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Systemic management of metastatic bone disease: Guidelines on treatment

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Prostate cancer patients with metastatic bone disease (MBD) are at high risk of skeletal-related events (SRE), such as bone pain, pathological fracture, spinal cord compression, or rarely hypercalcaemia, which lead to a rapid deterioration in the quality of life. In hormone-resistant prostate cancer (HRPC), evidence suggests a role for early commencement of bisphosphonate therapy to reduce the risk and/or delay progression to an SRE. Zoledronic acid is the only bisphosphonate proven to reduce this risk. Treatment options for an established SRE include bisphosphonates (if not already started), radiotherapy, surgery and analgesics.1

On average, the first SRE occurs approximately 10 months after diagnosis of Metastatic prostate cancer, and the median survival is about 40 months.2 Bone pain which is often poorly localized and worse at night is debilitating and significantly affects quality of life. Untreated, moderate to severe hypercalcaemia (serum calcium >3.0 mmol/L) may result in fatal cardiac arrhythmias and renal failure. Since reducing the complications of SREs improves quality of life, the current goal of treatment is the prevention and palliation of these complications in symptomatic as well as asymptomatic patients, with bisphosphonates, radiotherapy, orthopaedic interventions and analgesics, either individually or in combination.Bisphosphonates:Often used as a supplement to radiotherapy, bisphosphonates, stable analogues of thepyrophosphate molecule that inhibit bone resorption, have now become part of the standard therapy for the treatment and prevention of SREs in patients with metastatic prostate cancer. On the treatment algorithm, bisphosphonates (zoledronic acid) are used in asymptomatic patients followed by observation. In symptomatic patients, the use of zoledronic acid is followed by local field radiation + chemotherapy or chemotherapy + radioisotopes, depending on the extent of the lesion, i.e. focal or diffuse.3 Bisphosphonates have also been shown to be an effective therapy for the treatment of bone metastases in other cancers, especially advanced breast cancer.4,5Different types of bisphosphonates vary in clinical activity and potency due to differences in their chemical structure. Early generation bisphosphonates (e.g. etidronate and clodronate) have failed to show a great benefit to metastatic prostate cancer patients.6,7 A recent combined analysis reported that pamidronate, a more potent inhibitor of bone resorption than the first generation drugs (clodronate or etidronate), had no significant clinical benefit for the palliation of bone pain in metastatic prostate cancer patients. Zoledronic acid, a new generation high-potency bisphosphonate, is currently the only bisphosphonate licensed for use in prostate cancer, and has been shown to be a potent and effective treatment for the palliation and prevention of SREs in patients with advanced breast cancer, multiple myeloma and metastatic prostate cancer.9,10,11 Significant reduction in the proportion of patients with a pathological fracture demonstrated in a recent trial implies that the use of a potent bisphosphonate such as zoledronic acid that inhibits bone resorption may have a significant impact on the morbidity associated with osteoblastic lesions in metastatic prostate cancer patients.12 Patients on 4 mg zoledronic acid every 3 weeks also demonstrated a statistically significant and long lasting palliation of bone pain.9 However, doses of zoledronic acid greater than 4 mg are not recommended due to renal function deterioration. Radiotherapy:For the palliation of both localised and diffuse sites of pain, external beam radiation therapy can provide both dramatic and long lasting pain relief. Radionuclides, which only cause mild bone suppression as an adverse effect, have become more popular in the treatment of patients with multifocal bone pain as a result of prostate cancer induced metastases. Orthopaedic interventions:Primary internal stabilization of pathological fractures is often needed prior to radiotherapy. Prophylactic fixation may be considered in patients with metastatic disease in the spine or long bones.Analgesics:Management of pain should be in accordance to the guidelines determined by the World Health Organisation, with regular medication given in a stepwise approach from non-opioids, to ‘weak’ opioids, to strong opioids with appropriate adjuncts.In summary, the use of bisphosphonates, mainly zoledronic acid, has been shown to be effective in bone pain, reducing the number of pathological fractures, and delaying time to first SRE. Radiotherapy, orthopaedic interventions, and analgesics also play an essential role in selective cases. References:The British Association of Urological Surgeons (BAUS)1. The British Association of Urological Surgeons (BAUS). Systemic Management of Metastatic Bone Disease: Guidelines on Treatment. A section from the BAUS Guidelines on the Management and Treatment of Metastatic Prostate Cancer. 2. Coleman RE. Skeletal complications of malignancy. Cancer 1997; 80(8): 1588-94.3. Saad F, Guise T, Hussain A et al. The role of intravenous bisphosphonates in the mangemetn of Prostate Cancer: Treatment Guidelins. Am J Urol Rev 2004; 2(2): 9-15.4. Guidance on cancer services, improving outcomes in breast cancer, Manual update; NICE 2002. Available at Lipton A, Theriault RL 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 2000; 88(5): 1082-90.6. Dearnaley D, Sydes PMR et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003; 95(17): 1300-11.7. Ernst DS, Tannock IF, Winquist EW, et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003; 21(17): 3335-42. 8. Small EJ, Smith MR 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 2003; 21(23): 4277-84.9. Saad F, Gleason DM, Murray R et al. Long term efficacy of zoledronic acid for the prevention of skeletal-related events in patients with metastatic hormone-resistant prostate cancer. J Natl Cancer Inst 2004; 96(11): 879-82.10. Rosen LS, Gordon D et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 2001; 7(5): 377-87.11. Saad F, Gleason DM, Murray R et al. A randomised placebo controlled trial of zoledronic acid in patients with hormone-resistant prostate cancer. J Natl Cancer Inst 2002; 94: 1458-1468.12. Saad F, Murray R, Tchekmedyian S et al. Safety and efficacy of zoledronic acid in the treatment of patients with Hormone-resistant prostate cancer. Am J Urol 2004; 2 (supplement 2): 23-29.Please click here to view the full article.

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Posted On: 30 November, 2005
Modified On: 20 March, 2014


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