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Risk Factors for the Development of Bone Metastases in Prostate Cancer

This article discusses the risk factors for the development of bone metastases in prostate cancer and provides recommendations for bone scans and PSA measurements. It also explores the relationship of serum PSA and alkaline phosphatase levels with bone metastases.

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Risk Factors for the Development of Bone Metastases in Prostate Cancer

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  1. Risk Factors for the Development of Bone Metastases in Prostate Cancer Daniel P. Petrylak Columbia-Presbyterian Medical Center

  2. Questions to Urologists Treating Patients With Early PC • Should bone scans be performed at baseline? • What are risk factors for bone metastases? • How can bone health be maintained in PC patients? • Bone metastases • Bone mineral density

  3. Should bone scans be performed at baseline?

  4. Recommendations suggest that bone scans be performed on patients with chronic bone painor fracture Current Guidelines for Bone Scans in Patients With PC EAU = European Association of Urology; NCCN = National Comprehensive Cancer Network ; ESMO = European Society for Medical Oncology; PSA = Prostate-specific antigen; N/A = Not applicable. *Patients with life expectancy > 5 years or symptomatic disease.1. Aus G, et al. Eur Urol. 2005;48:546-551; 2. NCCN Clinical Practice Guidelines in Prostate Cancer V.1.2007; 3. ESMO Guidelines Task Force Ann Oncol. 2005;16:i34-i36.

  5. Current Guidelines for PSA Measurementsin Patients With PC EAU = European Association of Urology; NCCN = National Comprehensive Cancer Network; PSA = Prostate-specific antigen. *Patients with life expectancy > 10 years.1. Aus G, et al. Eur Urol. 2005;48:546-551; 2. NCCN Clinical Practice Guidelines in Prostate Cancer V.1.2007.

  6. Prostate-Specific Antigen (PSA) Levels May Predict Positive Bone Scans After Local Therapy for PC • Bone metastases are more common in patients withhigh PSA levels1 • Radionuclide bone scans are recommended when serum PSA level is > 20 µg/L after local therapy • Retrospective study of 96 patients with prostate cancer with (n = 29) and without (n = 67) bone metastases2 • Retrospective study of 406 patients with prostate cancer who received bone scans irrespective of their serum PSA levels3 • Retrospective study of protocol-specified bone scans and PSA data from 4,061 patients randomized to standard therapy within the Early Prostate Cancer program4 1. Salonia A, et al. Urology. 2006;68:362-366; 2. Wang ZL and Wang XF. 2005;11:825-827; 3. Klatte T, et al. Urologe A. 2006;45:1293-1299; 4. Chodak GW, et al. Presented at: AUA 2005; Abstract 1003.

  7. Relationship of Serum PSA and Alkaline Phosphatase Levels With Bone Metastases in Patients With PC • Methods • Retrospective study of 96 cases of PC with (n = 29) and without (n = 67) bone metastases • Baseline levels of serum PSA and ALP were assessed and a radionuclide bone scan was performed • Results • The median concentrations of serum PSA and ALP were statistically higher in patients with bone metastases (P < .01) • The percentage of bone-scan positive patients was higher in patients with PSA > 20 g/L or ALP > 90 U/L than in patients with PSA < 20 g/L or ALP < 90 U/L • Conclusions • Patients with bone metastases from PC have higher levels of PSA and ALP than those without • Radionuclide bone scans are recommended when serum PSA > 20 g/L or ALP > 90 U/L Wang ZL and Wang XF. Zhonghua Nan Ke Xue. 2005;11:825-827.

  8. Relationship of Serum PSA and Alkaline Phosphatase Levels With Bone Metastases in Patients With PC • Methods • Retrospective study of 406 patients who had received a staging bone scan irrespective of their PSA serum level and histology • Current guidelines and recommendations were evaluated, cost analyses were performed, and classification systems for bone metastases were reviewed • Results • The bone scan was positive in 41 (10%) of 406 patients • EAU guidelines were useful with respect to clinical value and cost efficiency • The Rigaud classification of bone metastases predicted outcome better than the Soloway or Crawford classification systems • Conclusions • According to the EAU guidelines supported by the authors, a bone scan should be performed in patients with PSA levels > 20 ng/mL with a G1/G2 histology and in patients with G3 histology and locally advanced disease irrespective of PSA level Klatte T, et al. Urologe A. 2006;45:1293-1299.

  9. PSA Levels as a Predictor of Positive Bone Scans During Follow-up After Standard Care for Prostate Cancer • Methods • Early Prostate Cancer (EPC) program investigation into the optimal PSA level for recommending a bone scan following local therapy for PC • Data from protocol-specified bone scans and PSA reports from 4,061 patients randomized to standard care alone within the EPC program • Results • 5,048 bone scans were included in this analysis • The incidence of positive bone scans was low in patients with PSA < 5 ng/mL or < 20 ng/mL (in patients managed by watchful waiting) and in patients who have undergone radical prostatectomy or radiotherapy • Conclusions • In the absence of other clinical indicators, bone scans are not indicated when PSA level is < 5 ng/mL in patients who have undergone radical prostatectomy or radiotherapy, and < 20 ng/mL in patients managed by watchful waiting Chodak GW, et al. Presented at: AUA 2005; Abstract 1003.

