Skip to main content

Advertisement

SpringerLink
Log in

Burden of skeletal-related events in prostate cancer: unmet need in pain improvement

  • Review Article
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Purpose

Up to 75 % of patients with prostate cancer experience metastatic bone disease, which leads to an increased risk for skeletal-related events (SREs) including pathological bone fracture, spinal cord compression, and hypercalcemia of malignancy. Our objective was to systematically review the literature on the impact of SREs on quality of life (QOL), morbidity, and survival with a primary focus on the impact of SREs on pain in prostate cancer patients.

Methods

We searched PubMed, limiting to peer-reviewed English-language human studies published in 2000–2010. The search was based on the US Food and Drug Administration and European Medicines Agency definition of an SRE, which includes pathologic fracture, spinal cord compression (SCC), hypercalcemia of malignancy, and radiotherapy or surgery to bone resulting from severe bone pain.

Results

A total of 209 articles were screened, of which 173 were excluded, and 36 were included in this review. Patients with SREs had more pain and worse survival compared with no SREs. Pathologic bone fractures worsened QOL and were associated with shorter survival. Radiation therapy of SCC alleviated pain and improved morbidity. SCC was associated with decreases in patient survival. Radiation therapy and surgery to bone improved pain.

Conclusions

Specific SREs are associated with worse outcomes, including increased pain, poorer QOL, morbidity, and survival. Treatment of SREs is associated with improved pain, although there remains a need for more effective treatment of SREs in prostate cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Article Open access 01 July 2023

Enisa Shevroja, Jean-Yves Reginster, … Nicholas C. Harvey

References

  1. National Cancer Institute. What You Need To Know About™ Prostate Cancer. Last accessed, 9/25/2014: http://www.cancer.gov/cancertopics/

  2. Hoffman RM (2011) Clinical practice. Screening for prostate cancer. N Engl J Med 365:2013–2019

    Article  CAS  PubMed  Google Scholar 

  3. Yennurajalingam S, Atkinson B, Masterson J, Urbauer D, Tu SM, Bruera E (2012) The impact of an outpatient palliative care consultation on symptom burden in advanced prostate cancer patients. J Palliat Med 15:20–24

    Article  PubMed  Google Scholar 

  4. American Cancer Society. Prostate Cancer. Last accessed, 9/25/2014: http://www.cancer.org/Cancer/ProstateCancer/index

  5. Rove KO, Crawford ED (2011) Evolution of treatment options for patients with CRPC and bone metastases: bone-targeted agents that go beyond palliation of symptoms to improve overall survival. Oncology 25:1362–1370, 1375–1381, 1387

  6. Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176

    Article  CAS  PubMed  Google Scholar 

  7. Costa L, Badia X, Chow E, Lipton A, Wardley A (2008) Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer 16:879–889

    Article  PubMed  Google Scholar 

  8. United States Food and Drug Administration. FDA Public Workshop on Clinical Trial Endpoints in Prostate Cancer. June 21–22, 2004. Bethesda, Maryland. Last accessed, 9/25/2014: http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm120857.pdf

  9. European Medicines Agency. Evaluation of Medicines for Human Use. Assessment Report for Zometa. International non-proprietary name/Common name: zoledronic acid. Proc. No. EMEA/H/C/000336/II/0031. Doc. Ref No: EMA/35729/2010. Last accessed, 9/25/2014: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000336/WC500074897.pdf

  10. Nørgaard M, Jensen A, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT (2010) Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol 184:162–167

    Article  PubMed  Google Scholar 

  11. DePuy V, Anstrom KJ, Castel LD, Schulman KA, Weinfurt KP, Saad F (2007) Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer. Support Care Cancer 15:869–876

    Article  PubMed  Google Scholar 

  12. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B, Zoledronic Acid Prostate Cancer Study Group (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468

    Article  CAS  PubMed  Google Scholar 

  13. Weinfurt KP, Li Y, Castel LD, Saad F, Timbie JW, Glendenning GA, Schulman KA (2005) The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol 16:579–584

    Article  CAS  PubMed  Google Scholar 

  14. Aass N, Fosså SD (2005) Pre- and post-treatment daily life function in patients with hormone resistant prostate carcinoma treated with radiotherapy for spinal cord compression. Radiother Oncol 74:259–265

