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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3587-3592 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.054 Efficacy and Safety of Ibandronate in the Treatment of Opioid-Resistant Bone Pain Associated With Metastatic Bone Disease: A Pilot StudyFrom the Supportive Care Clinic, Department of Internal Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium Address reprint requests to Jean-Jacques Body, MD, PhD, Department of Internal Medicine, Université Libre de Bruxelles, 1 rue Heger-Bordet, Bruxelles 1000, Belgium; e-mail: jj.body{at}bordet.be
PURPOSE: Bone metastases are associated with severe and sometimes intractable pain, compromising patient quality of life (QOL). This open-label pilot study investigated the effects of short-term intensive treatment with intravenous (IV) ibandronate on opioid-resistant bone pain in patients with skeletal metastases. PATIENTS AND METHODS: Eighteen patients with advanced tumors and metastatic bone disease received nonstandard treatment with 4 mg of ibandronate administered IV (2-hour infusion) for 4 consecutive days (16-mg total dose). Baseline opioid analgesic use was equivalent to 400 mg/d of morphine. Patients were assessed for 6 weeks or until death. Changes from baseline were determined for bone pain, opioid consumption, patient functioning, QOL, performance status, and biochemical markers of calcium metabolism and bone turnover. Renal function was assessed by serum urea and creatinine measurement. RESULTS: Short-term, intensive ibandronate treatment significantly reduced bone pain scores within 7 days (P < .001). Pain reductions were sustained over the study period. Ibandronate significantly improved QOL, patient functioning, and performance status (P < .05). Mean values of the urinary cross-links pyridinoline and deoxypyridinoline tended to increase after day 21, returning close to baseline values by day 42. There was no correlation between the change in crosslinks values and the change in pain scores after ibandronate treatment. Ibandronate was well tolerated, with no evidence of renal toxicity. CONCLUSION: Nonstandard, intensive treatment with IV ibandronate seems to have a marked analgesic effect in patients with opioid-resistant bone pain from metastatic bone disease. Further investigation is warranted.
Metastatic bone disease (MBD) occurs in as many as 80% of patients with advanced cancer, most commonly those with breast, prostate, lung, thyroid, and kidney tumors.1,2 Skeletal metastases are associated with a high incidence of pathologic fractures, spinal cord compression, and hypercalcemia.3 Many patients with MBD experience bone pain, which is frequently severe and disabling.4-6 Alleviation of bone pain is therefore a key aspect of supportive care in these patients. Opioids and nonsteroidal anti-inflammatory drugs are commonly used in the treatment of metastatic bone pain, although their clinical benefits depend on pain severity, duration, and the incidence of side effects in individual patients.3,5 Bisphosphonates also have the potential to reduce bone pain in MBD, probably by inhibiting the underlying pathologic processes of osteoclast-mediated bone resorption.2,7,8 The first- and second-generation bisphosphonates, clodronate and pamidronate, have been shown to exert significant analgesic effects in patients with bone pain arising from metastatic breast cancer or myeloma.9-17 However, the long-term administration of pamidronate does not lead to a statistically significant reduction in bone pain after 1 to 2 years of treatment.17 In a phase III trial of breast cancer patients, the effect of zoledronate on pain seemed to be similar to that of pamidronate.18 Ibandronate is another third-generation bisphosphonate that is under evaluation for the treatment of MBD. A large multicenter, randomized, double-blind trial of patients with MBD from breast cancer assessed the impact of intravenous (IV) ibandronate on skeletal-related events and bone pain. Patients receiving ibandronate 6 mg IV every 4 weeks for 2 years experienced highly significant reductions from baseline in bone pain score compared with placebo (P < .001) that were fully maintained over 2 years of treatment.19 In light of the analgesic effects provided by ibandronate therapy in this clinical trial, an independent pilot study was conducted to investigate whether high doses of IV ibandronate are able to offer pain relief in patients with severe, opioid-resistant metastatic bone pain (ie, persistent pain after multiple dose escalations or changes of opioids, to the maximum level permitted by dose-limiting side effects). The study used a high-intensity dosing regimen, rather than standard 6-mg doses every 3 to 4 weeks, because of the severity of pain at baseline, the significant morbidity experienced by these patients, and the renal safety of ibandronate.
