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New Tools for the Urologist in the Management of Patients With Bone Metastases

New Tools for the Urologist in the Management of Patients With Bone Metastases. Bob Djavan , MD Department of Urology University of Vienna Vienna, Austria and NYU, New York. Hormone Therapy and Bone Mets: Current Issues. Limited resources for monitoring BMD during ADT

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New Tools for the Urologist in the Management of Patients With Bone Metastases

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  1. New Tools for the Urologist in the Management of Patients With Bone Metastases BobDjavan,MD DepartmentofUrologyUniversityofViennaVienna,AustriaandNYU,NewYork

  2. Hormone Therapy and Bone Mets:Current Issues • Limited resources for monitoring BMD during ADT • How to balance DEXA costs versus patient benefits? • Emerging evidence that early treatment of bone metastases is beneficial • Limited resources for bone metastasis screening • Limited resources for palliative strategies • Challenge lies in identifying patients who will benefit most from surveillance and early treatment

  3. ADT Significantly Increases Fracture Risks Increased Risk 1.21 Any fracture 21% 1.76 Hip fracture 76% 1.18 18% Vertebral fracture 2.4 2.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 0.2 Relative risk In favor of no ADT In favor of ADT N = 8,341 PC patients with no GnRH agonist N = 3,779 PC patientstreated with GnRH agonist Smith M, et al. J Urol. 2006;175:136-139.

  4. Fractures Negatively Correlate With Survival in Prostate Cancer 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 20 40 60 80 100 120 140 160 180 200 Overall Survival N = 195 Cumulative proportion surviving History of fracture No history of fracture (P = .04, log-rank) Months Adapted with permission from Oefelein MG, et al. J Urol. 2002;168:1005-1007.

  5. Recommendations Any fracture after minimal trauma • Treatment of osteoporosis to prevent further fracture • Zoledronic acid (ZA) • Pamidronate • Alendronate • Risedronate Ensure adequate calcium intake and correct vitamin status Confirm fracture on x-ray* Suspected vertebral fracture • Assess BMD • DEXA • Hip • Radius • Lumbar spine • Quantitative CT • Lumbar spine T-score ≤– 2.5 (osteoporosis) • Risk factors for fracture • ADT • Prior fracture Repeat BMDafter 6 to 12 months T-score –1.0 to – 2.5 (osteopenia) T-score> –1.0 Repeat BMDafter 2 years *Rule out pathologic fracture from bone metastases. Adapted from Diamond TH, et al. Cancer. 2004;100:892-899.

  6. Can Bone Loss Increase the Risk of Metastasis?Bone Metastasis Model Orchiectomy or sham surgery (day 0) PC-3 (human prostate cancer cell line) 4 weeks postsurgery BMD Radiography Bone histology Padalecki SS, et al. Presented at: ASBMR 2002. Abstract SU072.

  7. Androgen Deprivation Increases Bone Metastases in an Animal Model P < .05 Tumor area, mm2 Sham Orch Orchiectomy Sham surgery Padalecki SS, et al. Presented at: ASBMR 2002. Abstract SU072.

  8. Zoledronic Acid Delays Metastasis to Bone in Patients with Solid Tumors Bone-metastases–free survival (BMFS) 1.2 N = 40 12-month BMFS rate Zoledronic acid60% Control10% Log-rank P < .0005 Zoledronic acid 1.0 YES NO 0.8 Cumulative percent, % 0.6 0.4 0.2 0 0 10 20 30 40 50 Bone-metastases–free interval, months Mystakidou, et al. Med Oncol. 2005;22:195-201.