    Article  PubMed  Google Scholar 

  15. van der Linden YM, Dijkstra SP, Vonk EJ, Marijnen CA, Leer JW, Dutch Bone Metastasis Study Group (2005) Prediction of survival in patients with metastases in the spinal column. Cancer 103:320–328

    Article  PubMed  Google Scholar 

  16. Berg RS, Yilmaz MK, Høyer M, Keldsen N, Nielsen OS, Ewertz M (2009) Half body irradiation of patients with multiple bone metastases: a phase II trial. Acta Oncol 48:556–561

    Article  CAS  PubMed  Google Scholar 

  17. Hamouda WE, Roshdy W, Teema M (2007) Single versus conventional fractionated radiotherapy in the palliation of painful bone metastases. Gulf J Oncol 1:35–41

    CAS  Google Scholar 

  18. Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, Suh JH, Demas WF, Movsas B, Petersen IA, Konski AA, Cleeland CS, Janjan NA, DeSilvio M (2005) Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst 97:798–804

    Article  PubMed  Google Scholar 

  19. Hird A, Chow E, Zhang L, Wong R, Wu J, Sinclair E, Danjoux C, Tsao M, Barnes E, Loblaw A (2009) Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three Canadian cancer centers. Int J Radiat Oncol Biol Phys 75:193–197

    Article  PubMed  Google Scholar 

  20. Ibrahim A, Crockard A, Antonietti P, Boriani S, Bünger C, Gasbarrini A, Grejs A, Harms J, Kawahara N, Mazel C, Melcher R, Tomita K (2008) Does spinal surgery improve the quality of life for those with extradural (spinal) osseous metastases? An international multicenter prospective observational study of 223 patients. J Neurosurg Spine 8:271–278

    Article  PubMed  Google Scholar 

  21. Liberman B, Gianfelice D, Inbar Y, Beck A, Rabin T, Shabshin N, Chander G, Hengst S, Pfeffer R, Chechick A, Hanannel A, Dogadkin O, Catane R (2009) Pain palliation in patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter study. Ann Surg Oncol 16:140–146

    Article  PubMed  Google Scholar 

  22. Salazar OM, Sandhu T, da Motta NW, Escutia MA, Lanzós-Gonzales E, Mouelle-Sone A, Moscol A, Zaharia M, Zaman S (2001) Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized phase III trial of the international atomic energy agency (IAEA). Int J Radiat Oncol Biol Phys 50:765–775

    Article  CAS  PubMed  Google Scholar 

  23. Sze WM, Shelley M, Held I, Mason M (2008) Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy (review). Cochrane Database Syst Rev 2:1–32

    Google Scholar 

  24. Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R (2007) Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110:1860–1867

    Article  PubMed  Google Scholar 

  25. Rades D, Stalpers LJA, Veninga T, Rudat V, Schulte R, Hoskin PJ (2006) Evaluation of functional outcome and local control after radiotherapy for metastatic spinal cord compression in patients with prostate cancer. J Urol 175:552–556

    Article  PubMed  Google Scholar 

  26. Tomblyn M (2012) The role of bone-seeking radionuclides in the palliative treatment of patients with painful osteoblastic skeletal metastases. Cancer Control 19(2):137–144

    CAS  PubMed  Google Scholar 

  27. Bączyk M, Czepczyński R, Milecki P, Pisarek M, Oleska R, Sowiński J (2007) 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun 28:245–250

    Article  PubMed  Google Scholar 

  28. Dafermou A, Colamussi P, Giganti M, Cittanti C, Bestagno M, Piffanelli A (2001) A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer. Eur J Nucl Med 28:788–798

    Article  CAS  PubMed  Google Scholar 

  29. Fizazi K, Beuzeboc P, Lumbroso J, Haddad V, Massard C, Gross-Goupil M, Di Palma M, Escudier B, Theodore C, Loriot Y, Tournay E, Bouzy J, Laplanche A (2009) Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol 27:2429–2435

    Article  CAS  PubMed  Google Scholar 

  30. Han SH, de Klerk JMH, Tan S, van het Schip AD, Derksen BH, van Dijk A, Kruitwagen CL, Blijham GH, van Rijk PP, Zonnenberg BA (2002) The Placorhen study: a double-blind, placebo-controlled, randomized radionuclide study with 186re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. J Nucl Med 43:1150–1156