Study Population Patients with a variety of malignant tumors and a history of moderate to severe opioid-resistant metastatic bone pain were eligible for inclusion in the study. All patients had bone metastases confirmed by x-ray and were experiencing bone pain that was insufficiently controlled with opioid analgesics. Patients were excluded from the study if they had received bone radiotherapy in the previous 4 weeks, had received bisphosphonate therapy in the 2 months before the study, or had moderate or severe hypercalcemia (serum calcium [Ca] >12 mg/dL), impaired renal function (serum creatinine > 1.5 mg/dL), a change to their systemic hormonal treatment or chemotherapy during the 4 weeks before study entry, or delirium or confusion. During the study, most patients received only ibandronate (plus opioids). Seven patients received ongoing antineoplastic treatments that remained unchanged during the study (four patients received chemotherapy, two patients received hormonal treatment, and one patient received hormonal treatment plus corticosteroids). One patient was being treated with corticosteroids alone. Two patients received new antineoplastic treatments (one hormonal therapy and one chemotherapy) during the study period, but these had no detectable effects on tumor mass. None of the patients had a change in their dose of corticosteroids or antidepressants or received radiotherapy during the evaluation period. Patients were withdrawn from the study if they received other interventions that could have affected their level of pain and quality of life (QOL). Participants gave verbal informed consent to participate in the study. The trial had previously been approved by the local ethics committee.
Study Design
Study Assessments Patient functioning was evaluated using the Edmonton Functional Assessment Tool (EFAT).22 Unlike other validated functional tools, EFAT is a multidimensional assessment tool with scoring on a scale from 0 (patient fully independent) to 30 (fully bedridden patient). It is used frequently to assess the functional performance of patients with advanced cancer over time because of its reliability in patients with poor functioning. Performance status was assessed by the Eastern Cooperative Oncology Group (ECOG) scale,23 and patient QOL was assessed daily using the well-being item scale from the Edmonton Symptom Assessment System (ESAS).24 The item is scored on a 10-point scale from 0 (best feeling of well-being) to 10 (worst possible feeling of well-being). Throughout the study, serum Ca (normal values [NL], 8.5 to 10.3 mg/dL), phosphorus (Pi; NL, 2.2 to 4.0 mg/dL), and parathormone (intact PTH; NL, 10 to 55 pg/mL; DiaSorin, Stillwater, MN) were assessed as markers of Ca metabolism. Alkaline phosphatase (NL < 115 mU/mL) and circulating osteocalcin (BGP; NL < 15.1 ng/mL, measured using two-site sandwich immunoradiometric assay)25 were assessed as markers of bone formation. Urinary markers of bone resorption (pyridinoline [PYD], NL < 81 nmol/mmol creatinine; and deoxypyridinoline [DPD], NL < 17 nmol/mmol creatinine crosslinks) were measured using high-performance liquid tomography (BioRad, Hercules, CA). Adverse events were closely monitored throughout the study.
Statistical Analyses
Patient Demographics The study included 18 patients (12 women and six men) with a variety of different tumor types (Table 1). The median age was 54 years (range, 33 to 76 years). One woman was treated twice, with an interval of more than 2 months between treatments. The median duration of inpatient hospitalization (n = 12) before starting therapy was 1 day (range, 0 to 6 days). Excluding a patient who died on day 2 of the study, these patients remained hospitalized for a median of 9 days (range, 4 to 25 days).
Efficacy: Bone Pain and Analgesic Consumption At baseline (day 0), all patients in the study were experiencing moderate to severe pain (visual analog scale pain score of 5 to 6) while receiving the equivalent of approximately 400 mg/d of oral morphine. Treatment with ibandronate significantly reduced pain scores within 7 days (P < .001). Patients continued to experience significantly reduced pain scores compared with baseline at day 21 (P < .0001) and day 42 (P < .05; Fig 1). A subanalysis showed that ibandronate significantly improved bone pain from day 7 to 42 in both patients with breast cancer and other tumor types (P < .05 v day 0).
Significant reductions from baseline in pain scores with ibandronate were not due to an increased use of analgesic therapy. Mean MEDD scores were similar from baseline to end point (day 42).
