- Email: [email protected]
Managing metastatic bone disease: Three case studies
Managing Metastatic Bone Disease: Three Case Studies Robert Coleman,a Axel Heidenreich,b and Richard Bellc Metastatic bone disease constitutes a major clinical problem. Skeletal complications are common and lead to significant morbidity, and patients live with metastatic bone disease for several years, increasing the prevalence of this problem. Effective management aims to reduce the incidence of skeletal complications and relieve symptoms, such as severe bone pain, which adversely affect patient mobility and quality of life. This article describes and discusses strategies for managing metastatic bone disease, with particularly emphasis on the role of the bisphosphonate ibandronate. Two case histories show the long-term efficacy and tolerability of oral ibandronate in the treatment of metastatic breast cancer. The third case history illustrates the benefits of rapid pain relief from an intensive, high-dose regimen of intravenous ibandronate in metastatic prostate cancer. Semin Oncol 31:83-86 © 2004 Elsevier Inc. All rights reserved.
T
he burden of metastatic bone disease is substantial.1 Most patients with bone metastases will experience several skeletal complications per year, and this has a profound impact on their life. Effective strategies to reduce the incidence and treat skeletal complications are essential. The primary aim of therapy is to minimize pain and morbidity, and to improve mobility and quality of life.
Long-Term Disease Management in Breast Cancer The following two case studies illustrate some of the complexities facing clinicians managing women with breast cancer. They show how an effective and safe agent such as ibandronate can provide enormous benefits for years, helping patients to live a normal life despite the ultimate morbidity of their clinical condition.
Case Study 1 Ms A was diagnosed with a small T1, N0, M0 carcinoma of the left breast in May 1990. She was node-negative, and estrogen receptor status was not routinely determined in the United Kingdom at that time. The patient had a mastectomy and received no adjuvant systemic therapy. In July 1993, Ms A was admitted to hospital with acute left-sided chest pain following a recent partial thyroidectomy. A suspected postoperative pulmonary embolus was excluded, and because of the patient’s history of breast cancer, further investigations were performed. A bone scan revealed hot spots in the third thoracic vertebra (T3), left third rib, right first rib, sternum, and left skull. Plain radiographs showed a patchy change in the third left rib consistent with a metastatic lesion. Ms A started tamoxifen and had palliative radiotherapy to her left third rib (8 Gy single fraction). By October 1993, the patient had further bone pain, particularly in the lower lumbar spine and sacrum. She was empirically treated with local radiotherapy (8 Gy single fraction) and referred for possible bisphosphonate treatment.
aYorkshire
Cancer Research Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, UK. bDepartment of Urology, University of Cologne, Germany. cAndrew Love Cancer Center, The Geelong Hospital, Geelong, Australia. Dr Coleman serves as Clinical Investigator and Research Consultant for Roche Laboratories and Novartis, Inc. Dr Heidenreich has financial interest with Roche Laboratories, Novartis, Inc, and Aventis Pharma. Dr Bell is a consultant to and has received honoraria from Roche Laboratories, Novartis, Inc, AstraZeneca International, and Genentech Inc. Address reprint requests to Robert Coleman, MD, Yorkshire Cancer Research Department of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, UK. E-mail: [email protected].