  10. What are risk factors for bone metastases in asymptomatic biochemically relapsed PC patients?

  11. Natural History of Bone Metastasis Failing ADT: Insight From a Clinical Trial • Purpose • Randomized placebo-controlled trial to evaluate the effects of zoledronic acid on time to first bone metastasis in men with nonmetastatic prostate cancer • Trial was terminated early because of low event rate, and the placebo group was studied to describe the natural history of prostate cancer • Patients and Methods • Patients had nonmetastatic prostate cancer and castrate testosterone levels at study entry, documentation of PSA progression (3 serial increases), no radiographic evidence of bone metastases • Bone scans were obtained every 4 months ADT = Androgen-deprivation therapy; PSA = Prostate-specific antigen. Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

  12. Natural History of Rising Serum Prostate-Specific Antigen in Men With Castrate Nonmetastatic PC SD = Standard deviation; PSA = Prostate-specific antigen; ADT = Androgen-deprivation therapy. Adapted with permission from Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

  13. At 2 years, 42% of patients had developed bone metastases or died 33% of patients had developed ≥ 1 bone metastasis 21% of patients had died Median bone metastasis-free survival was 907 days Two-Year Analysis of Bone Metastases and Survival 1.0 Death Bone metastasis Bone metastasis or death 0.8 0.6 Proportion of patients with an event 0.4 0.2 0 0.5 1.0 1.5 2.0 2.5 3.0 0 Years since random assignment Adapted with permission from Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

  14. High Baseline PSA Levels and PSA Velocity Are Significant Risk Factors for Shorter Time to First Bone Metastasis P value Univariate analysis 2.96 < .001 Baseline PSA > 10 ng/mL 1.47* High PSA velocity < .001 Multivariate analysis 3.18 Baseline PSA > 10 ng/mL < .001 1.50* High PSA velocity < .001 0 1 2 3 4 5 6 7 *For each log (ng/mL)/year increase in PSA velocity. Data from Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

  15. Higher PSA Levels and Shorter PSA Doubling Time Are Associated With Shorter Metastasis-Free Survival 1.0 PSA < 7.7 ng/mL PSA 7.7 - 24.0 ng/mL PSA > 24.0 ng/mL 1.0 PSADT < 6.3 months PSADT 6.3 - 18.8 months PSADT > 18.8 months 0.8 0.8 0.6 0.6 Proportion of patients with bone metastases or died Proportion of patients with bone metastases or died 0.4 0.4 0.2 0.2 0 0 0 0.5 1.0 1.5 2.0 2.5 3.0 0 0.5 1.0 1.5 2.0 2.5 3.0 Years since random assignment Years since random assignment PSADT = PSA doubling time. Adapted with permission from Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.

  16. How can bone health be maintained in prostate cancer patients? Bone metastases Bone mineral density

  17. Bone health of men with prostate cancer is at risk throughoutthe disease course Patients With Prostate Cancer Have Many Factors That Can Erode Bone Health Advancing disease Average3 - 5 years PSA begins to rise again Recurrent disease Restage patient Initiate chemotherapy Check forbone metastases Average7 years PSA begins to rise Localized disease Hormone therapyinitiated (generally nobone metastases) Check for cancertreatment-inducedbone loss (baseline BMD and risk factors) Radiation New patient; PSA rising Watchful waiting Surgery Radiation Check for age-relatedbone loss Adapted with permission from Crawford ED. Eur Urol. 2004;3(suppl.):10-15.

  18. Patients With PC May Benefit From Early Bisphosphonate Therapy • Patients with PC develop primarily osteoblastic lesions, but these lesions are associated with increased osteolytic activity and increased bone resorption • Bone metastases can lead to painful and debilitating SREs • Do patients with hormone-sensitive prostate cancer benefit from bisphosphonate therapy?

  19. Early Bisphosphonate Treatment May Provide Greater Clinical Benefit to Patients With HSPC • Patients with at least 1 bone metastasis from prostate cancer (N = 308) received IV zoledronic acid 4 mg every 4 weeks for 15 months • In patients with HSPC, PSA < 2 ng/mL, and no previous treatment with chemotherapy (n = 29), 2 (6.9%) had at least 1 SRE on study 65/283 n = 2/29 Wirth M, et al. Presented at: ESMO 2006; Abstract 457P.

  20. Prospective Data Are Needed to Determine the Optimal Role of Bisphosphonates in Patients With HSPC • CALGB-90202 • Phase III randomized trial of zoledronic acid for the prevention of skeletal-related events in patients with prostate cancer and bone metastases undergoing ADT

  21. How can bone health be maintained in prostate cancer patients? Bone metastases Bone mineral density

  22. ADT Decreases BMD1 and Increases Fracture Risk2 50 2 40 1 0 30 –1 – ADT (n = 13) + ADT (n = 15) –2 20 –3 10 –4 –5 0 0 1 2 3 4 5 6 7 8 9 12-month analysis P < .001 +ADT Fracture incidence, % patients Change from baseline, % Lumbar spine Total hip –ADT Years 1. Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661; 2. Daniell HW. J Urol. 1997;157:439-444.

  23. Bisphosphonates May Provide Benefits to Patients With HSPC by Preventing BMD Loss During ADT 1. Bruder JM, et al. J Clin Densitom. 2006;9:431-437; 2. Smith MR, et al. N Engl J Med. 2001;345:948-955; 3. Casey R, et al. Presented at: European Association of Urology 2006; Abstract 136; 4. Smith MR, et al. J Urol. 2003;169:2008-2012.

  24. Conclusions • PSA and AP levels correlate with risk for positive bone scans in patients with newly diagnosed or biochemically relapsing HSPC • Absolute PSA level and PSA doubling-time in non-metastatic HRPC can identify high-risk patients • Bisphosphonates may preserve bone health during ADT and in patients with metastatic HSPC

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