Efficacy: QOL and Patient Function
Ibandronate also provided benefits for functional status, as shown by a reduction in EFAT scores at all time points compared with baseline values, with statistical significance reached at day 21 (P < .05; Fig 3A). Mean performance status scores on the ECOG scale significantly improved at days 21 and 42 (P < .05; Fig 3B).
Biochemical Markers of Bone Metabolism and Turnover Treatment with ibandronate was associated with reductions in serum Ca and Pi that reached a nadir on day 7, returning to baseline levels by day 42 (Table 2 indicates the mean values). At day 7, 38% of patients (five of 13 patients) had asymptomatic hypocalcemia (median serum Ca of 7.7 mg/dL; range, 6.2 to 8.2 mg/dL), and 36% of patients (five of 14 patients) had asymptomatic hypophosphatemia (median serum Pi of 2.7 mg/dL; range, 1.5 to 3.9 mg/dL). None of these patients required treatment. The decrease in serum Ca was accompanied by a significant increase in PTH concentrations at day 7 (median, 55 pg/mL; range, 21 to 272 pg/mL; mean, 120 pg/mL; standard deviation ± 31 pg/mL), which did not persist beyond 21 days (Table 2).
Urinary PYD decreased from a median of 175 nmoL/mmoL creatinine (range, 72 to 428 nmoL/mmoL creatinine) to a median of 109 nmoL/mmoL creatinine (range, 42 to 348 nmoL/mmoL creatinine) between days 7 to 21 of the study period (day 21, P < .01). Urinary DPD decreased from a baseline median of 30 nmoL/mmoL creatinine (range, 8 to 73 nmoL/mmoL creatinine) to 15 nmoL/mmoL creatinine (range, 2 to 75 nmoL/mmoL creatinine) between days 7 to 21 (P < .01 at day 21; Table 2). Mean values of PYD and DPD tended to increase after day 21, returning close to baseline values by day 42. There was no correlation between the change in PYD and DPD values and the change in pain scores after ibandronate treatment. Analysis of markers of bone formation revealed that both osteocalcin and alkaline phosphatase levels increased slightly after ibandronate therapy (Table 2).
Safety There were 15 survivors at the time of final assessment (day 42). The median survival time was 154 days (range, 2 to 428 days). One patient died during therapy (at day 2 from respiratory distress as a result of lung metastases), and two other patients died during the study evaluation period (one patient at day 11 from respiratory insufficiency and one patient at day 12 from pulmonary and cardiac failure). Deaths were considered to be due to cancer progression and not related to study treatment.
The results of this small-scale, independent, open-label study suggest that short-term intensive treatment with ibandronate (16 mg IV in 4 days) is associated with marked analgesic effects in patients with severe, opioid-resistant metastatic bone pain from breast cancer and other tumor types. Because this was an open-label study, it is possible that a placebo effect may have contributed to patient reports of analgesia after treatment. A randomized, placebo-controlled trial conducted using a similar spectrum of patients and the same intensive dosing regimen would be required to refute this hypothesis. It is also possible that the improvement in pain and functioning observed by day 7 could have been the result of a change in setting (hospital admission) in some of the patients. However, mean pain scores were maintained below baseline up to day 42, long after the median duration of inpatient stay (9 days). All but one patient experienced pain relief during the study, and six of these patients were being treated at the day-care hospital. It is therefore likely that ibandronate was having a real effect on patient symptoms and well-being. The alleviation of bone pain with ibandronate has previously been reported in a phase III randomized trial of patients with metastatic breast cancer in which ibandronate 6 mg was infused every 3 to 4 weeks.19 A reduction in bone pain score below baseline with ibandronate 6 mg was obtained within 4 weeks at the first study assessment. The reduction in bone pain score with ibandronate 6 mg was significant compared with placebo (P < .001) and was maintained below baseline throughout the 2-year study period. Although pain relief has been reported with other bisphosphonates in clinical trials, ibandronate is the only bisphosphonate to demonstrate marked reductions in bone pain that are prolonged and sustained below baseline levels over 2 years of treatment.10-19 The intensive IV ibandronate therapy in this study was able to significantly relieve bone pain within 7 days, an effect that was maintained for a further 5 weeks. Further investigation would be required to assess whether repeated cycles of such therapy could relieve opioid-resistant metastatic bone pain in the longer term. Although their benefits are well documented, the mechanisms of action behind the analgesic effects of bisphosphonate therapy