Current Oncology Reports

, Volume 13, Issue 3, pp 222–230

Optimal Management of Bone Metastases in Prostate Cancer

Article
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Abstract

The biological basis of the selective outgrowth of disseminated prostate cancer cells within the hematopoietic bone microenvironment remains a compelling biological mystery. A major proportion of the morbidity and mortality related to prostate cancer can be traced to the burden of bone metastases. The optimal management of bone health in men with prostate cancer requires control of the underlying epithelial neoplasm, attenuation of the subverted bone remodeling process that accompanies disease progression, reduction in the bone complications of disease-directed therapy, and management of co-existing comorbidities that enhance bone fragility. While bone-homing radioisotopes, bisphosphonates, and RANK ligand inhibitors have demonstrated reduction in bone pain and/or other skeletal-related events, further advances into definitive improvements in survival and/or global quality of life are required. A deeper understanding of the biology of bone metastases will likely facilitate a bone-directed therapeutic approach toward a major impact on the survival of men with this important disease.

Keywords

Prostate cancer Bone metastases Management Skeletal-related events 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jemal A, Center MA, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomark Prev. 2010;19:1893–907.CrossRefGoogle Scholar
  2. 2.
    Jemal A, Siegal R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.PubMedCrossRefGoogle Scholar
  3. 3.
    Loberg RD, Logothetis CJ, Keller ET, Pienta KJ. Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype. J Clin Oncol. 2005;23:8232–41.PubMedCrossRefGoogle Scholar
  4. 4.
    Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1, 589 patients. Hum Pathol. 2000;31:578–83.PubMedCrossRefGoogle Scholar
  5. 5.
    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. 2002;94:1458–68.PubMedGoogle Scholar
  6. 6.
    Norgaard M, Jensen AO, Jacobsen JB, et al. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184:162–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Shiozawa Y, Havens AM, Pienta KJ, Taichman RS. The bone marrow niche: habitat to hematopoietic and mesenchymal stem cells, and unwitting host to molecular parasites. Leukemia. 2008;22:941–50.PubMedCrossRefGoogle Scholar
  8. 8.
    Welch HG, Black WC. Overdiagnosis in Cancer. J Natl Cancer Inst. 2010;102:605–13.PubMedCrossRefGoogle Scholar
  9. 9.
    Gleave M, Kelly WK. High-risk localized prostate cancer: a case for early chemotherapy. J Clin Oncol. 2005;23:8186–91.PubMedCrossRefGoogle Scholar
  10. 10.
    De Bono JS, Logothetis CJ, Fizazi K, et al. Abiraterone acetate plus low-dose prednisone improves overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel-based chemotherapy: results of COU-AA-301, a randomized double-blind placebo-controlled Phase III Study. Ann Oncol. 2010;21(suppl 8): Abstract LBA 5.Google Scholar
  11. 11.
    Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and Pharmacokinetic Study of XRP6258, a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res. 2009;15:723–30.PubMedCrossRefGoogle Scholar
  12. 12.
    De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomized open-label trial. Lancet. 2010;376:1147–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.PubMedCrossRefGoogle Scholar
  14. 14.
    Tu SM, Millikan RE, Mengistu B, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomized phase II trial. Lancet. 2001;357:336–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Tu SM, Mathew P, Wong FC, et al. Phase I study of concurrent weekly docetaxel and repeated samarium-153 lexidronam in patients with castration-resistant metastatic prostate cancer. J Clin Oncol. 2009;27:3319–24.PubMedCrossRefGoogle Scholar
  16. 16.
    Morris M, Pandit-Taskar N, Carrasquillo J, et al. Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol. 2009;27:2436–42.PubMedCrossRefGoogle Scholar
  17. 17.
    Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomized, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Kingsley LA, Fournier PGJ, Chirgwin JM, et al. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6:2609–17.PubMedCrossRefGoogle Scholar
  19. 19.
    Casimiro S, Guise T, Chirgwin J, et al. The critical role of the bone microenvironment in cancer metastases. Mol Cell Endocrinol. 2009;310:71–81.PubMedCrossRefGoogle Scholar
  20. 20.
    •• Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med. 2009;360:53–62. This provides seminal insight into the mechanism of action of nitrogen-containing bisphosphonates. PubMedCrossRefGoogle Scholar
  21. 21.
    Saad F, Gleason D, Murray R, 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;96:879–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Weinfurt KP, Anstrom KJ, Castel LD, Schulman KA, Saad F. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol. 2006;17:986–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Schneider A, Kalikin LM, Mattos AC, et al. Bone turnover mediates preferential localization of prostate cancer in the skeleton. Endocrinology. 2005;146:1727–36.PubMedCrossRefGoogle Scholar
