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Reducing the burden of skeletal-related events in prostate cancer patients with bone metastases: A new challenge in oncology, "Beyond the Abstract," by Ignacio Durán, MD and Laura Gutiérrez

BERKELEY, CA (UroToday.com) - Bone metastases are a common complication of advanced cancer. As a consequence of an increased bone turnover and an imbalance between osteogenesis and osteolysis, an important proportion of patients with bone metastases experience skeletal-related events (SREs), defined as pathological fracture, radiation to bone, spinal cord compression, or surgery to bone. Due to the need for surgery and lengthy hospitalizations in most cases,[1] these events have devastating consequences for the quality of life of patients.[2] Most SREs also cause a decrease in the ability to perform basic functions of daily living, and have a negative impact on mortality.[3]

Published data on the cost of SREs in Spain and other European or American countries are scarce, but all available data suggest that they are associated with a high health care burden.[2, 4, 5, 6, 7] In our cohort of 93 Spanish patients with solid tumours (56% with prostate or breast cancer), the mean cost per SRE ranged between €2,378 (radiation to bone) and €7,903 (spinal cord compression), thus confirming previous findings. To put into context the significance of our results, it is crucial to estimate the absolute number of SREs occurring in real-life. In the world, there presently are almost 30 million adult patients with solid tumours, of which 40% have breast, colorectal, or prostate cancer.[8] Bone metastases are common in many cancer types, but breast and prostate cancers have a special predilection for colonization in bone. The prevalence of bone metastases in these two cancer types is around 70%.[9] In patients with bone metastases from breast and prostate cancer, not receiving any bone-targeted agent, the incidence of SREs is around 38-64% within 1-2 years, with a median time to first SRE between 7 and 12 months.[10, 11] This implies that, probably, more than 50% of patients with advanced prostate or breast cancer will suffer at least one SRE during the course of their disease. Thus, more effort should be directed toward improved treatment and prevention of these morbid and costly complications. Globally, prostate cancer is the third most common tumour (11% of all cancers), with around 3.2 million people affected. In Spain, it is the most frequent (17% of all cancers), with 92 000 prevalent patients, whereas, in the WHO European region, it is in the second place (15%).[8] A recent data from two large US health systems revealed that relatively few (one in 5) patients with bone metastases from prostate cancer receive intravenous (IV) bisphosphonates, and that only one in 10 receives them in a preventive way (i.e., prior to an SRE).[12]

Currently, there are several bone-targeted agents available with proven efficacy in the prevention and delay of SREs in patients with bone metastases secondary to solid tumours. Among all available agents, zoledronic acid, the most effective bisphosphonate, reduces the annual incidence of SREs by 52%, compared with placebo, in prostate cancer patients[11, 13] and has been historically considered the standard of care. Denosumab, a fully-human antibody that specifically targets the RANK ligand has been recently commercialized and has demonstrated its superiority in breast, prostate and other solid tumours,[14] reducing the risk of a first SRE by 17% compared with zoledronic acid. Furthermore, the subcutaneous administration of denosumab (every 4 weeks) is more convenient for the patient and hospital than the IV infusion of zoledronic acid (every 3–4 weeks, with monitoring of renal function).[15] Considering these advantages, it seems that denosumab could be the drug of choice from the patient´s perspective. Some studies also suggest that, despite its higher cost compared to zoledronic acid, denosumab is cost-effective for the health care system when SRE-related costs and administration costs (approximately 3-times higher for zoledronic acid) are taken into account.[16, 17] Since other pharmaco-economic evaluations led to discordant results,[18, 19] more studies using standardized time horizons and calculations of SRE reduction are needed, in the future, to clarify this point.

For the moment, the most recent guidelines from the United States (National Comprehensive Cancer Network (NCCN)) and Europe (guidelines of the European Association of Urology (EAU)) recommend the use of either zoledronic acid or denosumab to prevent or delay SRE in patients with bone metastases from castration-resistant prostate cancer, and recognize the superior clinical benefits and tolerability of denosumab compared with zoledronic acid.[20, 21]

In conclusion, the high personal and economic burden of each SRE constitutes a challenge for the physician taking care of cancer patients. The risk of suffering an SRE in patients with bone metastases from solid tumours justifies the use of bone-targeted agents in those populations where these compounds have shown a clinical benefit. In particular the use of zoledronic acid or denosumab should be considered in those patients with castration-resistant prostate cancer and bone involvement, taking into account that the latter has shown superiority in delaying the occurrence of SREs when compared with the former. The use of bone-targeted agents will not only improve patients’ quality of life but will probably also reduce the cost of cancer management for the health care system.

