- Email: [email protected]
Ibandronate in metastatic bone pain
Ibandronate in Metastatic Bone Pain Axel Heidenreich,a Carsten Ohlmann,b and Jean-Jacques Bodyc Bone pain is a frequent complication of metastatic bone disease, with severe consequences for patient mobility and quality of life. Bisphosphonates can reduce bone pain and augment palliative radiotherapy, although relief is often for a relatively short period of time. Ibandronate is the first bisphosphonate to provide sustained bone pain relief over 2 years and, unlike other bisphosphonates, has shown improvements in quality of life. In phase III studies of patients with bone disease from breast cancer, intravenous ibandronate 6 mg and oral ibandronate 50 mg reduced bone pain below baseline levels within 6 weeks. Significant reductions were maintained throughout the 96-week study phase compared with placebo (P <.001). Two open, nonrandomized studies examined the effect of intensive, high-dose intravenous ibandronate (4 mg on 4 consecutive days, or 6 mg on 3 consecutive days) in patients with breast cancer or other tumor types with opioid-resistant bone pain and in patients with urologic cancer. In each study, ibandronate rapidly relieved moderate-to-severe metastatic bone pain, improving quality of life and patient functioning. Both intravenous and oral ibandronate provide effective long-term relief from metastatic bone pain. This clinical benefit may reduce the burden of metastatic bone disease on health care resources by limiting the need for analgesics and radiotherapy to the bone. Semin Oncol 31:67-72 © 2004 Elsevier Inc. All rights reserved.
S
evere bone pain is experienced by 60% to 80% of patients with metastatic bone disease,1-3 and has a profound impact on quality of life. Bone pain can lead to impaired mobility, reduced functional capacity, and increased dependency on others. Therefore, effective pain relief is an important goal in managing metastatic bone disease. Palliation commonly involves a multidisciplinary approach, combining analgesics and systemic chemotherapy, hormonal therapy, or radiolabeled drugs with localized treatments such as radiotherapy and surgery. While many patients have adequate and prolonged pain relief with these treatments, others have refractory or recurrent pain.4-6 Palliative treatment can be confounded by treatment-related side effects that need extra care, with a further impact on patients’ quality of life and health care resources.4,5,7
aDivision
of Oncological Urology, Department of Urology, University of Cologne, Germany. bDepartment of Urology, Philipps-University Marburg, Germany. cInstitut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Dr Heidenreich has financial interest with Roche Laboratories, Novartis, Inc, and Aventis Pharma. Dr Body has served as a consultant to and received honoraria from Roche Laboratories and Novartis Inc. Address reprint requests to Prof Dr med Axel Heidenreich, Division of Oncological Urology, Department of Urology, University of Cologne, Joseph – Stelzmann – Str. 9, 50931 Köln, Germany.
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.07.026
Bisphosphonates for Metastatic Bone Pain Bisphosphonates are effective for preventing and treating skeletal-related complications from metastatic bone disease,8-13 and are an important addition to other strategies for treating bone pain. Until recently, intravenous (IV) bisphosphonates were used for optimal pain management. Trials of IV clodronate, pamidronate, and zoledronic acid showed that these agents relieved pain, although results were inconsistent across trials.11,14-17 The mechanism of pain relief by bisphosphonates is unclear, but it may be because of their disruptive effects on bone resorption because there appears to be a link between metastatic bone pain and the rate of bone resorption.18 Bisphosphonates may also interfere with the synthesis and production of pain mediators, such as prostaglandin E2 and interleukins 1 and 6.6 Ibandronate is a new-generation, highly potent aminobisphosphonate available in IV and oral formulations. Recent data show that both formulations have similar clinical benefits in patients with breast cancer and bone metastases (summarized by Tripathy elsewhere in this supplement). In October 2003, the European Agency for the Evaluation of Medicinal Products granted ibandronate marketing authorization in the European Union for the prevention of skeletal events in patients with breast cancer and bone metastases. 67
A. Heidenreich, C. Ohlmann, and J.-J. Body
68
Figure 1 Mean change from baseline in bone pain score over approximately 2 years: phase III IV ibandronate trial in patients with advanced breast cancer.19
Approved doses are IV ibandronate 6 mg every 3 to 4 weeks, and oral ibandronate 50 mg once daily. This review briefly describes the effects of IV and oral ibandronate on metastatic bone pain. Ibandronate is the first bisphosphonate to show long-term pain relief and, unlike other bisphosphonates, has shown improvements in quality of life.
