1 Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium; 2 Department of Obstetrics and Gynaecology, University Hospital, Heidelberg, Germany; 3 Department of Clinical Chemotherapy, Cancer Research Center, Moscow, Russia; 4 Krankenhaus der Barmherzigen Brueder, Onkologische Ambulanz, Regensburg; 5 Mutterhaus der Borromaeerinnen, Trier, Germany; 6 Cancer Research Center, Department of Chemotherapy, Moscow, Russia; 7 F. Hoffmann-La Roche Ltd, Basel, Switzerland; 8 F. Hoffmann-La Roche Inc., Nutley, NJ, USA
Received 23 January 2003; revised 26 March 2003; accepted 14 May 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer.
Patients and methods:
A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 34 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly.
Results
SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated.
Conclusions:
These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.
Key words: bisphosphonate, bone metastases, breast cancer, ibandronate, pain, radiotherapy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The majority of bone metastases from breast cancer are osteolytic, causing elevated bone resorption [4]. Inhibitors of bone resorption, particularly bisphosphonates, have therefore been extensively used for treatment of metastatic breast cancer [5]. While the exact mechanism of action of bisphosphonates on bone resorption remains unclear, they are thought to act through inhibition of osteoclast activity and possibly osteoclast differentiation [6, 7]. Bisphosphonate use may also result in a decrease in tumour burden by rendering the bone microenvironment a less favourable site for the growth of tumour cells [810]. Intravenous (i.v.) pamidronate became established as a standard treatment for bone metastases due to breast cancer, notably based on the results of two randomised, placebo-controlled clinical trials in patients with metastatic breast cancer being treated with either chemotherapy [11] or hormonal therapy [12]. Pamidronate was effective in reducing skeletal morbidity in patients receiving both types of treatment, although there were substantial differences between the two studies in terms of the extent of the effect, and the number and types of skeletal events that were reduced by pamidronate treatment. The discrepancies may have been due to differences in the patient populations.
Ibandronate is a third-generation bisphosphonate that is 50100 times more potent than pamidronate in animal studies. Ibandronate markedly inhibits bone resorption and is effective in the treatment of tumour-induced hypercalcaemia [13]. It is currently being evaluated in both i.v. and oral formulations for the treatment of bone metastases in patients with breast cancer. The aim of the present study was to evaluate the efficacy and safety of i.v. ibandronate in the treatment of skeletal complications in women with breast cancer and bone metastases. Unlike previous studies of bisphosphonates in breast cancer, the patient population in this trial was not selected for variables such as the regimen used in cancer treatment (hormonal or chemotherapy), the presence or absence of any visceral metastases and the size of the lytic lesion. The mixed population thus obtained is likely to be more representative of the patient population for whom bisphosphonate treatment is indicated, since the recommended criterion for bisphosphonate use in patients with breast cancer is the diagnosis of bone metastases, irrespective of these other variables [14, 15].
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Inclusion criteria
Women aged 18 years with histologically confirmed breast cancer and bone metastases demonstrated by X-ray and/or computed tomography and/or nuclear magnetic resonance scan with a World Health Organization (WHO) performance status
2 were included in the study. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was received by local ethics committees and all patients gave written informed consent.
Exclusion criteria
Patients were excluded if they had a life expectancy <60 weeks, were pregnant or had received bisphosphonate or gallium nitrate treatment within the past 6 months, any investigational drug or aminoglycoside antibiotic within the past 30 days, or previous high-dose chemotherapy (dose intensity >3 times standard therapy). Patients were also excluded if they had hypercalcaemia or hypocalcaemia (albumin-corrected serum calcium >2.7 mM or <2 mM), serum creatinine >3 mg/dl, Pagets disease of bone, primary hyperparathyroidism, aspirin-sensitive asthma, or known liver or brain metastases.