are poorly understood.4,6,11,26 A previously published study of IV pamidronate, a second-generation bisphosphonate used in the treatment of MBD, found some correlation between the symptomatic benefits of treatment, including pain relief, and changes in markers of bone resorption.26 We could not confirm this correlation between pain relief and bone formation or resorption markers. This may have been due to the small patient numbers or differences between studies in the patient population. However, it is highly unlikely that metastatic bone pain can simply be explained by enhanced bone resorption. Although phase III clinical trials of ibandronate have demonstrated the significant effects of treatment on markers of bone turnover compared with placebo, with accompanying improvements in symptoms, correlations between these outcome measures were not directly investigated (data on file, Hoffman-La Roche, Basel, Switzerland). In this study, ibandronate was given by IV infusion at a daily dose of 4 mg on 4 consecutive days. This dose of ibandronate (16 mg in 4 days) is nonstandard and considerably higher than the dose used in clinical trials of IV ibandronate in patients with MBD (6 mg infused over 1 hour every 3 to 4 weeks). We selected a higher than standard dose in an attempt to provide rapid pain relief because of the severity of the bone pain in the patient group on entry to the study. The choice of specific dosing schedule was essentially empirical, as there were no data available on the effect of higher doses of ibandronate on bone pain at the time the study was conducted. It was anticipated that the intensive dosing schedule could be used safely in patients with metastatic bone disease because of clinical trial evidence for the tolerability of this IV bisphosphonate.19 Ibandronate treatment was well tolerated in this study, with few adverse events reported. Although a transient and asymptomatic hypocalcemia was observed immediately after treatment, this was countered by a concurrent surge in PTH and subsequent normalization of serum Ca levels. Importantly, there was no evidence of renal function deterioration (creatinine and urea levels remained stable in each patient, including a woman with breast cancer who was treated twice with a 16-mg total dose of ibandronate over a 2-month period). The results of this pilot study support those of a phase III trial of 6 mg of IV ibandronate and suggest that, unlike currently available IV bisphosphonates (zoledronate and pamidronate),18,27-29 relatively high doses of IV ibandronate have no apparent renal toxicity.19 Indeed, in a recent prospective study of patients with metastatic prostate, renal, or bladder cancer, ibandronate 6 mg infused over 3 consecutive days significantly relieved severe metastatic bone pain without having any detrimental effect on renal functioning.30 It remains to be shown, however, that repeating such high-dose regimens at regular intervals would maintain this high level of tolerability. Because opioid-resistant metastatic bone pain is exceedingly difficult to manage, ibandronate may offer an interesting new therapeutic modality for patients with this symptom. Patients with advanced cancers who require sedating analgesics to control intractable pain might experience diminished QOL. In the current study, treatment with IV ibandronate alleviated severe, opioid-resistant bone pain while improving QOL, patient functioning, and performance status. Bone pain reductions were also accompanied by QOL benefits in the phase III trial of 6 mg of IV ibandronate.19 Morphine consumption for persistent pain symptoms remained fairly stable during the course of this study, which suggests that ibandronate was benefiting patients as an adjuvant, coanalgesic therapy. The lack of adverse events with ibandronate also indicated that ibandronate improves bone pain and performance status without adding to the treatment burden of advanced malignant disease. Tolerability is a useful property of any coanalgesic, as opioid analgesia can lead to side effects, including sedation and constipation, which require additional management. The analgesic activity of bisphosphonates has previously been shown in patients with breast cancer, multiple myeloma, and prostate cancer.9-18,30,31 This study suggests that ibandronate has analgesic activity in patients with severe, opioid-resistant bone pain from breast cancer and a variety of other tumor types. The positive effects of intensive ibandronate treatment in this pilot study clearly warrant further investigation in controlled clinical trials of patients with opioid-resistant bone pain from MBD, including all tumor types.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Jean-Jacques Body, Novartis, Hoffmann-La Roche. Performed contract work within the last 2 years: Jean-Jacques Body, Novartis, Hoffmann-La Roche.