Metastatic Bone Pain Relief with Intravenous Ibandronate in Breast Cancer A randomized, placebo-controlled phase III trial assessed the effect of IV ibandronate 6 mg on bone pain, analgesic use, and quality of life in women with advanced breast cancer and bone metastases.12,19 One hundred fifty-four women received IV ibandronate 6 mg and 158 patients received placebo (for full details of study design see Tripathy elsewhere in this supplement). Bone pain was assessed using a 5-point scale (0 ⫽ none to 4 ⫽ intolerable) and analgesic use with a 7-point scale (0 ⫽ none to 6 ⫽ opiates ⱖ100 mg morphine daily or equivalent).20 The European Organization for Research and Treatment of Cancer QLQ-C30 scale21 was used to measure quality of life. Scores for the five functional domains (physical, role, cognitive, emotional, and social) were combined to obtain a global quality-oflife score. At baseline, the incidence of bone pain was distributed evenly between the two treatment groups. Treatment with ibandronate rapidly reduced bone pain levels. The mean change in bone pain scores from baseline was significantly lower with IV ibandronate than with placebo (⫺0.28 v ⫹0.21; P ⬍.001) and remained below that of baseline throughout the 96-week study (Fig 1).19 Use of analgesics was lower with IV ibandronate than with placebo, although this effect was not statistically significant (mean change from baseline 0.51 v 0.90; P ⫽ .08). Nonetheless, these results
indicate that the improvement in bone pain in patients on ibandronate was not because of more use of analgesics. As expected in this population, quality of life deteriorated in all patients during the study.19 However, IV ibandronate was associated with a significantly smaller reduction in global quality of life than placebo (mean change from baseline ⫺10.1 v ⫺45.0; P ⫽ .005). Physical, emotional, and social functioning deteriorated significantly less in the ibandronate than in the placebo group (P ⱕ.05).
High-Dose Intravenous Ibandronate for OpioidResistant Metastatic Bone Pain An open-label, pilot study assessed the effect of IV ibandronate on moderate-to-severe, opioid-resistant bone pain using nonstandard, intensive dosing.22 The investigators chose a relatively high and intense treatment regimen because of the severity of the patients’ bone pain at study entry and the favorable safety profile of ibandronate. The study included 18 patients with metastatic breast cancer (n ⫽ 10) or other tumor types with metastatic bone disease, including adrenal, thyroid, liver, lung, head and neck, and prostate cancer (n ⫽ 8). Patients were treated with IV ibandronate 4 mg infused over 2 hours on 4 consecutive days (total 16 mg) in a supportive care setting. Efficacy was evaluated over 6 weeks. Bone pain was measured using a visual analogue scale (VAS) (0 ⫽ no pain to 10 ⫽ maximum pain).23,24 Pain was also evaluated indirectly using the Morphine Equivalent Daily Dose index of opioid consumption.24 Quality of life was assessed using the Edmonton Symptom Assessment System well-being scale (0 ⫽ good to 10 ⫽ poor)25 and patient functioning using the Edmonton Functional Assessment Tool (0 ⫽ fully independent to 30 ⫽ fully bedridden).26 Performance status was graded using the Eastern Cooperative Oncology Group scale.27 In the study ibandronate significantly reduced mean VAS
Ibandronate in metastatic bone pain
69
Figure 2 Mean change from baseline in bone pain score with high-dose IV ibandronate for opioid-resistant bone pain.29
pain scores within 7 days (P ⬍.001), and these reductions were maintained over 6 weeks (P ⬍.05) (Fig 2). This was achieved without increasing analgesic use; Morphine Equivalent Daily Dose scores remained the same from baseline to endpoint. High-dose IV ibandronate also significantly improved patients’ quality of life on the Edmonton Symptom Assessment System well-being scale by day 7, as well as functional status, Edmonton Functional Assessment Tool scores, and performance status by day 21 (P ⬍.05 v baseline for all measures).