    CAS  PubMed  Google Scholar 

  31. Liepe K, Kropp J, Runge R, Kotzerke J (2003) Therapeutic efficiency of rhenium-188-HEDP in human prostate cancer skeletal metastases. Br J Cancer 89:625–629

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Liepe K, Runge R, Kotzerke J (2005) The benefit of bone-seeking radiopharmaceuticals in the treatment of metastatic bone pain. J Cancer Res Clin Oncol 131:60–66

    Article  CAS  PubMed  Google Scholar 

  33. Liepe K, Runge R, Kotzerke J (2005) Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care 22:457–464

    Article  PubMed  Google Scholar 

  34. Liepe K, Kotzerke J (2007) A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases. Nucl Med Commun 28:623–630

    Article  CAS  PubMed  Google Scholar 

  35. Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, Salberg G, Bruland OS (2005) First clinical experience with α-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 11:4451–4459

    Article  CAS  PubMed  Google Scholar 

  36. Nilsson S, Strang P, Ginman C, Zimmermann R, Edgren M, Nordström B, Ryberg M, Kälkner KM, Westlin JE (2005) Palliation of bone pain in prostate cancer using chemotherapy and strontium-89: a randomized phase II study. J Pain Symptom Manag 29:352–357

    Article  CAS  Google Scholar 

  37. Palmedo H, Manka-Waluch A, Albers P, Schmidt-Wolf IG, Reinhardt M, Ezziddin S, Joe A, Roedel R, Fimmers R, Knapp FF Jr, Guhlke S, Biersack HJ (2003) Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: randomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate. J Clin Oncol 21:2869–2875

    Article  CAS  PubMed  Google Scholar 

  38. Sartor O, Reid RH, Hoskin PJ, Quick DP, Ell PJ, Coleman RE, Kotler JA, Freeman LM, Olivier P, Quadramet 424Sm10/11 Study Group (2004) Samarium-153-lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 63:940–945

    Article  PubMed  Google Scholar 

  39. Sartor O, Reid RH, Bushnell DL, Quick DP, Ell PJ (2007) Safety and efficacy of repeat administration of samarium Sm-153 lexidronam to patients with metastatic bone pain. Cancer 109:637–643

    Article  CAS  PubMed  Google Scholar 

  40. Tripathi M, Singhal T, Chandrasekhar N, Kumar P, Bal C, Jhulka PK, Bandopadhyaya G, Malhotra A (2006) Samarium-153 ethylenediamine tetramethylene phosphonate therapy for bone pain palliation in skeletal metastases. Indian J Cancer 43:86–92

    Article  CAS  PubMed  Google Scholar 

  41. Turner SL, Gruenewald S, Spry N, Gebski V, Metastron Users Group (2001) Less pain does equal better quality of life following strontium-89 therapy for metastatic prostate cancer. Br J Cancer 84:297–302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Yaneva MP, Semerdjieva M, Radev LR, Ivanova EK, Geiman M, Vlaikova MI, Mihova LS (2005) Radionuclide therapy of cancer patients with bone metastases. Folia Med 47:63–69

    Google Scholar 

  43. Zafeirakis A, Papatheodorou G, Arhontakis A, Gouliamos A, Vlahos L, Limouris GS (2010) Predictive implications of bone turnover markers after palliative treatment with 186Re-HEDP in hormone-refractory prostate cancer patients with painful osseous metastases. Eur J Nucl Med Mol Imaging 37:103–113

    Article  CAS  PubMed  Google Scholar 

  44. Leondi AH, Souvatzoglou MA, Rapti AS, Leontopoulou SA, Papadaki EK, Datseris EI, Anagnostopoulou US, Zerva CJ (2004) Palliative treatment of painful bone metastases with 186rhenium-HEDP in patients with lung cancer. Q J Nucl Med Mol Imaging 48:211–219

    CAS  PubMed  Google Scholar 

  45. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS (2007) Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8:587–594

    Article  CAS  PubMed  Google Scholar 

  46. Jønler M, Nielsen OS, Groenvold M, Hedlund PO, Damber L, Hedelin H, Waldén M, Scandinavian Prostate Cancer Group Study 5 Study Group (2005) Quality of life in patients with skeletal metastases of prostate cancer and status prior to start of endocrine therapy: results from the Scandinavian Prostate Cancer Group Study 5. Scand J Urol Nephrol 39:42–48