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminocol.2004.07.028
Initial Bisphosphonate Treatment At that time, oral ibandronate was in the early stages of development and Ms A agreed to enter a placebo-controlled, phase I/II dose-finding study of oral ibandronate in patients with metastatic bone disease.2 In November 1993, she was randomized to ibandronate 20 mg daily and her bone pain improved within 2 weeks. By February 1994, Ms A had further pain to her left anterior chest and persistent bone scan abnormalities. Her third left rib was retreated with radiother83
84 apy (20 Gy in four fractions). The patient asked to continue ibandronate 20 mg daily on a compassionate-use protocol. Her bone pain symptoms settled, and a bone scan in 1995 showed a partial remission on tamoxifen plus daily oral ibandronate. Complications In 1997, an ultrasound scan revealed a left renal mass, which on nephrectomy was confirmed as renal cell carcinoma, but without adverse histologic features. The patient’s breast cancer was stable, and she continued with tamoxifen and ibandronate for more than 3 years. In March 2001, however, the patient had increasing pain in her left chest. Investigations showed multiple hot spots in her ribs and a sclerotic lesion in the left first rib. She had palliative radiotherapy (20 Gy in five fractions) to this and to her right posterior ribs. Her endocrine treatment was switched to anastrozole because her breast cancer seemed to be progressing on tamoxifen. Ms A’s symptoms then settled. In February 2002, after the patient had taken ibandronate for more than 8 years without problems and with good symptomatic relief, compassionate use was withdrawn. Ms A began intravenous (IV) zoledronic acid 4 mg, and received six 4-weekly cycles. At the start her creatinine level was a little above the upper limit of normal (136 mol/L), and continued to rise over the 6 months (136, 154, 125, 164, 187, 241 mol/L, respectively). When her creatinine level exceeded 200 mol/L, zoledronic acid was stopped because the risk of further treatment was felt to be too great. In November 2002, a right renal mass was found and confirmed as renal cell carcinoma on biopsy. The patient declined partial nephrectomy, opting for a palliative approach. Because Ms A’s renal function had improved (creatinine, 147 mol/L) after stopping zoledronic acid, she recommenced this bisphosphonate in January 2003. This time, zoledronic acid was given every 3 months to improve safety, and because the levels of the urinary bone resorption marker N-telopeptide were normal (10 to 20 nmol/mmol creatinine). Unfortunately, the pain relief from this schedule lasted only 2 to 3 weeks per cycle. During 2003, Ms A developed lung metastases and was admitted to a local hospice for symptom control on several occasions. Update: Further Ibandronate In November 2003, with worsening bone pain, Ms A asked if she could recommence ibandronate; a new compassionateuse protocol (oral ibandronate 50 mg daily) had opened in the United Kingdom in advance of the launch. At this time, her creatinine level was 158 mol/L. Although Ms A is now entering the terminal stage of her life with symptoms related primarily to her lung metastases, she no longer has bone pain with daily ibandronate, nor is there any problem with renal toxicity.
Case Study 2 In 1995, Ms B was diagnosed with an infiltrating duct carcinoma of the breast, stage T1, N1, M0, grade II, estrogen- and progesterone receptor-positive and HER2-negative. Follow-
R. Coleman, A. Heidenreich, and R. Bell ing mastectomy and axillary dissection, she had six cycles of adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil), and was then started on tamoxifen. During routine follow-up in January 1998, Ms B complained of a troublesome cough, dyspnea on exertion, and bone aches and pains. A chest x-ray confirmed a right pleural effusion on which cytologic studies were consistent with metastatic breast cancer. A bone scan was positive in the sternum, thoracic spine, humeri, and ribs, and a skeletal survey showed a mixture of sclerotic and lytic metastases. There was no evidence of imminent fracture. Computed tomography scan did not show evidence of liver or lung disease. Initial Interventions Ms B started second-line endocrine therapy with letrozole, and entered the placebo-controlled, phase III study of oral ibandronate (see Tripathy elsewhere in this supplement). She had rapid relief of her bone pain and improved mobility, thus enabling her to continue working and looking after her family. When the code was broken after 96 weeks of trial participation, it was found that she had been randomized to oral ibandronate 50 mg daily. Further Complications By May 1998, Ms B’s pleural effusion had progressed and was aspirated again. Her bone scan suggested minor progression, but she was pain-free. Ms B was eager to avoid alopecia, and after discussion agreed to receive 10 cycles of single-agent mitoxantrone. There was complete resolution of the pleural effusion and computed tomography scan showed no residual abnormality in the chest. Her bones had also improved, with no sign of lytic disease, but only sclerotic lesions visible on x-ray. We decided to stop mitoxantrone because of concerns of cumulative toxicity, but continued this patient on the ibandronate protocol. At the end of the ibandronate study (around February 2000) our patient was well. Radiology demonstrated predominantly sclerotic disease in bone and there was no evidence of visceral disease. An IV bisphosphonate was commenced because at that time we were uncertain whether or not she had been receiving active drug on the study. Ms B was given two doses of pamidronate 90 mg, infused over 2 hours. She experienced flu-like side effects, and asked to remain on oral treatment, which in fact she had not stopped taking (and so was receiving both bisphosphonates concurrently). Openlabel ibandronate was then continued. Ms B remained well until February 2003, when a routine chest x-ray showed an asymptomatic, large, pleural-based mass in the left chest. On computed tomography scan, this seemed to be arising from internal mammary nodes. However, there was no other sign of disease and her bone disease was stable and asymptomatic. After discussion, Ms B started oral capecitabine in addition to oral ibandronate; she wanted a treatment that was not unduly toxic and which would allow her to maintain her active lifestyle. She had a complete response in regard to the soft tissue mass within 4 months, at which point capecitabine was stopped. Ms B is currently well and free of bone pain. She is working
Managing metastatic bone disease: case studies full-time and has received oral ibandronate 50 mg daily for more than 6 years without any safety concerns. Discussion In both of the case studies, oral ibandronate provided meaningful clinical benefits. In addition to minimizing skeletal morbidity, the use of oral ibandronate was more convenient than IV bisphosphonate therapy. Each patient avoided more than 80 infusions that would have been needed with IV administration.