High-Dose Intravenous Ibandronate for Metastatic Bone Pain from Urologic Cancer Two open, nonrandomized prospective trials have assessed the efficacy of high-dose IV ibandronate in treating painful bone metastases in patients with prostate cancer and other types of urologic cancer.28,29 Twenty-five and fifty-three patients with prostate cancer and with either prostate, renal or bladder cancer, respectively, were treated with IV ibandronate 6 mg infused over 1 hour for 3 consecutive days (the “loading dose”), followed by a single infusion of IV ibandronate 6 mg every 4 weeks for 20 weeks. Bone pain was assessed using a VAS (0 ⫽ no pain to 10 ⫽ maximum pain),24 and patients recorded analgesic use in a pain diary. Patient functioning was assessed using the Karnofsky Index. In the prostate cancer trial, using the visual analogue scale from 1 to 10, palliative response with significant reduction in pain score from 6.5 (5 to 10) to 2.0 (0 to 4; P ⬍.001) was achieved in 23 of the 25 patients (92%), which was associated with a significant decrease of daily consumption of analgesics.28 In the urologic cancer trial, 44 of the 53 patients (83%) experienced bone pain relief (defined as a 3-point reduction in VAS) from day 2 of ibandronate treatment, and 25% of patients were completely pain free.29 The mean VAS score on
day 3 was significantly reduced from baseline (2.5 v 6.8; P ⬍.001) and remained below baseline throughout the 20week study (Fig 3). The reduction in bone pain score led to improved patient functioning throughout the study (Fig 3). Analgesic use was reduced by more than 50% in 85% of patients.
Oral Ibandronate for Metastatic Bone Pain Relief in Advanced Breast Cancer Two randomized, placebo-controlled trials assessed the efficacy of oral ibandronate (50 mg daily) in reducing bone pain in patients with metastatic bone disease from breast cancer.30 A total of 287 patients received ibandronate and 277 received placebo (for full details of study designs see Tripathy elsewhere in this supplement). Bone pain, analgesic use, and quality of life were assessed as for the phase III trial with IV ibandronate, described above. Data from the two trials were pooled for analysis, as predefined in the study protocols. Bone pain scores were rapidly reduced and remained below baseline in the ibandronate group throughout the 96week study, and increased progressively in the placebo group (Fig 4).30 At endpoint, the mean change in baseline score was significantly lower with oral ibandronate than with placebo (⫺0.1 v ⫹0.2; P ⫽ .001). Although analgesic use increased scores in both groups, patients on ibandronate used significantly fewer analgesics than patients on placebo (0.60 v 0.85 [morphine consumption analogue score]; P ⫽ .019). As in the phase III study of IV ibandronate, quality of life deteriorated in both groups of patients. However, the decrease in global assessment of quality of life was significantly greater with placebo than with oral ibandronate (⫺26.8 v ⫺8.3; P ⫽ .032).30 On the individual functioning scales of
A. Heidenreich, C. Ohlmann, and J.-J. Body
70
Figure 3 Mean change in bone pain and Karnofsky Index scores with high-dose ibandronate in patients with metastatic urologic cancer.29
the European Organization for Research and Treatment of Cancer QLQ-C30, physical and role functioning scores were significantly higher in the ibandronate than in the placebo group (P ⱕ.05).