Competing Interests:
Laura Gutiérrez is an employee of AMGEN S.A. and holds stock. Ignacio Duran has received honoraria derived from participation in advisory boards for AMGEN S.A.

Acknowledgments:
This study was funded by Amgen, S.A. Writing assistance was provided by Dr. Neus Valveny from TFS Develop. 

References:

  1. Pockett R, Castellano D, McEwan P, Oglesby A, Barber B, Chung K. The hospital burden of disease associated with bone metastases and skeletal‐related events in patients with breast cancer, lung cancer, or prostate cancer in Spain. European Journal of Cancer Care. 2010;19(6):755-60.
  2. Weinfurt K, Li Y, Castel L, Saad F, Timbie J, Glendenning G, et al. The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Annals of Oncology. 2005;16(4):579-84.
  3. Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer. 2007;110(8):1860-7.
  4. Hagiwara M, Delea T, Saville M, Chung K. Healthcare utilization and costs associated with skeletal-related events in prostate cancer patients with bone metastases. Prostate Cancer and Prostatic Diseases. 2012.
  5. Hechmati G, Cure S, Gouepo A, Hoefeler H, Lorusso V, Luftner D, et al. Cost of skeletal-related events in European patients with solid tumours and bone metastases: data from a prospective multinational observational study. J Med Econ. 2013;16(5):691-700.
  6. Lage MJ, Barber BL, Harrison DJ, Jun S. The cost of treating skeletal-related events in patients with prostate cancer. Am J Manag Care. 2008;14(5):317-22.
  7. Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-7.
  8. Globocan 2008. http://globocan.iarc.fr/. Accessed 21 November 2013.
  9. Rubens RD, Coleman RE. Bone metastases. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE. Clinical Oncology. New York: Churchill Livingstone, 1995:643–65.
  10. Lipton A, Theriault RL, Hortobagyi GN, Simeone J, Knight RD, Mellars K, 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.
  11. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-82.
  12. Oster G, Lamerato L, Glass AG, Richert-Boe KE, Lopez A, Chung K, et al. Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Supportive Care in Cancer. 2013;21(12):3279-86.
  13. Saad F. Clinical benefit of zoledronic acid for the prevention of skeletal complications in advanced prostate cancer. Clin Prostate Cancer. 2005;4(1):31-7.
  14. Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. European Journal of Cancer. 2012;48(16):3082-92.
  15. Oglesby A, Sherif B, Odom D, Leahy M, Qian Y. Time and costs associated with preparing and administering zoledronic acid in patients with breast or prostate cancer and metastatic bone disease. Community Oncology. 2009;6(11):494-502.
  16. Lothgren M, Ribnicsek E, Schmidt L, Habacher W, Lundkvist J, Pfeil AM, et al. Cost per patient and potential budget implications of denosumab compared with zoledronic acid in adults with bone metastases from solid tumours who are at risk of skeletal-related events: an analysis for Austria, Sweden and Switzerland. European Journal of Hospital Pharmacy: Science and Practice. 2013.
  17. Stopeck A, Rader M, Henry D, Danese M, Halperin M, Cong Z, et al. Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. Journal of Medical Economics. 2012;15(4):712-23.
  18. Snedecor SJ, Carter JA, Kaura S, Botteman MF. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A cost-effectiveness analysis. Journal of Medical Economics. 2012;16(1):19-29.
  19. Xie J, Namjoshi M, Wu EQ, Parikh K, Diener M, Yu AP, et al. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm. 2011;17(8):621-43.
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  21. NCCN Guidelines in Oncology. Prostate Cancer. www.nccn.org Version 4.2011. Accessed 21 November 2013.

Written by:
Ignacio Durán, MDa and Laura Gutiérrezb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aUnidad Gestión Clínica Oncologia Integral, Hospital Universitario Virgen del Rocío, Avda Manuel Siurot s/n, 41013 Sevilla, Spain; e-mail:

bHealth Economics, Amgen, Moll de Barcelona, s/n, 08039 Barcelona, Spain; e-mail:

Cost analysis of skeletal-related events in Spanish patients with bone metastases from solid tumours - Abstract

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