Treatment
Each patient was randomised to receive either placebo or ibandronate 2 mg by i.v. bolus injection, or placebo or 6 mg ibandronate by i.v. infusion over 12 h. The study was thus blinded with respect to placebo or ibandronate treatment, but the dose was open-label due to differences in the mode of delivery. Each study arm received either injection or infusion of ibandronate or placebo on day 0. Subsequent treatments were administered at 3- or 4-weekly intervals for a minimum of 60 weeks and a maximum of 96 weeks. Patients were limited to a maximum of 24 treatments during the study. Owing to the severe nature of the underlying disease, there were no restrictions on concomitant medication. All concomitant medication was documented throughout the study.
Baseline assessments
Baseline assessments included: confirmation of inclusion and exclusion criteria, laboratory tests, urine tests, WHO performance status, recording of concomitant medication and radiotherapy, and assessment of bone pain and analgesic consumption.
Efficacy assessments
The primary efficacy parameter was the number of 12-week periods with new skeletal complications (bone events), allowing for the time the patient spent on study. This was expressed as the skeletal morbidity period rate (SMPR), calculated as the number of periods with new bone complications divided by the total observation time in periods. Bone events were defined as any of: vertebral fractures; pathological non-vertebral fractures; radiotherapy for bone complications (uncontrolled bone pain or impending fractures); or surgery for bone complications (fractures or impending fractures). The SMPR was used rather than the simple skeletal morbidity rate (number of events divided by time on study) since skeletal complications occurring close together are often likely to be related, rather than distinct, events. All skeletal complications occurring within a single 12-week period were considered as a single occurrence, avoiding double or triple counting of the same event. However, the SMPR calculation does not fully allow for time on study, since patients who withdrew or died very early, without experiencing a complication, would receive the same score (zero) as patients who completed 96 weeks on study without experiencing any skeletal complications. In a study on metastatic breast cancer, where patients may be very ill and a high proportion of withdrawals would be expected, the influence of early withdrawals on SMPR may be substantial. To avoid this the SMPR was calculated using a revised event ratio method, as follows:
The revised event ratio calculation avoids the occurrence of zero in the numerator of the fraction, thus ensuring that sufficient weighting is given to the time spent on study when calculating the number of periods with bone events [16]. Thus for patients with zero bone events, the SMPR ratio is lower the longer the time spent on study.
The assessment of vertebral fractures identified on spine radiographs was performed morphometrically [17].
Confirmatory analyses of the primary efficacy point included the proportion of patients with new bone events and the time to first new bone event. Secondary efficacy parameters included assessment of bone pain, analgesic consumption, WHO performance status, patient survival and markers of bone turnover.
Adverse events
Adverse events were monitored throughout the study and graded according to WHO criteria.
Statistics
The global null hypothesis was tested at the two-sided -level of 5% using the non-parametric JonckheereTerpstra method [18, 19]. If the global hypothesis was rejected, pairwise comparisons between treatments were performed using the Wilcoxon rank sum method maintaining an overall two-sided
-level of 5% and following a closed-test procedure. The primary and secondary efficacy analyses were conducted on the intention-to-treat population. The placebo groups (injection and infusion) were combined for all efficacy and safety analyses.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Treatment administration and duration
A total of 249 patients (53% of all patients randomised to treatment) completed 60 weeks of study treatment (58% ibandronate 6 mg; 57% ibandronate 2 mg; 45% placebo), while 187 patients (40%) completed 96 weeks (43% ibandronate 6 mg; 47% ibandronate 2 mg; 31% placebo). The median time on study (time from randomisation to study termination) was markedly longer for patients in both ibandronate groups (18.1 months) compared with placebo (13.1 months) (Figure 1).
|
|
|
Analysis of the unadjusted SMPR confirmed the sensitivity of the revised event ratio method. The mean unadjusted SMPR for all new bone events was significantly reduced in the 6 mg group compared with placebo (26% reduction; P = 0.019), whereas the treatment difference between the 2 mg group and placebo was not statistically significant (10% reduction; P = 0.638). Only the ratio for events requiring radiotherapy in the 6 mg treatment group approached statistical significance at the 5% level (P = 0.057).