Managing Metastatic Bone Pain from Prostate Cancer Controlling bone pain in end-stage prostate cancer is a major clinical problem; many patients are affected, and pain has a profound impact on their quality of life. Bone metastases develop in 70% to 80% of patients with prostate cancer,1,3,4 and up to 80% of those patients will have bone pain5 along with other skeletal complications. Although narcotic analgesics, radiotherapy, and radiolabeled drugs are the mainstays of pain management, treatment is often suboptimal. Bisphosphonates are an alternative strategy for preventing and treating the skeletal complications of bone metastases from prostate cancer, including bone pain. The following case highlights the different strategies for pain relief in patients with advanced prostate cancer and discusses why ibandronate was chosen for this patient.
Case Study 3 Mr C, a 76-year-old white man, was diagnosed with metastatic prostate cancer in 2002. He received androgen ablation with luteinizing hormone-releasing hormone (LHRH)-analogues. Four months later, Mr C presented with bone pain in the lumbar spine and left hip, and bone scintigraphy showed multiple osseous metastases. X-ray to the lumbar spine excluded pathologic fractures. Treatment Options This patient had received no analgesic treatment from his primary care physician, and so several options were considered: 1. Analgesics according to the first step of the analgesic “ladder” from the World Health Organization cancer pain relief program (ie, non-opioid drugs, such as paracetamol or aspirin and other nonsteroidal anti-inflammatory [NSAID] medications). 2. Palliative radiotherapy. 3. Radiolabeled drugs such as strontium-89 chloride or samarium-153 texidronan (ethylenediaminetetramethylenephosphate; EDTMP). 4. Palliative chemotherapy, such as mitoxantrone plus prednisone. 5. High-dose bisphosphonates. Because this patient had not received analgesics, the first option was worth considering, as nonopioid analgesics can
85 relieve mild pain for a while. If NSAIDs are used, the daily dose should be closely monitored and kept as low as possible to reduce the risk of gastrointestinal, hepatic, and renal toxicity.6 Palliative radiotherapy to the patient’s left hip and lumbar spine would have a good chance of relieving his pain. The success of palliative radiotherapy is generally about 70%, with pain relief lasting for 6 to 12 months.7,8 In most cases, a short treatment schedule of one to five fractions is successful, and several randomized trials have shown that a single fraction of 8 Gy is adequate.1,9 However, like analgesics, palliative radiotherapy does not reduce the risk of future metastases, and it is only a matter of time before other lesions start to grow. The cumulative effect of multiple courses of radiotherapy on suppressing bone marrow function should also be considered. The third option could also help this patient. Radiolabeled drugs have been developed with high avidity for bone, particularly to sites of new bone formation such as sclerotic metastases. They deliver radiation locally to the bone with minimal systemic effects. Most patients have pain relief for 3 to 6 months after a single IV dose, and retreatment is possible if needed. Strontium-89 chloride and samarium-153 EDTMP are both approved in the United States for the treatment of bone metastases, including those from prostate cancer.10-13 Palliative chemotherapy such as mitoxantrone plus prednisone gave effective pain relief in a controlled, randomized trial.14 However, the role of chemotherapy in metastatic prostate cancer is still being investigated, and none can be recommended as a standard treatment. The benefits of palliative chemotherapy would need to be weighed against the risk of side effects. If this patient wanted chemotherapy, we would offer it in the context of a clinical trial. We chose to treat Mr C with high-dose, intensive IV ibandronate. Bisphosphonates offer not only the possibility of pain relief but also, unlike the other treatments discussed here, have proven efficacy in reducing other skeletal complications of bone metastases.15-19 Both zoledronic acid and ibandronate relieve bone pain compared with placebo in patients with metastatic prostate cancer.17,20 However, although zoledronic acid was better than placebo at reducing pain, pain scores increased in both groups compared with baseline throughout the 15-month treatment period.17 In contrast, in an open study using intensive ibandronate, pain relief was rapid, with mean bone pain scores significantly below baseline on day 3 (2.5 v 6.8; P ⬍.001)20 (see also Heidenreich elsewhere in this supplement). Pain scores were maintained below baseline throughout the 20-week study. Treatment with ibandronate was well tolerated. Intervention and Outcome Mr C had significant pain relief within 4 days of starting IV ibandronate (6 mg on 3 consecutive days, followed by IV ibandronate 6 mg every 4 weeks). Despite this very early treatment with ibandronate, the patient suffered a pathologic fracture of the vertebral body 15 months later, for which he received palliative radiotherapy. Ibandronate was continued for another 5 months without significant side effects until the patient succumbed because of progressive disease.