  24. 24.
    Gomes Jr RR, Buttke P, Paul EM, Sikes RA. Osteosclerotic prostate cancer metastasis to murine bone are enhanced with increased bone formation. Clin Exp Metastasis. 2009;26:641–51.PubMedCrossRefGoogle Scholar
  25. 25.
    Guise TA, Mohammad KS, Clines G, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12(20 Suppl):6213s–6s.PubMedCrossRefGoogle Scholar
  26. 26.
    Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27:1564–71.PubMedCrossRefGoogle Scholar
  28. 28.
    • Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine n-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182:509–16. These results support biological activity of denosumab in zoledronic acid (4 mg)-resistant osteolysis. PubMedCrossRefGoogle Scholar
  29. 29.
    •• Fizazi K, Carducci MA, Smith MR, et al. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration resistant prostate cancer (abstract #4507). J Clin Oncol. 2010;28:18s. (suppl: abstr LBA4507). This is the first comparative study of denosumab and zoledronic acid in metastatic prostate cancer, leading to FDA approval of denosumab. Google Scholar
  30. 30.
    Fizazi K. The role of Src in prostate cancer. Ann Oncol. 2007;18:1765–73.PubMedCrossRefGoogle Scholar
  31. 31.
    Yu EY, Wilding G, Posadas E, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15(23):7421–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Lara Jr PN, Longmate J, Evans CP, et al. A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study. Anticancer drugs. 2009;20(3):179–84.PubMedCrossRefGoogle Scholar
  33. 33.
    Araujo J, Mathew P, Armstrong AJ, et al. Dasatinib and docetaxel combination treatment for patients with metastatic castration-resistant prostate cancer: analysis of Study CA180-086. Eur J Cancer Suppl. 2009;7:415S (abstract 7028).CrossRefGoogle Scholar
  34. 34.
    Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005;5:21–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Carducci MA, Saad F, Abrahamsson PA, et al. A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer. 2007;110:1959–66.PubMedCrossRefGoogle Scholar
  36. 36.
    Armstrong AJ, Creel P, Turnbull J, et al. A Phase I–II study of docetaxel and atrasentan in men with castration-resistant metastatic prostate cancer. Clin Cancer Res. 2008;14:6270–6.PubMedCrossRefGoogle Scholar
  37. 37.
    James ND, Caty A, Payne H, et al. Final safety and efficacy analysis of the specific endothelin-A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II Trial. BJU. 2010;7:966–73.Google Scholar
  38. 38.
    Schelman WR, Liu G, Wilding G, et al. A phase I study of zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest New Drugs 2009 Sep 19 (Epub ahead of print).Google Scholar
  39. 39.
    Ellis WJ, Vessella RL, Buhler KR, et al. Characterization of a novel androgen-sensitive, prostate-specific antigen-producing prostatic carcinoma xenograft: LuCaP 23. Clin Cancer Res. 1996;6:1039–48.Google Scholar
  40. 40.
    Li ZG, Mathew P, Yang J, et al. Androgen-receptor negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms. J Clin Invest. 2008;118:2697–710.PubMedCrossRefGoogle Scholar
  41. 41.
    Kelly WK, Halabi S, Carducci MA, et al. A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): survival results of CALGB 90401. J Clin Oncol. 2010;28:18s (suppl;abstr LBA4511).Google Scholar
  42. 42.
    Sonpavde G, Periman PO, Bernold D, et al. Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy. Ann Oncol. 2010;21:319–24.PubMedCrossRefGoogle Scholar
  43. 43.
    Mathew P, Thall PF, Bucana CD, et al. Platelet-derived growth factor receptor inhibition and chemotherapy for castration-resistant prostate cancer with bone metastases. Clin Cancer Res. 2007;13:5816–24.PubMedCrossRefGoogle Scholar
  44. 44.
    Bradley DA, Daignault S, Ryan CJ, et al. Cilengitide (EMD 121974, NSC 707544) in asymptomatic metastatic castration resistant prostate cancer patients: a randomized phase II trial by the prostate cancer clinical trials consortium. Invest New Drugs. 2010 Aug 10Google Scholar
  45. 45.
    •• Smith M, Egerdie B, Toriz NH, et al. Denosumab in men receiving androgen-Deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745–55. This is the first study to demonstrate fracture risk reduction in men with nonmetastatic prostate cancer receiving hormonal therapy. PubMedCrossRefGoogle Scholar
  46. 46.
    Smith MR, Morton RA, Barnette KG, et al. Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol. 2010;184:1316–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Cranney A, Horsley T, O’Donnell S, et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess Full Rep. 2007;158:1–235.PubMedGoogle Scholar
  48. 48.
    Saylor PJ, Kaufman DS, Michaelson MD, Lee RJ, Smith MR. Application of a fracture risk algorithm to men treated with androgen deprivation therapy for prostate cancer. J Urol. 2010;183:2200–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23:4925–34.PubMedCrossRefGoogle Scholar
  50. 50.
    Smith MR, Cook RJ, Coleman R, et al. Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer. Urology. 2007;70:315–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Hematology OncologyTufts Medical CenterBostonUSA

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