Comparison of Ibandronate with Other Bisphosphonates in the Relief of Metastatic Bone Pain As yet, there are no direct comparisons of ibandronate with other current bisphosphonates for metastatic bone pain. Additionally, the different methods for reporting pain levels and analgesic use makes comparison across trials difficult. Early studies with oral clodronate found little or no significant effect on bone pain.17,31-33 While other studies reported significant relief of bone pain with IV clodronate,16 this is rarely used in clinical practice. There are conflicting results for the
efficacy of IV pamidronate 90 mg in alleviating bone pain. Some studies reported a significant benefit when pamidronate was compared with placebo or chemotherapy alone in patients with breast cancer or multiple myeloma,14,15,34,35 while others failed to show significant long-term pain relief compared with placebo in patients with breast cancer36,37 and prostate cancer.38 In a placebo-controlled study of zoledronic acid in patients with advanced prostate cancer, bone pain scores increased in both treatment groups, but were consistently lower in the zoledronic acid than placebo group.11 The analgesic effect of zoledronic acid has also been investigated in a comparative study with pamidronate in patients with breast cancer or multiple myeloma.9 Among patients with bone pain scores greater than 0 at baseline, 53% to 69% of all patients experienced an improvement in their bone pain score. The mean change in bone pain score remained below baseline throughout the 13-month study. Analgesic use either decreased or remained fairly stable. However, there was no statistical dif-
Figure 4 Mean change from baseline in bone pain score over approximately 2 years: phase III oral ibandronate trial in patients with advanced breast cancer.19
Ibandronate in metastatic bone pain ference between pamidronate or zoledronic acid for either of these clinical outcomes. The statistical significance of the change in bone pain score compared with baseline was not reported. More recently, Rosen et al39 have reported 12month extension data for the comparative trial of zoledronic acid and pamidronate. However, the long-term analgesic effects of both agents were not discussed. Few studies of bisphosphonates have assessed quality of life in patients with metastatic bone disease. These trials were generally placebo-controlled, and failed to show any significant benefits of the active agent, including oral clodronate 1,600 mg/day,40 IV pamidronate 90 mg,35 and IV zoledronic acid 4 mg.11
71
14.
15.
16.
17.
18.
Conclusion The results of phase III and open-label studies indicate that both IV and oral ibandronate provide sustained relief from metastatic bone pain, improving patient quality of life, mobility, and independence. Improvements were reported in patients with various types of tumor, including breast and prostate cancer, as well as in cancer patients with difficult-to-treat, opioid-resistant bone pain. Ibandronate is the only bisphosphonate to maintain pain scores below baseline levels over about 2 years. Unlike other bisphosphonates, ibandronate improves quality of life compared with placebo. Trials comparing the effects of IV and oral ibandronate on bone pain versus other bisphosphonates are warranted to assess fully this promising treatment for managing metastatic bone pain.
19.
References
24.
1. Bonica JJ: Management of cancer pain. Acta Anaesthesiol Scand Suppl 74:75-82, 1982 (suppl) 2. Galasko CSB: Skeletal MetastasesLondon, Butterworth, 1986 3. Solomayer EF, Diel IJ, Meyberg GC, et al: Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59:271-278, 2000 4. Serafini AN: Therapy of metastatic bone pain. J Nucl Med 42:895-906, 2001 5. Janjan N: Bone metastases: approaches to management. Semin Oncol 28:28-34, 2001 (suppl 11) 6. Mercadante S: Malignant bone pain: pathophysiology and treatment. Pain 69:1-18, 1997 7. World Health Organization. Cancer pain relief and palliative care: report of a WHO expert committee. Geneva, Switzerland, World Health Organization, 1990 8. Body JJ, Bartl R, Burckhardt P, et al: Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 16:3890-3899, 1998 9. 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 10. Pavlakis N, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 1:CD003474, 2002 11. 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 12. 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 13. Body JJ, Diel IJ, Lichinitzer M, et al: Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone
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disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 90:1133-1137, 2004 Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 334:488-493, 1996 Conte PF, Latreille J, Mauriac L, et al: Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. J Clin Oncol 14:2552-2559, 1996 Ernst DS, MacDonald RN, Paterson AH, et al: A double-blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 7:4-11, 1992 Heidenreich A, Hofmann R, Engelmann UH: The use of bisphosphonates for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol 165:136-140, 2001 Vinholes JJ, 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 Diel IJ, Body J-J, 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 401: 1704-1712, 2004 Coleman RE. Assessment of response to treatment, in Rubens RD, Forgelman I (eds): Bone Metastases: Diagnosis and Treatment. Berlin, Springer, 1991, pp 99-120 Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-375, 1993 Mancini I, Dumon J-C, Body J-J: Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study. J Clin Oncol 22:3587-3592, 2004 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 Jacox A, Carr DB, Payne R, et al: Management of cancer pain. Quick reference guide for clinicians. Clinical Practice Guideline No. 9. Rockville, MD, Agency for Health Care Policy and Research, US Department of Health and Human Services, Public Health Service, AHCPR Publication No. 94-0592, March 1994 Bruera E, Schoeller T, Wenk R, et al: A prospective multicenter assessment of the Edmonton staging system for cancer pain. J Pain Symptom Manage 10:348-355, 1995 Kaasa T, Loomis J, Gillis K, et al: The Edmonton Functional Assessment Tool: preliminary development and evaluation for use in palliative care. J Pain Symptom Manage 13:10-19, 1997 Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649655, 1993 Heidenreich A, Elert A, Hofmann R: Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 5:231-235, 2002 Heidenreich A, Ohlmann C, Olbert P, et al: High-dose ibandronate is effective and well tolerated in the treatment of pain and hypercalcemia due to metastatic urologic cancer [abstract 897]. Eur J Cancer 1:S270, 2003 (suppl 5) Body J-J, Diel IJ, Bell R, et al: Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 111:306-312, 2004 Elomaa I, Kylmala T, Tammela T, et al: Effect of oral clodronate on bone pain – A controlled study in patients with metastatic prostate cancer. Int Urol Nephrol 24:159-166, 1992 Lahtinen R, Laasko M, Palva I, et al: Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 340:10491052, 1992 O’Rourke N, McCloskey E, Houghton F, et al: Double-blind, placebocontrolled, dose-response trial of oral clodronate in patients with bone metastases. J Clin Oncol 13:929-934, 1995
72 34. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 335:1785-1791, 1996 35. 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 randomized, placebo-controlled trials. Cancer 88:1082-1090, 2000 36. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 16:2038-2044, 1998 37. Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 17:846-854, 1999
A. Heidenreich, C. Ohlmann, and J.-J. Body 38. Small EJ, Smith MR, Seaman JJ, et al: Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 21:4277-4284, 2003 39. 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 98:1735-1744, 2003 40. Kristensen B, Ejlertsen B, Groenvold M, et al: Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 246:67-74, 1999
S
evere bone pain is experienced by 60% to 80% of patients with metastatic bone disease,1-3 and has a profound impact on quality of life. Bone pain can lead to impaired mobility, reduced functional capacity, and increased dependency on others. Therefore, effective pain relief is an important goal in managing metastatic bone disease. Palliation commonly involves a multidisciplinary approach, combining analgesics and systemic chemotherapy, hormonal therapy, or radiolabeled drugs with localized treatments such as radiotherapy and surgery. While many patients have adequate and prolonged pain relief with these treatments, others have refractory or recurrent pain.4-6 Palliative treatment can be confounded by treatment-related side effects that need extra care, with a further impact on patients’ quality of life and health care resources.4,5,7
aDivision
of Oncological Urology, Department of Urology, University of Cologne, Germany. bDepartment of Urology, Philipps-University Marburg, Germany. cInstitut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium. Dr Heidenreich has financial interest with Roche Laboratories, Novartis, Inc, and Aventis Pharma. Dr Body has served as a consultant to and received honoraria from Roche Laboratories and Novartis Inc. Address reprint requests to Prof Dr med Axel Heidenreich, Division of Oncological Urology, Department of Urology, University of Cologne, Joseph – Stelzmann – Str. 9, 50931 Köln, Germany.
