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Predictive implications of bone turnover markers after palliative treatment with 186Re-HEDP in hormone-refractory prostate cancer patients with painful osseous metastases

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Abstract

Purpose

To prospectively evaluate the predictive value of various bone formation and resorption markers in patients with bone metastases from prostate cancer after palliative treatment with 186Re-1,1-hydroxyethylidene diphosphonate (186Re-HEDP).

Methods

Included in the study were 36 men with prostate cancer, suffering from painful osseous metastases and treated with 186Re-HEDP. None had received any treatment that would have interfered with bone metabolism before 186Re-HEDP treatment or throughout the follow-up period. For each patient, pretreatment and posttreatment serum levels of osteocalcin (OC), bone alkaline phosphatase (BALP), aminoterminal (PINP) and carboxyterminal (PICP) propeptides of type I collagen, amino-terminal (NTx) and carboxyterminal (CTx) telopeptides of type I collagen and their combinations were compared with the level and duration of pain response to radionuclide treatment.

Results

Pain response was correlated only with pretreatment ΝΤx/PINP, PICP/PINP and NTx/CTx ratios and posttreatment decrease in baseline NTx and PICP values (p=0.0025–0.035). According to multivariate and ROC analyses, the best marker-derived predictors of better and longer duration of response to 186Re-HEDP treatment were a posttreatment decrease in NTx of ≥20% (RR=3.44, p=0.0005) and a pretreatment NTx/PINP ratio of ≥1.2 (RR=3.04, p=0.036)

Conclusion

NTx, a potent collagenous marker of bone resorption, along with the novel NTx/PINP ratio provide useful cut-off values for identifying a group of patients suffering from painful osseous metastases from hormone-refractory prostatic carcinoma who do not respond to palliative treatment with 186Re-HEDP. This information could help avoid an inefficient and expensive radionuclide treatment. Also, in the cohort of patients who will eventually undergo such treatment, the medium-term posttreatment changes in NTx offer valuable predictive information regarding long-term palliative response.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics. CA Cancer J Clin 2008;58(2):71–96.

    Article  PubMed  Google Scholar 

  2. McRea LE, Karafin L. Carcinoma of the prostate: metastases, therapy, and survival – a statistical analysis of 500 cases. Int Coll Surg J 1958;29:723–8.

    Google Scholar 

  3. Pectasides D, Nikolaou M, Farmakis D, Kanakis I, Gaglia A, Kountourakis P, et al. Clinical value of bone remodelling markers in patients with bone metastases treated with zoledronic acid. Anticancer Res 2005;25:1457–63.

    CAS  PubMed  Google Scholar 

  4. Arai Y, Takeuchi H, Oishi K, Yoshida O. Osteocalcin: is it a useful marker of bone metastasis and response to treatment in advanced prostate cancer? Prostate 1992;20:169–77.

    Article  CAS  PubMed  Google Scholar 

  5. Demers LM, Costa L, Lipton A. Biochemical markers and skeletal metastases. Cancer 2000;88:2919–26.

    Article  CAS  PubMed  Google Scholar 

  6. Vinholes J, Coleman R, Eastell R. Effects of bone metastases on bone metabolism: implications for diagnosis, imaging and assessment of response to cancer treatment. Cancer Treat Rev 1996;22:289–331.

    Article  CAS  PubMed  Google Scholar 

  7. Koopmans N, de Jong IJ, Breeuwsma AJ, van der Veer E. Serum bone turnover markers (PINP and ICTP) for the early detection of bone metastases in patients with prostate cancer: a longitudinal approach. J Urol 2007;178:849–53.

    Article  CAS  PubMed  Google Scholar 

  8. Costa L, Demers LM, Gouveia A. Correlation of urinary N-telopeptide levels with progression of bone metastases: a prospective study (abstract 12). Cancer 2000;88(Suppl):3094.

    Google Scholar 

  9. Coleman RE. The clinical use of bone resorption markers in patients with malignant bone disease. Cancer 2002;94:2521–33.

    Article  PubMed  Google Scholar 

  10. Cook RJ, Coleman R, Brown J, Lipton A, Major P, Hei YJ, et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 2006;12:3361–7.

    Article  CAS  PubMed  Google Scholar 

  11. Ryan CW, Huo D, Bylow K, Demers LM, Stadler WM, Henderson TO, et al. Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid. BJU Int 2007;100(1):70–5.