86
Conclusion These case histories show the efficacy of IV and oral ibandronate in treating metastatic bone disease in patients with breast or prostate cancer. The oral formulation was safe and well tolerated for several years in both breast cancer patients, and the convenient formulation enabled them to continue their normal daily activities. An intensive, high-dose regimen of IV ibandronate gave the patient with metastatic prostate cancer very rapid pain relief. This example might pave the way for using an IV loading dose followed by an oral maintenance therapy for optimal management of metastatic bone disease. The efficacy and safety of ibandronate compares favorably with other bisphosphonates, and the results of direct, comparative trials are awaited with interest.
References 1. Coleman RE: Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165-176, 2001 2. Coleman RE, Purohit OP, Black C, et al: Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease. Ann Oncol 10:311-316, 1999 3. Carlin BI, Andriole GL: The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma. Cancer 88:2989-2994, 2000 (suppl 12) 4. Pentyala SN, Lee J, Hsieh K, et al: Prostate cancer: a comprehensive review. Med Oncol 17:85-105, 2000 5. Berrutti A, Dogliotti L, Bitossi R, et al: Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline. J Urol 164:1248-1253, 2000 6. Janjan N: Bone metastases: approaches to management. Semin Oncol 28:28-34, 2001 (suppl 11) 7. Rasmusson B, Vejborg I, Jensen AB, et al: Irradiation of bone metastases in breast cancer patients: a randomized study with 1 year follow-up. Radiother Oncol 34:179-184, 1995 8. Hortobagyi GN: Novel approaches to the management of bone metastases. Semin Oncol 30:161-166, 2003 (suppl 16)
R. Coleman, A. Heidenreich, and R. Bell 9. Janjan NA: Radiation of bone metastases: conventional techniques and the role of systemic radiopharmaceuticals. Cancer 80:1628-1645, 1997 (suppl 8) 10. Lewington VJ, McEwan AJ, Ackery DM, et al: A prospective, randomized double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to the bone. Eur J Cancer 27:954-958, 1991 11. Resche I, Chatal JF, Pecking A, et al: A dose-controlled study of 153SmEthylenediaminetetramethylenephosphate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 33:1583-1591, 1997 12. Robinson RG, Preston DF, Baxter KG, et al: Clinical experience with strontium-89 in prostatic and breast cancer patients. Semin Oncol 20: 44-48, 1993 (suppl 2) 13. Serafini AN, Houston SJ, Resche I, et al: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol 16:1574-1581, 1998 14. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative endpoints. J Clin Oncol 14:1756-1764, 1996 15. 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 16. Pavlakis N, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 1:CD003474, 2002 17. 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 18. Body J-J, 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 19. Body JJ, Diel IJ, Lichinitzer M, et al: Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 90:1133-1137, 2004 20. 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)
T
he burden of metastatic bone disease is substantial.1 Most patients with bone metastases will experience several skeletal complications per year, and this has a profound impact on their life. Effective strategies to reduce the incidence and treat skeletal complications are essential. The primary aim of therapy is to minimize pain and morbidity, and to improve mobility and quality of life.
Long-Term Disease Management in Breast Cancer The following two case studies illustrate some of the complexities facing clinicians managing women with breast cancer. They show how an effective and safe agent such as ibandronate can provide enormous benefits for years, helping patients to live a normal life despite the ultimate morbidity of their clinical condition.
