer Drugs (1992) 3:455–462.[Medline]

2. Coleman RE. Bisphosphonates: clinical experience. Oncologist (2004) 9(Suppl_4):14–27.[Abstract/Free Full Text]

3. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev (2005) 3. CD003474.

4. Body JJ, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol (2003) 14:1399–1405.[Abstract/Free Full Text]

5. Body J, Kanis J, Diel I, et al. Risk reductions in metastatic breast cancer: multivariate poisson regression analyses of oral and i.v. ibandronate. Proc Am Soc Clin Oncol (2003) 22:46. (Abstr 184).

6. Diel IJ, Body JJ, Lichinitser MR, et al. Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer (2004) 40:1704–1712.[CrossRef][Web of Science][Medline]

7. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer (2003) 98:1735–1744.[CrossRef][Web of Science][Medline]

8. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med (2003) 349:1676–1679.[Free Full Text]

9. Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol (2001) 12:1164–1172.[Abstract/Free Full Text]

10. Lyubimova NV, Kushlinsky NE, Lichinister MR, et al. Renal safety of intravenous ibandronate in breast cancer patients with metastatic bone disease. Clin Drug Investig (2003) 23:707–716.[CrossRef][Medline]

11. Body JJ, Diel IJ, Tripathy D, et al. Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: phase III trial results. Eur J Cancer Care (Engl) (2006) 15:299–302.[CrossRef][Medline]

12. Chern B, Joseph D, Joshua D, et al. Bisphosphonate infusions: patient preference, safety and clinic use. Support Care Cancer (2004) 12:463–466.[CrossRef][Web of Science][Medline]

13. Neugebauer G, Köhler W, Akinkunmi L, et al. Influence of peak ibandronate concentrations after 6mg IV administration with shortened infusion time (15 and 30 minutes) on renal safety in man. J Clin Oncol (2001) 20:122a. (Abstr 486).

14. Body JJ, Lichinister M, Andreeva N, et al. Safety of an intravenous (i.v.) dose of ibandronate followed by daily oral dosing in metastatic bone disease: results of an open-label study. J Clin Oncol (2004) 22(Suppl 14). (Abstr 735).

15. Bondronat®. Summary of Product Characteristics. http://www.emea.europa.eu/humandocs/PDFs/EPAR/Bondronat/H-101-PI-en.pdf. (26 October 2007, date last accessed).

16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16:31–41.[Web of Science][Medline]

17. Body JJ, Pfister T, Bauss F. Preclinical perspectives on bisphosphonate renal safety. Oncologist (2005) 10(Suppl 1):3–7.[Abstract/Free Full Text]

18. Pfister T, Atzpodien E, Bauss F. The renal effects of minimally nephrotoxic doses of ibandronate and zoledronate following single and intermittent intravenous administration in rats. Toxicology (2003) 191:159–167.[CrossRef][Web of Science][Medline]

19. Von Moos R. Bisphosphonate treatment recommendations for oncologists. Oncologist (2005) 10(Suppl 1):19–24.[Abstract/Free Full Text]

20. Maxwell C, Swift R, Goode M, et al. Advances in supportive care of patients with cancer and bone metastases: nursing implications of zoledronic acid. Clin J Oncol Nurs (2003) 7(4):403–408.[CrossRef][Medline]


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
19/7/1266    most recent
mdn038v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by von Moos, R.
Right arrow Articles by Pecherstorfer, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by von Moos, R.
Right arrow Articles by Pecherstorfer, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?