We thank Thomson Gardiner-Caldwell US for editorial assistance.
The study and data analysis were supported by Foundation Medic and Les Amis de l'Institut Bordet. Preliminary data from this study were previously reported in abstract form. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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8. Body JJ, Bartl R, Burckhardt P, et al: Current use of bisphosphonates in oncology. J Clin Oncol 16:3890-3899, 1998 9. Pavlakis N, Stockler M: Bisphosphonates for breast cancer (Cochrane Review). Oxford, United Kingdom, The Cochrane Library, Issue 2, 2002 (update software) 10. Tubiana-Hulin M, Beuzeboc P, Mauriac L, et al: Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases. Bull Cancer 88:701-707, 2001[Medline] 11. Ernst DS, MacDonald RN, Paterson AHG, et al: A double-blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 7:4-11, 1992[CrossRef][Medline] 12. Ernst DS, Brasher P, Hagen N, et al: A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain. J Pain Symptom Manage 13:319-326, 1997[CrossRef][Medline]
13. Robertson AG, Reed NS, Ralston SH: Effect of oral clodronate on metastatic bone pain: A double-blind, placebo-controlled study. J Clin Oncol 13:2427-2430, 1995 14. Cascinu S, Graziano F, Alessandroni P, et al: Different doses of pamidronate in patients with painful osteolytic bone metastases. Support Care Cancer 6:139-143, 1998[CrossRef][Medline] 15. Koerberle D, Bacchus L, Thuerlimann B, et al: Pamidronate treatment in patients with malignant osteolytic bone disease and pain: A prospective randomized double-blind trial. Support Care Cancer 7:21-27, 1999[CrossRef][Medline] 16. McCloskey EV, MacLennan IC, Drayson MT, et al: Randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma: MRC Working Party on Leukaemia in Adults. Br J Haematol 100:317-325, 1998[CrossRef][Medline] 17. 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 16:2038-2044, 1998[Abstract] 18. 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 7:377-387, 2001[Medline]
19. 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 14:1399-1405, 2003 20. Bruera E, Michaud M, Vigano A, et al: Multidisciplinary symptom control clinic in a cancer center: A retrospective study. Support Care Cancer 9:162-168, 2001[CrossRef][Medline] 21. Jacox A, Carr DB, Payne R, et al: Management of Cancer Pain: Quick Reference Guide for Clinicians (Clinical Practice Guideline No. 9, AHCPR Publication No. 94-0592). Rockville, MD, Agency for Health Care Policy and Research, United States Department of Health and Human Services, Public Health Service, March 1994 22. Kaasa T, Loomis J, Gillis K, Bruera E: The Edmonton Functional Assessment Tool: Preliminary development and evaluation for use in palliative care. J Pain Symptom Manage 13:10-19, 1997[CrossRef][Medline] 23. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline] 24. Bruera E, Kuehn N, Miller MJ, et al: The Edmonton symptom assessment system (ESAS): A simple method for the assessment of palliative care patients. J Palliat Care 7:6-9, 1991[Medline]
25. Dumon JC, Wantier H, Mathieu F, et al: Technical and clinical validation of a new immunoradiometric assay for human osteocalcin. Eur J Endocrinol 135:231-237, 1996
26. Vinholes JJF, Purohit OP, Abbey ME, et al: Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 8:1243-1250, 1997 27. Adami S, Zamberlan N: Adverse effects of bisphosphonates: A comparative review. Drug Saf 14:158-170, 1996[Medline] 28. Bounameaux HM, Schifferli J, Montani JP, et al: Renal failure associated with intravenous bisphosphonates. Lancet 1:471, 1983 29. Body JJ: Dosing regimens and main adverse events of bisphosphonates. Semin Oncol 28:49-53, 2001 (suppl 11) 30. Heidenreich A, Ohlmann C, Olbert P, et al: High-dose ibandronate is effective and well tolerated in the treatment of pain and hypercalcaemia due to metastatic urologic cancer. Eur J Cancer 1:S270, 2003 (suppl 5)
31. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458-1468, 2002 Submitted July 8, 2003; accepted June 3, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