    Article  PubMed  Google Scholar 

  47. Vogel CL, Yanagihara RH, Wood AJ, Schnell FM, Henderson C, Kaplan BH, Purdy MH, Orlowski R, Decker JL, Lacerna L, Hohneker JA (2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist 9:687–695

    Article  CAS  PubMed  Google Scholar 

  48. Oudard S, Banu E, Medioni J, Scotte F, Banu A, Levy E, Wasserman J, Kacso G, Andrieu JM (2009) What is the real impact of bone pain on survival in patients with metastatic hormone-refractory prostate cancer treated with docetaxel? BJU Int 103:1641–1646

    Article  CAS  PubMed  Google Scholar 

  49. Tangen CM, Faulkner JR, Crawford ED, Thompson IM, Hirano D, Eisenberger M, Hussain M (2003) Ten-year survival in patients with metastatic prostate cancer. Clin Prostate Cancer 2:41–45

    Article  PubMed  Google Scholar 

  50. Fulfaro F, Leto G, Badalamenti G, Arcara C, Cicero G, Valerio MR, Di Fede G, Russo A, Vitale A, Rini GB, Casuccio A, Intrivici C, Gebbia N (2005) The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers. J Chemother 17:555–559

    Article  CAS  PubMed  Google Scholar 

  51. (2010) PROLIA (denosumab) [package insert]. Thousand Oaks, California: Amgen Inc

  52. Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J (2014) New agents for prostate cancer. Ann Oncol. Mar 20

  53. Matza LS, Fallowfield LJ, Chung KC, Currie BM, Van Brunt K, Patrick DL (2012) Patient-reported outcome instruments used to assess pain and functioning in studies of bisphosphonate treatment for bone metastases. Support Care Cancer 20(4):657–677. doi:10.1007/s00520-011-1356-9, Review

    Article  PubMed Central  PubMed  Google Scholar 

  54. Clark MJ, Harris N, Griebsch I, Kaschinski D, Copley-Merriman C (2014) Patient-reported outcome labeling claims and measurement approach for metastatic castration-resistant prostate cancer treatments in the United States and European Union. Health Qual Life Outcomes 12(1):104

    Article  PubMed Central  PubMed  Google Scholar 

  55. Basch E, Trentacosti AM, Burke LB, Kwitkowski V, Kane RC, Autio KA, Papadopoulos E, Stansbury JP, Kluetz PG, Smith H, Justice R, Pazdur R (2014) Pain palliation measurement in cancer clinical trials: the US Food and Drug Administration perspective. Cancer 120(5):761–767. doi:10.1002/cncr.28470

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

This study was funded by Bristol-Myers Squibb. Two of the co-authors, Michael S. Broder and Dasha Cherepanov, are employees of Partnership for Health Analytic Research, LLC (PHAR), a health services research company paid to conduct this research. Ben Gutierrez is a former employee of Bristol-Myers Squibb Company; he is currently an employee of Otsuka America Pharmaceutical, Inc. Yuliya Linhares, Cedars-Sinai Medical Center, has consulted for PHAR.

Disclaimer

Part of this review was previously presented at the International Society for Pharmacoeconomics and Outcomes Research 14th European Congress, held on March 5–8, 2011, in Madrid, Spain.

Author information

Authors and Affiliations

  1. Partnership for Health Analytic Research, LLC, 280 S. Beverly Dr., Suite 404, Beverly Hills, CA, 90212, USA

    M. S. Broder & D. Cherepanov

  2. Otsuka America Pharmaceutical, Inc., 1 University Square Dr., Princeton, NJ, 08540, USA

    B. Gutierrez

  3. Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite AC1076, Los Angeles, CA, 90048, USA

    Y. Linhares

Authors
  1. M. S. Broder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Cherepanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. Linhares
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. Cherepanov.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Broder, M.S., Gutierrez, B., Cherepanov, D. et al. Burden of skeletal-related events in prostate cancer: unmet need in pain improvement. Support Care Cancer 23, 237–247 (2015). https://doi.org/10.1007/s00520-014-2437-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-014-2437-3

Keywords

Search

Navigation