Case Study 1 Ms A was diagnosed with a small T1, N0, M0 carcinoma of the left breast in May 1990. She was node-negative, and estrogen receptor status was not routinely determined in the United Kingdom at that time. The patient had a mastectomy and received no adjuvant systemic therapy. In July 1993, Ms A was admitted to hospital with acute left-sided chest pain following a recent partial thyroidectomy. A suspected postoperative pulmonary embolus was excluded, and because of the patient’s history of breast cancer, further investigations were performed. A bone scan revealed hot spots in the third thoracic vertebra (T3), left third rib, right first rib, sternum, and left skull. Plain radiographs showed a patchy change in the third left rib consistent with a metastatic lesion. Ms A started tamoxifen and had palliative radiotherapy to her left third rib (8 Gy single fraction). By October 1993, the patient had further bone pain, particularly in the lower lumbar spine and sacrum. She was empirically treated with local radiotherapy (8 Gy single fraction) and referred for possible bisphosphonate treatment.
aYorkshire
Cancer Research Academic Unit of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, UK. bDepartment of Urology, University of Cologne, Germany. cAndrew Love Cancer Center, The Geelong Hospital, Geelong, Australia. Dr Coleman serves as Clinical Investigator and Research Consultant for Roche Laboratories and Novartis, Inc. Dr Heidenreich has financial interest with Roche Laboratories, Novartis, Inc, and Aventis Pharma. Dr Bell is a consultant to and has received honoraria from Roche Laboratories, Novartis, Inc, AstraZeneca International, and Genentech Inc. Address reprint requests to Robert Coleman, MD, Yorkshire Cancer Research Department of Clinical Oncology, Cancer Research Centre, Weston Park Hospital, Sheffield, UK. E-mail: [email protected].
0093-7754/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminocol.2004.07.028
Initial Bisphosphonate Treatment At that time, oral ibandronate was in the early stages of development and Ms A agreed to enter a placebo-controlled, phase I/II dose-finding study of oral ibandronate in patients with metastatic bone disease.2 In November 1993, she was randomized to ibandronate 20 mg daily and her bone pain improved within 2 weeks. By February 1994, Ms A had further pain to her left anterior chest and persistent bone scan abnormalities. Her third left rib was retreated with radiother83
84 apy (20 Gy in four fractions). The patient asked to continue ibandronate 20 mg daily on a compassionate-use protocol. Her bone pain symptoms settled, and a bone scan in 1995 showed a partial remission on tamoxifen plus daily oral ibandronate. Complications In 1997, an ultrasound scan revealed a left renal mass, which on nephrectomy was confirmed as renal cell carcinoma, but without adverse histologic features. The patient’s breast cancer was stable, and she continued with tamoxifen and ibandronate for more than 3 years. In March 2001, however, the patient had increasing pain in her left chest. Investigations showed multiple hot spots in her ribs and a sclerotic lesion in the left first rib. She had palliative radiotherapy (20 Gy in five fractions) to this and to her right posterior ribs. Her endocrine treatment was switched to anastrozole because her breast cancer seemed to be progressing on tamoxifen. Ms A’s symptoms then settled. In February 2002, after the patient had taken ibandronate for more than 8 years without problems and with good symptomatic relief, compassionate use was withdrawn. Ms A began intravenous (IV) zoledronic acid 4 mg, and received six 4-weekly cycles. At the start her creatinine level was a little above the upper limit of normal (136 mol/L), and continued to rise over the 6 months (136, 154, 125, 164, 187, 241 mol/L, respectively). When her creatinine level exceeded 200 mol/L, zoledronic acid was stopped because the risk of further treatment was felt to be too great. In November 2002, a right renal mass was found and confirmed as renal cell carcinoma on biopsy. The patient declined partial nephrectomy, opting for a palliative approach. Because Ms A’s renal function had improved (creatinine, 147 mol/L) after stopping zoledronic acid, she recommenced this bisphosphonate in January 2003. This time, zoledronic acid was given every 3 months to improve safety, and because the levels of the urinary bone resorption marker N-telopeptide were normal (10 to 20 nmol/mmol creatinine). Unfortunately, the pain relief from this schedule lasted only 2 to 3 weeks per cycle. During 2003, Ms A developed lung metastases and was admitted to a local hospice for symptom control on several occasions. Update: Further Ibandronate In November 2003, with worsening bone pain, Ms A asked if she could recommence ibandronate; a new compassionateuse protocol (oral ibandronate 50 mg daily) had opened in the United Kingdom in advance of the launch. At this time, her creatinine level was 158 mol/L. Although Ms A is now entering the terminal stage of her life with symptoms related primarily to her lung metastases, she no longer has bone pain with daily ibandronate, nor is there any problem with renal toxicity.