New bone events
The mean number of new bone events per patient was significantly lower in the ibandronate 6 mg treatment group (2.65 events per patient) than in the ibandronate 2 mg (4.24 events per patient) or placebo (3.64 events per patient) groups (P = 0.032 for 6 mg ibandronate versus placebo) (Table 4). This appeared to be primarily due to a reduction in new bone events requiring radiotherapy. The number of 12-week periods with at least one new bone event was 20% lower in the ibandronate 6 mg group (145 periods) than in either the placebo (181 periods) or 2 mg (193 periods) groups (P = 0.09 for ibandronate 6 mg versus placebo). The proportion of patients who did not experience any new bone events during the study was higher in the ibandronate 6 mg group (49%) than in the ibandronate 2 mg (38%) or placebo (38%) group, although this did not reach statistical significance (P = 0.052).
|
|
|
More than 50% of patients in all three treatment groups experienced serious adverse events, with more than 98% considered unrelated to treatment. The proportion of patients experiencing serious adverse events was higher in the placebo group (63%) than the 6 mg (53%) or 2 mg (58%) ibandronate groups. The most common serious adverse event was malignancy progression, which also occurred more frequently in the placebo group (40%) than in the 6 mg (53%) or 2 mg (58%) ibandronate groups. Only three patients experienced serious adverse events that were considered to be related to treatment; one in the ibandronate 2 mg group (asthenia and hydronephrosis) and two in the ibandronate 6 mg group (one with bone pain and one with lung oedema).
There was no evidence of renal toxicity associated with ibandronate treatment: the incidence of renal adverse events was low and did not differ between placebo and ibandronate groups. The percentage of patients with increased creatinine levels (300 mM) was low and was similar between treatment groups (2.6% ibandronate 6 mg, 0.7% ibandronate 2 mg, 1.3% placebo). No patient withdrew from the study due to renal adverse events.
A total of 34 patients died during the study (up to 28 days following the last dose of study drug). Of these, 15 were in the placebo group, 11 in the 2 mg and eight in the 6 mg ibandronate groups. Death was most commonly due to malignancy progression, and no death was considered to be related to study treatment.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Previous studies have demonstrated efficacy of i.v. bisphosphonates in reducing the incidence of new bone events [11, 12, 15]. Unlike the present study, however, these trials were in selected patient populations. In addition, the primary end point was the skeletal morbidity rate, which, unlike the SMPR used in our study, may increase the likelihood of multiple counting of related events. Overall skeletal morbidity in the placebo group was lower in the current study than seen in the earlier studies using pamidronate [11, 12]. This may have been partly related to differences in methodology between the studies. In the pamidronate studies, all skeletal-related events were recorded separately. In contrast, in the current study, only one skeletal-related event could count within a given 12-week period; an event such as fracture that subsequently led to surgery and/or radiation only contributed once to the analysis. In addition, the patient population in the current study may have had less advanced metastatic disease at baseline: 45% of patients in the placebo group and 58% in each of the ibandronate groups completed 60 weeks on the study, whereas in the two pamidronate studies only 26% of patients on placebo and 31% of patients on treatment completed the full 48 weeks of study [15]. The proportion of patients who did not experience any new bone events was 49% in the ibandronate 6 mg group and 47% in the pamidronate trials. Furthermore, ibandronate 6 mg reduced and maintained bone pain scores below baseline during the 96-week study phase. This contrasts favourably with the studies of pamidronate, where pain scores were not maintained below baseline throughout the whole of the study period [11, 12]. In our study, the median time from randomisation to first new bone event with ibandronate 6 mg was 50.6 weeks, whereas the median time from randomisation to first new bone event in the pamidronate trials was 50.8 weeks [11, 12]. Our results suggest that ibandronate is at least as effective as pamidronate in patients with breast cancer and bone metastases. Importantly, ibandronate was associated with additional clinical benefits on bone pain scores. The efficacy of ibandronate shown here was thus achieved in a patient population representative of those for whom bisphosphonate treatment is clinically recommendedthat is, all patients with breast cancer and bone metastases, irrespective of the size of lytic lesion, mode of cancer treatment or presence of other metastases. American Society of Clinical Oncology guidelines recommend use of bisphosphonates as soon as bone metastases are diagnosed [14].