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2004.07.026
Bisphosphonates for Metastatic Bone Pain Bisphosphonates are effective for preventing and treating skeletal-related complications from metastatic bone disease,8-13 and are an important addition to other strategies for treating bone pain. Until recently, intravenous (IV) bisphosphonates were used for optimal pain management. Trials of IV clodronate, pamidronate, and zoledronic acid showed that these agents relieved pain, although results were inconsistent across trials.11,14-17 The mechanism of pain relief by bisphosphonates is unclear, but it may be because of their disruptive effects on bone resorption because there appears to be a link between metastatic bone pain and the rate of bone resorption.18 Bisphosphonates may also interfere with the synthesis and production of pain mediators, such as prostaglandin E2 and interleukins 1 and 6.6 Ibandronate is a new-generation, highly potent aminobisphosphonate available in IV and oral formulations. Recent data show that both formulations have similar clinical benefits in patients with breast cancer and bone metastases (summarized by Tripathy elsewhere in this supplement). In October 2003, the European Agency for the Evaluation of Medicinal Products granted ibandronate marketing authorization in the European Union for the prevention of skeletal events in patients with breast cancer and bone metastases. 67
A. Heidenreich, C. Ohlmann, and J.-J. Body
68
Figure 1 Mean change from baseline in bone pain score over approximately 2 years: phase III IV ibandronate trial in patients with advanced breast cancer.19
Approved doses are IV ibandronate 6 mg every 3 to 4 weeks, and oral ibandronate 50 mg once daily. This review briefly describes the effects of IV and oral ibandronate on metastatic bone pain. Ibandronate is the first bisphosphonate to show long-term pain relief and, unlike other bisphosphonates, has shown improvements in quality of life.
Metastatic Bone Pain Relief with Intravenous Ibandronate in Breast Cancer A randomized, placebo-controlled phase III trial assessed the effect of IV ibandronate 6 mg on bone pain, analgesic use, and quality of life in women with advanced breast cancer and bone metastases.12,19 One hundred fifty-four women received IV ibandronate 6 mg and 158 patients received placebo (for full details of study design see Tripathy elsewhere in this supplement). Bone pain was assessed using a 5-point scale (0 ⫽ none to 4 ⫽ intolerable) and analgesic use with a 7-point scale (0 ⫽ none to 6 ⫽ opiates ⱖ100 mg morphine daily or equivalent).20 The European Organization for Research and Treatment of Cancer QLQ-C30 scale21 was used to measure quality of life. Scores for the five functional domains (physical, role, cognitive, emotional, and social) were combined to obtain a global quality-oflife score. At baseline, the incidence of bone pain was distributed evenly between the two treatment groups. Treatment with ibandronate rapidly reduced bone pain levels. The mean change in bone pain scores from baseline was significantly lower with IV ibandronate than with placebo (⫺0.28 v ⫹0.21; P ⬍.001) and remained below that of baseline throughout the 96-week study (Fig 1).19 Use of analgesics was lower with IV ibandronate than with placebo, although this effect was not statistically significant (mean change from baseline 0.51 v 0.90; P ⫽ .08). Nonetheless, these results
indicate that the improvement in bone pain in patients on ibandronate was not because of more use of analgesics. As expected in this population, quality of life deteriorated in all patients during the study.19 However, IV ibandronate was associated with a significantly smaller reduction in global quality of life than placebo (mean change from baseline ⫺10.1 v ⫺45.0; P ⫽ .005). Physical, emotional, and social functioning deteriorated significantly less in the ibandronate than in the placebo group (P ⱕ.05).