Case Study 2 In 1995, Ms B was diagnosed with an infiltrating duct carcinoma of the breast, stage T1, N1, M0, grade II, estrogen- and progesterone receptor-positive and HER2-negative. Follow-
R. Coleman, A. Heidenreich, and R. Bell ing mastectomy and axillary dissection, she had six cycles of adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil), and was then started on tamoxifen. During routine follow-up in January 1998, Ms B complained of a troublesome cough, dyspnea on exertion, and bone aches and pains. A chest x-ray confirmed a right pleural effusion on which cytologic studies were consistent with metastatic breast cancer. A bone scan was positive in the sternum, thoracic spine, humeri, and ribs, and a skeletal survey showed a mixture of sclerotic and lytic metastases. There was no evidence of imminent fracture. Computed tomography scan did not show evidence of liver or lung disease. Initial Interventions Ms B started second-line endocrine therapy with letrozole, and entered the placebo-controlled, phase III study of oral ibandronate (see Tripathy elsewhere in this supplement). She had rapid relief of her bone pain and improved mobility, thus enabling her to continue working and looking after her family. When the code was broken after 96 weeks of trial participation, it was found that she had been randomized to oral ibandronate 50 mg daily. Further Complications By May 1998, Ms B’s pleural effusion had progressed and was aspirated again. Her bone scan suggested minor progression, but she was pain-free. Ms B was eager to avoid alopecia, and after discussion agreed to receive 10 cycles of single-agent mitoxantrone. There was complete resolution of the pleural effusion and computed tomography scan showed no residual abnormality in the chest. Her bones had also improved, with no sign of lytic disease, but only sclerotic lesions visible on x-ray. We decided to stop mitoxantrone because of concerns of cumulative toxicity, but continued this patient on the ibandronate protocol. At the end of the ibandronate study (around February 2000) our patient was well. Radiology demonstrated predominantly sclerotic disease in bone and there was no evidence of visceral disease. An IV bisphosphonate was commenced because at that time we were uncertain whether or not she had been receiving active drug on the study. Ms B was given two doses of pamidronate 90 mg, infused over 2 hours. She experienced flu-like side effects, and asked to remain on oral treatment, which in fact she had not stopped taking (and so was receiving both bisphosphonates concurrently). Openlabel ibandronate was then continued. Ms B remained well until February 2003, when a routine chest x-ray showed an asymptomatic, large, pleural-based mass in the left chest. On computed tomography scan, this seemed to be arising from internal mammary nodes. However, there was no other sign of disease and her bone disease was stable and asymptomatic. After discussion, Ms B started oral capecitabine in addition to oral ibandronate; she wanted a treatment that was not unduly toxic and which would allow her to maintain her active lifestyle. She had a complete response in regard to the soft tissue mass within 4 months, at which point capecitabine was stopped. Ms B is currently well and free of bone pain. She is working
Managing metastatic bone disease: case studies full-time and has received oral ibandronate 50 mg daily for more than 6 years without any safety concerns. Discussion In both of the case studies, oral ibandronate provided meaningful clinical benefits. In addition to minimizing skeletal morbidity, the use of oral ibandronate was more convenient than IV bisphosphonate therapy. Each patient avoided more than 80 infusions that would have been needed with IV administration.
Managing Metastatic Bone Pain from Prostate Cancer Controlling bone pain in end-stage prostate cancer is a major clinical problem; many patients are affected, and pain has a profound impact on their quality of life. Bone metastases develop in 70% to 80% of patients with prostate cancer,1,3,4 and up to 80% of those patients will have bone pain5 along with other skeletal complications. Although narcotic analgesics, radiotherapy, and radiolabeled drugs are the mainstays of pain management, treatment is often suboptimal. Bisphosphonates are an alternative strategy for preventing and treating the skeletal complications of bone metastases from prostate cancer, including bone pain. The following case highlights the different strategies for pain relief in patients with advanced prostate cancer and discusses why ibandronate was chosen for this patient.