A separate analysis of secondary efficacy parameters from the study by Diel et al. [20] has shown that ibandronate 6 mg significantly improved quality of life compared with placebo. In addition, treatment with ibandronate significantly improved survival in the subpopulation of patients with bone and visceral metastases.
In terms of safety, although the majority of patients experienced serious adverse events, these were overwhelmingly related to the underlying disease, with less than 2% considered to be related to treatment. Differences between the ibandronate and placebo groups were small, and there was no evidence of renal toxicity of ibandronate. Adverse effects on renal function can occur with i.v. administration of currently available bisphosphonates. For example, the 8 mg dose of zoledronate was withdrawn from all clinical trials because of concerns over renal safety [21]. Moreover, in a phase III trial of zoledronate and pamidronate in patients with bone metastases from breast cancer, the 5-min infusion time for zoledronate was increased to 15 min to limit the amount of renal impairment [22]. Before the amendment, 13.2% of patients experienced deterioration of renal function, whereas 8.8% of patients still experienced elevated serum creatinine levels when the infusion time was increased. After the 15-min infusion amendment the incidence of renal impairment was similar between zoledronate (8.8%) and pamidronate (8.2%). In the present study, the proportion of patients with increased creatinine levels was similar between groups (2.6% ibandronate 6 mg versus 1.3% placebo). Although the definitions of renal dysfunction vary between studies, our results suggest that ibandronate has a more favourable renal safety profile than other bisphosphonates. Comparative trials are warranted.
The uneven withdrawal rate between the treatment and placebo groups is an important factor in interpretation of these data. The higher withdrawal rate for the placebo group meant that these patients had less time on study and therefore less opportunity to experience a skeletal-related event. This factor would be expected to favour placebo, but patients treated with ibandronate experienced fewer skeletal-related events overall.
Both doses of ibandronate demonstrated some efficacy, but the 6 mg dose appeared more effective without increased toxicity. These data therefore indicate that i.v. ibandronate 6 mg is an effective and well-tolerated treatment for patients with breast cancer and bone metastases.
![]() |
Acknowledgements |
---|
The following principal investigators participated in this study: J. J. Body, J. S. de Gréve, I. Mancini, Brussels, Belgium; S. Van Belle, Gent, Belgium; F. Cavalli, Bellinzona, Switzerland; B. Thuerlimann, St Gallen, Switzerland; R. Herrmann, Basel, Switzerland; M. Clemens, Tuebingen, Germany; I. J. Diel, Heidelberg, Germany; W. Eiermann, München, Germany; G. Kaiser, Nuernberg, Germany; P. Nauen, Herne, Germany; R. Obenaus, Berlin, Germany; A. E. Schindler, A. Vogt, Essen, Germany; E. D. Kreuser, Regensburg, Germany; K. Hoeffken, Jena, Germany; W. Dornoff, Trier, Germany; L. M. Ahlemann, Luedenscheid, Germany; U. Essers, Aachen, Germany; V. G. Porta, Valencia, Spain; J. M. Ferrero, Nice, France; P. Pouillard, A. de Gramont, Paris, France; N. Pinon, Reims, France; S. Reme, Montpellier, France; J. P. Labat, Brest, France; L. Guillevin, J. F. Morere, Bobigny, France; C. Krzisch, Salouel, France; Z. Mechl, Kuwait; O. Bruland, Oslo, Norway; O. K. Andersen, Tonsberg, Norway; R. Bremnes, Tromsoe, Norway; E. P. Ferreira, Porto, Portugal; A. Fernandes, Lisbon, Portugal; H. Bassara, Poznan, Poland; M. R. Lichinitser, V. A. Gorbunova, Moscow, Russia; V. F. Semiglazov, St Petersburg, Russia; J. Hansen, Vasteras, Sweden; I. Lorenz, Brno, Czech Republic; A. Howell, Manchester, UK; D. Cameron, Edinburgh, UK; C. J. Tyrell, Plymouth, UK; T. J. Powels, Sutton, UK; J. McAleer, Belfast, UK; P. J. Barrett-Lee, Cardiff, UK; K. Cash, Little Rock, AR, USA; J. Craig, Fairfield, LA, USA; D. A. Decker, Royal Oak, MI, USA; R. Gams, Columbus, OH, USA; R. Gottlieb, Lancaster, PA, USA; R. Gucalp, Bronx, NY, USA; A. Hage-Boutros, Camden, NJ, USA; K. Havlin, Durham, NC, USA; J. Hon, Huntsville, AL, USA; J. Gale Katterhagen, Burlingame, CA, USA; M. Lewis, Jackson, TN, USA; T. Panella, Knoxville, TN, USA; P. Plezia, Tucson, AZ, USA; S. Rivkin, Seattle, WA, USA; J. Sandbach, Austin, TX, USA; J. Wade, Decatur, IL, USA; P. Woolley, Johnstown, PA, USA; P. Conkling Norfolk, VA, USA; T. J. Ervin, Portland, MA, USA; M. Martinez-Rio, Boca Raton, FL, USA; D. Tripathy, Dallas, TX, USA; M. Meshad, Mobile, AL, USA; J. P. Jordaan, Durban, South Africa; I. D. Werner, Cape Town, South Africa; G. Falkson, Pretoria, South Africa.