    Article  CAS  PubMed  Google Scholar 

  12. Demers LM, Costa L, Lipton A. Biochemical markers and skeletal metastases. Clin Orthop 2003;415:S138–47.

    Article  PubMed  Google Scholar 

  13. Jung K, Lein M, Stephan C, Von Hösslin K, Semjonow A, Sinha P, et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with metastatic spread: diagnostic and prognostics implications. Int J Cancer 2004;111:783–91.

    Article  CAS  PubMed  Google Scholar 

  14. de Klerk JMH, van Dijk A, van Rijk PP, Zonnenberg BA, van het Schip AD. Pharmacokinetics of rhenium-186 after administration of Re-186-HEDP to patients with bone metastases (abstract). J Nucl Med 1991;32:1082.

    Google Scholar 

  15. Han SH, de Klerk JM, Tan S, van het Schip AD, Derksen BH, van Dijk A, et al. The PLACORHEN study: a double-blind placebo-controlled randomized radionuclide study with 186Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. Placebo controlled rhenium study. J Nucl Med 2002;43:1150–6.

    CAS  PubMed  Google Scholar 

  16. Dafermou A, Colamussi P, Giganti M, Cittanti C, Bestagno M, Piffanelli A. A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer. Eur J Nucl Med 2001;28:788–98.

    Article  CAS  PubMed  Google Scholar 

  17. Demers LM. Bone markers in the management of patients with skeletal metastases. Cancer 2003;97(3 Suppl):874–9.

    Article  PubMed  Google Scholar 

  18. Bodei L, Lam M, Chiesa C, Flux G, Brans B, Chiti A, et al. EANM procedure guideline for treatment of refractory metastatic bone pain. Eur J Nucl Med Mol Imaging 2008;35(10):1934–40.

    Article  PubMed  Google Scholar 

  19. Fang N, Li Y, Xu YS, Ma D, Fu P, Gao HQ, et al. Serum concentrations of IL-2 and TNF-a in patients with painful bone metastases: correlation with responses to 89SrCl2 therapy. J Nucl Med 2006;47:242–6.

    CAS  PubMed  Google Scholar 

  20. Soloway MS, Hardeman SW, Hickey D, Raymond J, Todd B, Soloway S, et al. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 1988;61:195–202.

    Article  CAS  PubMed  Google Scholar 

  21. Siegel S, Castellan J Jr. Nonparametric statistics for the behavioural sciences. 2nd ed. New York: McGraw Hill; 1988.

    Google Scholar 

  22. Motulsky H. Intuitive biostatistics. New York: Oxford University; 1995. p. 113–7.

    Google Scholar 

  23. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29–36.

    CAS  PubMed  Google Scholar 

  24. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Accoc 1958;53:457–81.

    Article  Google Scholar 

  25. Papatheofanis FJ. Quantitation of biochemical markers of bone resorption following strontium-89-chloride therapy for metastatic prostatic carcinoma. J Nucl Med 1997;38:1175–9.

    CAS  PubMed  Google Scholar 

  26. Papatheofanis FJ. Serum PICP as a bone formation marker in Sr-89 and external beam radiotherapy of prostatic bony metastases. Br J Radiol 1997;70:594–8.

    CAS  PubMed  Google Scholar 

  27. Guerrieri P, Modoni S, Parisi S, Fusco V, Oriolo V, Rendina G, et al. Bone formation markers and pain palliation in bone metastases treated with strontium-89. Am J Clin Oncol 1994;17:77–9.

    Article  CAS  PubMed  Google Scholar 

  28. Lam MG, Dahmane A, Stevens WH, van Rijk PP, de Klerk JM, Zonnenberg BA. Combined use of zoledronic acid and 153Sm-EDTMP in hormone-refractory prostate cancer patients with bone metastases. Eur J Nucl Med Mol Imaging 2008;35:756–65.

    Article  CAS  PubMed  Google Scholar 

  29. Johansen JS, Brasso K, Iversen P, Teisner B, Garnero P, Price PA, et al. Changes of biochemical markers of bone turnover and YKL-40 following hormonal treatment for metastatic prostate cancer are related to survival. Clin Cancer Res 2007;13:3244–9.

    Article  CAS  PubMed  Google Scholar 

  30. Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, et al. Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid. Cancer 2008;113:193–201.

    Article  CAS  PubMed  Google Scholar 

  31. Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999;45:1359–68.