High-Dose Intravenous Ibandronate for OpioidResistant Metastatic Bone Pain An open-label, pilot study assessed the effect of IV ibandronate on moderate-to-severe, opioid-resistant bone pain using nonstandard, intensive dosing.22 The investigators chose a relatively high and intense treatment regimen because of the severity of the patients’ bone pain at study entry and the favorable safety profile of ibandronate. The study included 18 patients with metastatic breast cancer (n ⫽ 10) or other tumor types with metastatic bone disease, including adrenal, thyroid, liver, lung, head and neck, and prostate cancer (n ⫽ 8). Patients were treated with IV ibandronate 4 mg infused over 2 hours on 4 consecutive days (total 16 mg) in a supportive care setting. Efficacy was evaluated over 6 weeks. Bone pain was measured using a visual analogue scale (VAS) (0 ⫽ no pain to 10 ⫽ maximum pain).23,24 Pain was also evaluated indirectly using the Morphine Equivalent Daily Dose index of opioid consumption.24 Quality of life was assessed using the Edmonton Symptom Assessment System well-being scale (0 ⫽ good to 10 ⫽ poor)25 and patient functioning using the Edmonton Functional Assessment Tool (0 ⫽ fully independent to 30 ⫽ fully bedridden).26 Performance status was graded using the Eastern Cooperative Oncology Group scale.27 In the study ibandronate significantly reduced mean VAS
Ibandronate in metastatic bone pain
69
Figure 2 Mean change from baseline in bone pain score with high-dose IV ibandronate for opioid-resistant bone pain.29
pain scores within 7 days (P ⬍.001), and these reductions were maintained over 6 weeks (P ⬍.05) (Fig 2). This was achieved without increasing analgesic use; Morphine Equivalent Daily Dose scores remained the same from baseline to endpoint. High-dose IV ibandronate also significantly improved patients’ quality of life on the Edmonton Symptom Assessment System well-being scale by day 7, as well as functional status, Edmonton Functional Assessment Tool scores, and performance status by day 21 (P ⬍.05 v baseline for all measures).
High-Dose Intravenous Ibandronate for Metastatic Bone Pain from Urologic Cancer Two open, nonrandomized prospective trials have assessed the efficacy of high-dose IV ibandronate in treating painful bone metastases in patients with prostate cancer and other types of urologic cancer.28,29 Twenty-five and fifty-three patients with prostate cancer and with either prostate, renal or bladder cancer, respectively, were treated with IV ibandronate 6 mg infused over 1 hour for 3 consecutive days (the “loading dose”), followed by a single infusion of IV ibandronate 6 mg every 4 weeks for 20 weeks. Bone pain was assessed using a VAS (0 ⫽ no pain to 10 ⫽ maximum pain),24 and patients recorded analgesic use in a pain diary. Patient functioning was assessed using the Karnofsky Index. In the prostate cancer trial, using the visual analogue scale from 1 to 10, palliative response with significant reduction in pain score from 6.5 (5 to 10) to 2.0 (0 to 4; P ⬍.001) was achieved in 23 of the 25 patients (92%), which was associated with a significant decrease of daily consumption of analgesics.28 In the urologic cancer trial, 44 of the 53 patients (83%) experienced bone pain relief (defined as a 3-point reduction in VAS) from day 2 of ibandronate treatment, and 25% of patients were completely pain free.29 The mean VAS score on
day 3 was significantly reduced from baseline (2.5 v 6.8; P ⬍.001) and remained below baseline throughout the 20week study (Fig 3). The reduction in bone pain score led to improved patient functioning throughout the study (Fig 3). Analgesic use was reduced by more than 50% in 85% of patients.