![]() |
Footnotes |
---|
Members of the MF 4265 Study Group are listed in the Acknowledgements.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Theriault RL, Hortobagyi GN. Bone metastasis in breast cancer. Anticancer Drugs 1992; 3: 455462.[ISI][Medline]
3. Coleman RE. Skeletal complications of malignancy. Cancer 1997; 80 (Suppl 8): 15881594.[CrossRef][ISI][Medline]
4. Body JJ, Dumon JC, Gineyts E, Delmas PD. Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy. Br J Cancer 1997; 75: 408412.[ISI][Medline]
5. Body JJ, Bartl R, Burckhardt P et al. Current use of bisphosphonates in oncology. J Clin Oncol 1998; 16: 38903899.[Abstract]
6. Fleisch H. Bisphosphonates in Bone Disease, 4th edition. San Diego, CA: Academic Press 2000.
7. Russell RG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999; 25: 97106.[CrossRef][ISI][Medline]
8. Diel IJ, Solomayer E-F, Costa SD et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998; 339: 357363.
9. Mundy GR, Yoneda T. Bisphosphonates as anticancer drugs. N Engl J Med 1998; 339: 398400.
10. Paterson AH, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 5965.[Abstract]
11. Hortobagyi GN, Theriault RL, Lipton A et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998; 16: 20382044.[Abstract]
12. Theriault RL, Lipton A, Hortobagyi GN et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomised, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999; 17: 846854.
13. Ralston SH, Thiebaud D, Herrmann Z et al. Doseresponse study of ibandronate in the treatment of cancer-associated hypercalcaemia. Br J Cancer 1997; 75: 295300.[ISI][Medline]
14. Hillner BE, Ingle JN, Berenson JR et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 2000; 18: 13781391.
15. Lipton A, Theriault RL, Hortobagyi GN et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomised, placebo-controlled trials. Cancer 2000; 88: 10821090.[CrossRef][ISI][Medline]
16. Scott M, Möcks J, Givens S et al. Morbidity measures in the presence of recurrent composite endpoints. Pharm Stat 2003; 2: 3949.[CrossRef][ISI]
17. McCloskey EV, Spector TD, Eyres KS et al. The assessment of vertebral deformity: a method for use in population studies and clinical trials. Osteoporos Int 1993; 3: 138147.[ISI][Medline]
18. Jonckheere AR. A distribution-free k-sample test against ordered alternatives. Biometrika 1954; 41: 133145.[ISI]
19. Terpstra TJ. The asymptotic normality and consistency of Kendalls s test against trend, when ties are present in one ranking. Indag Math 1952; 14: 327333.
20. Diel IJ, Lichinitser MR, Body JJ et al. Improvement of bone pain, quality of life and survival time of breast cancer patients with metastatic bone disease treated with intravenous ibandronate. Eur J cancer 1999; 35 (Suppl 4): S83 (Abstr 269).
21. Body JJ. Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 2001; 28 (Suppl 11): 4953.
22. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7: 377387.[ISI][Medline]