    CAS  PubMed  Google Scholar 

  32. Hoskin PJ, Stratford MR, Folkes LK, Regan J, Yarnold JR. Effect of local radiotherapy for bone pain on urinary markers of osteoclast activity. Lancet 2000;355:1428–9.

    Article  CAS  PubMed  Google Scholar 

  33. Michaelson MD, Marujo RM, Smith MR. Contribution of androgen deprivation therapy to elevated osteoclast activity in men with metastatic prostate cancer. Clin Cancer Res 2004;10(8):2705–8.

    Article  CAS  PubMed  Google Scholar 

  34. Lein M, Miller K, Wirth M, Weissbach L, May C, Schmidt K, et al. Bone turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid. Prostate 2009;69(6):624–32.

    Article  CAS  PubMed  Google Scholar 

  35. Akimoto S, Furuya Y, Akakura K, Shimazaki J, Ito H. Inability of bone turnover marker as strong prognostic indicator in prostate cancer patients with bone metastasis: comparison with the extent of disease (EOD) grade. Prostate. 1999;38:28–34.

    Article  CAS  PubMed  Google Scholar 

  36. Shimozuma K, Sonoo H, Fukunaga M, Ichihara K, Aoyama T, Tanaka K. Biochemical markers of bone turnover in breast cancer patients with bone metastases: a preliminary report. Jpn J Clin Oncol 1999;29:16–22.

    Article  CAS  PubMed  Google Scholar 

  37. Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 2005;97:59–69.

    Article  CAS  PubMed  Google Scholar 

  38. Reynard JM, Peters TJ, Gillatt D. Prostate-specific antigen and prognosis in patients with metastatic prostate cancer – a multivariable analysis of prostate cancer mortality. Br J Urol 1995;75:507–15.

    Article  CAS  PubMed  Google Scholar 

  39. Smith JA, Lange PH, Janknegt RA, Abbou CC, deGery A. Serum markers as a predictor of response duration and patient survival after hormonal therapy for metastatic carcinoma of the prostate. J Urol. 1997;157:1329–34.

    Article  PubMed  Google Scholar 

  40. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol 1990;143:747–52.

    CAS  PubMed  Google Scholar 

  41. Koizumi M, Yonese J, Fukui I, Ogata E. Metabolic gaps in bone formation may be a novel marker to monitor the osseous metastasis of prostate cancer. J Urol 2002;167:1863–6.

    Article  PubMed  Google Scholar 

  42. Jukkola A, Tahtela R, Tholix E, Vuorinen K, Blanco G, Risteli L, et al. Aggressive breast cancer leads to discrepant serum levels of the type I procollagen propeptides PINP and PICP. Cancer Res 1997;57:5517–20.

    CAS  PubMed  Google Scholar 

  43. Santala M, Simojoki M, Risteli J, Risteli L, Kauppila A. Type I and type III collagen metabolites and peritoneal cells in predicting the clinical outcome of epithelial ovarian cancer patients. Clin Cancer Res 1999;5:4091–6.

    CAS  PubMed  Google Scholar 

  44. Lara PN, Stadler WM, Longmate J, Quinn DI, Wexler J, Van Loan M, et al. A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases. Clin Cancer Res 2006;12(5):1556–63.

    Article  CAS  PubMed  Google Scholar 

  45. Seibel MJ, Lang M, Geilenkeuser WJ. Interlaboratory variation of biochemical markers of bone turnover. Clin Chem 2001;47:1443–50.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nuclear Medicine, 401 Army Hospital of Athens, Mesogeion & Kanellopoulou 1, 11525, Athens, Greece

    Athanasios Zafeirakis

  2. Clinical Research Unit, 401 Army Hospital of Athens, Athens, Greece

    Georgios Papatheodorou

  3. Department of Urology, 401 Army Hospital of Athens, Athens, Greece

    Athanasios Arhontakis

  4. Department of Radiology, Aretaieion University Hospital, Athens Medical School, Athens, Greece

    Athanasios Gouliamos & Lambros Vlahos

  5. Department of Nuclear Medicine, Aretaieion University Hospital, Athens Medical School, Athens, Greece

    Georgios S. Limouris

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  1. Athanasios Zafeirakis
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  2. Georgios Papatheodorou
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Correspondence to Athanasios Zafeirakis.

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Zafeirakis, A., Papatheodorou, G., Arhontakis, A. et al. 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 (2010). https://doi.org/10.1007/s00259-009-1243-5

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  • DOI: https://doi.org/10.1007/s00259-009-1243-5

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