Oral Ibandronate for Metastatic Bone Pain Relief in Advanced Breast Cancer Two randomized, placebo-controlled trials assessed the efficacy of oral ibandronate (50 mg daily) in reducing bone pain in patients with metastatic bone disease from breast cancer.30 A total of 287 patients received ibandronate and 277 received placebo (for full details of study designs see Tripathy elsewhere in this supplement). Bone pain, analgesic use, and quality of life were assessed as for the phase III trial with IV ibandronate, described above. Data from the two trials were pooled for analysis, as predefined in the study protocols. Bone pain scores were rapidly reduced and remained below baseline in the ibandronate group throughout the 96week study, and increased progressively in the placebo group (Fig 4).30 At endpoint, the mean change in baseline score was significantly lower with oral ibandronate than with placebo (⫺0.1 v ⫹0.2; P ⫽ .001). Although analgesic use increased scores in both groups, patients on ibandronate used significantly fewer analgesics than patients on placebo (0.60 v 0.85 [morphine consumption analogue score]; P ⫽ .019). As in the phase III study of IV ibandronate, quality of life deteriorated in both groups of patients. However, the decrease in global assessment of quality of life was significantly greater with placebo than with oral ibandronate (⫺26.8 v ⫺8.3; P ⫽ .032).30 On the individual functioning scales of
A. Heidenreich, C. Ohlmann, and J.-J. Body
70
Figure 3 Mean change in bone pain and Karnofsky Index scores with high-dose ibandronate in patients with metastatic urologic cancer.29
the European Organization for Research and Treatment of Cancer QLQ-C30, physical and role functioning scores were significantly higher in the ibandronate than in the placebo group (P ⱕ.05).
Comparison of Ibandronate with Other Bisphosphonates in the Relief of Metastatic Bone Pain As yet, there are no direct comparisons of ibandronate with other current bisphosphonates for metastatic bone pain. Additionally, the different methods for reporting pain levels and analgesic use makes comparison across trials difficult. Early studies with oral clodronate found little or no significant effect on bone pain.17,31-33 While other studies reported significant relief of bone pain with IV clodronate,16 this is rarely used in clinical practice. There are conflicting results for the
efficacy of IV pamidronate 90 mg in alleviating bone pain. Some studies reported a significant benefit when pamidronate was compared with placebo or chemotherapy alone in patients with breast cancer or multiple myeloma,14,15,34,35 while others failed to show significant long-term pain relief compared with placebo in patients with breast cancer36,37 and prostate cancer.38 In a placebo-controlled study of zoledronic acid in patients with advanced prostate cancer, bone pain scores increased in both treatment groups, but were consistently lower in the zoledronic acid than placebo group.11 The analgesic effect of zoledronic acid has also been investigated in a comparative study with pamidronate in patients with breast cancer or multiple myeloma.9 Among patients with bone pain scores greater than 0 at baseline, 53% to 69% of all patients experienced an improvement in their bone pain score. The mean change in bone pain score remained below baseline throughout the 13-month study. Analgesic use either decreased or remained fairly stable. However, there was no statistical dif-
Figure 4 Mean change from baseline in bone pain score over approximately 2 years: phase III oral ibandronate trial in patients with advanced breast cancer.19
Ibandronate in metastatic bone pain ference between pamidronate or zoledronic acid for either of these clinical outcomes. The statistical significance of the change in bone pain score compared with baseline was not reported. More recently, Rosen et al39 have reported 12month extension data for the comparative trial of zoledronic acid and pamidronate. However, the long-term analgesic effects of both agents were not discussed. Few studies of bisphosphonates have assessed quality of life in patients with metastatic bone disease. These trials were generally placebo-controlled, and failed to show any significant benefits of the active agent, including oral clodronate 1,600 mg/day,40 IV pamidronate 90 mg,35 and IV zoledronic acid 4 mg.11
71
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16.
17.
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Conclusion The results of phase III and open-label studies indicate that both IV and oral ibandronate provide sustained relief from metastatic bone pain, improving patient quality of life, mobility, and independence. Improvements were reported in patients with various types of tumor, including breast and prostate cancer, as well as in cancer patients with difficult-to-treat, opioid-resistant bone pain. Ibandronate is the only bisphosphonate to maintain pain scores below baseline levels over about 2 years. Unlike other bisphosphonates, ibandronate improves quality of life compared with placebo. Trials comparing the effects of IV and oral ibandronate on bone pain versus other bisphosphonates are warranted to assess fully this promising treatment for managing metastatic bone pain.
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