Case Study 3 Mr C, a 76-year-old white man, was diagnosed with metastatic prostate cancer in 2002. He received androgen ablation with luteinizing hormone-releasing hormone (LHRH)-analogues. Four months later, Mr C presented with bone pain in the lumbar spine and left hip, and bone scintigraphy showed multiple osseous metastases. X-ray to the lumbar spine excluded pathologic fractures. Treatment Options This patient had received no analgesic treatment from his primary care physician, and so several options were considered: 1. Analgesics according to the first step of the analgesic “ladder” from the World Health Organization cancer pain relief program (ie, non-opioid drugs, such as paracetamol or aspirin and other nonsteroidal anti-inflammatory [NSAID] medications). 2. Palliative radiotherapy. 3. Radiolabeled drugs such as strontium-89 chloride or samarium-153 texidronan (ethylenediaminetetramethylenephosphate; EDTMP). 4. Palliative chemotherapy, such as mitoxantrone plus prednisone. 5. High-dose bisphosphonates. Because this patient had not received analgesics, the first option was worth considering, as nonopioid analgesics can
85 relieve mild pain for a while. If NSAIDs are used, the daily dose should be closely monitored and kept as low as possible to reduce the risk of gastrointestinal, hepatic, and renal toxicity.6 Palliative radiotherapy to the patient’s left hip and lumbar spine would have a good chance of relieving his pain. The success of palliative radiotherapy is generally about 70%, with pain relief lasting for 6 to 12 months.7,8 In most cases, a short treatment schedule of one to five fractions is successful, and several randomized trials have shown that a single fraction of 8 Gy is adequate.1,9 However, like analgesics, palliative radiotherapy does not reduce the risk of future metastases, and it is only a matter of time before other lesions start to grow. The cumulative effect of multiple courses of radiotherapy on suppressing bone marrow function should also be considered. The third option could also help this patient. Radiolabeled drugs have been developed with high avidity for bone, particularly to sites of new bone formation such as sclerotic metastases. They deliver radiation locally to the bone with minimal systemic effects. Most patients have pain relief for 3 to 6 months after a single IV dose, and retreatment is possible if needed. Strontium-89 chloride and samarium-153 EDTMP are both approved in the United States for the treatment of bone metastases, including those from prostate cancer.10-13 Palliative chemotherapy such as mitoxantrone plus prednisone gave effective pain relief in a controlled, randomized trial.14 However, the role of chemotherapy in metastatic prostate cancer is still being investigated, and none can be recommended as a standard treatment. The benefits of palliative chemotherapy would need to be weighed against the risk of side effects. If this patient wanted chemotherapy, we would offer it in the context of a clinical trial. We chose to treat Mr C with high-dose, intensive IV ibandronate. Bisphosphonates offer not only the possibility of pain relief but also, unlike the other treatments discussed here, have proven efficacy in reducing other skeletal complications of bone metastases.15-19 Both zoledronic acid and ibandronate relieve bone pain compared with placebo in patients with metastatic prostate cancer.17,20 However, although zoledronic acid was better than placebo at reducing pain, pain scores increased in both groups compared with baseline throughout the 15-month treatment period.17 In contrast, in an open study using intensive ibandronate, pain relief was rapid, with mean bone pain scores significantly below baseline on day 3 (2.5 v 6.8; P ⬍.001)20 (see also Heidenreich elsewhere in this supplement). Pain scores were maintained below baseline throughout the 20-week study. Treatment with ibandronate was well tolerated. Intervention and Outcome Mr C had significant pain relief within 4 days of starting IV ibandronate (6 mg on 3 consecutive days, followed by IV ibandronate 6 mg every 4 weeks). Despite this very early treatment with ibandronate, the patient suffered a pathologic fracture of the vertebral body 15 months later, for which he received palliative radiotherapy. Ibandronate was continued for another 5 months without significant side effects until the patient succumbed because of progressive disease.
86
Conclusion These case histories show the efficacy of IV and oral ibandronate in treating metastatic bone disease in patients with breast or prostate cancer. The oral formulation was safe and well tolerated for several years in both breast cancer patients, and the convenient formulation enabled them to continue their normal daily activities. An intensive, high-dose regimen of IV ibandronate gave the patient with metastatic prostate cancer very rapid pain relief. This example might pave the way for using an IV loading dose followed by an oral maintenance therapy for optimal management of metastatic bone disease. The efficacy and safety of ibandronate compares favorably with other bisphosphonates, and the results of direct, comparative trials are awaited with interest.
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