  9. Hormone therapy and bone loss • Bone loss during ADT can result in fractures • Potentially debilitating or life-limiting • New monitoring and treatment recommendations help optimize use of bisphosphonate therapy and DEXA • In addition to reducing fracture risk, reductions in bone metabolism may lower the risk of metastasis to bone • Further studies are needed

  10. How do bone metastases affect the course of advanced prostate cancer?

  11. Higher %PABS Correlates with Higher Mortality • Retrospective analysis of patients with advanced PC (N = 56) • Pretreatment radionuclide bone scans reviewed and %PABS quantified • Cox proportional hazard model variables • %PABS • Serum alk phos levels • Tumor grade • Number of bone lesions PABS = Positive area on bone scan. N = 56.Noguchi M, et al. Br J Cancer. 2003;88:195-201.

  12. Higher %PABS Correlates with Higher Mortality Relative risk of death compared with respective control group (univariate) 2.603 2.6-fold PABS ≥ 4.6% P = .0016 5.65 2.452 2.5-fold Alk Phos > 467 P = .0027 2.222 5.43 2.2-fold P = .0044 ≥ 14 Bone lesions 2.153 2.2-fold 4.82 P = .0044 Poor tumor grade 4.54 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 Relative risk Higher risk of death Lower risk of death In a multivariate model, %PABS was the only significant variable.PABS = Positive area on bone scan. N = 56.Noguchi M, et al. Br J Cancer. 2003;88:195-201.

  13. Conclusions • Bone mets add to the total tumor burden • Reducing the skeletal burden by treating bone mets may improve patient outcome • This is consistent with the trend for improved survival in Study 039 • Similar results have been reported for other solid tumors

  14. Bone Metastases :When?Who is at risk?

  15. Prostate Cancer Relapse or Recurrence • Biochemical parameters (eg, PSA kinetics) • Imaging technologies for detection • Nomograms to predict risk of disease recurrence • Guidelines for diagnostic work-up of recurrent PC • How/who to screen for bone metastases

  16. Nomogram for Risk of Recurrence After Initial Surgery 10 20 30 40 50 60 70 80 90 100 0 Points Preop PSA 0.1 0.2 0.3 0.5 0.7 1 2 3 4 6 8 10 100 4 6 8 10 Gleason Sum 5 3 7 9 Inv. Capsule Established Pros. Cap. Inv. None Focal Pos Surgical Margins Neg Yes Seminal Ves. Invasion No Pos Lymph Nodes Neg Total Points 0 40 80 120 160 200 240 280 84-Month Recurrence Free Prob. 0.99 0.98 0.95 0.9 0.8 0.7 0.5 0.3 0.1 0.01 With permission from Kattan M, et al. J Clin Oncol. 1999;17:1499-1507.

  17. NCCN Guidelines for Refractory PC • IfpatienthasthefollowingafterRRP • FailuretoachieveundetectablePSAlevel • RisingPSA • PositiveDREorpost-radiotherapyrisingPSAinacandidateforlocaltherapy • Consideronsalvagework-up • BoneScan • Biopsy • CT/MRI • ProstaScint RPA = Radical prostatectomy; PSA = Prostate-specific antigen; DRE = Digital rectal examination. National Comprehensive Cancer Network, Inc. NCCN Clinical Practice guidelines in Oncology™ Prostate Cancer. Version 1. 2007. Available at: http://www.nccn.org.

  18. Imaging Techniques

  19. 99TC-MDP Full-Body Bone Scan

  20. Imaging Techniques for Bone Mets Multi-FOV SPECT 99 TC-MDP Bone Scan 18F PET Posterior Anterior 82 yr-old PC patient With permission from Even-Sapir E, et al. J Nucl Med. 2006;47:287-297.

  21. Imaging Techniques for Bone Mets SPECT CT 18F PET Image fusion With permission from Even-Sapir E, et al. J Nucl Med. 2006;47:287-297.

  22. How are bone metastases treated?

  23. NCCN Guidelines • If patient with blastic bone mets and/or other mets has disease that has relapsed after initial ADT • Try second-line hormonal therapy or adding an antiandrogen; discontinue antiandrogen for relapse while on LHRH agonist + antiandrogen • After clinical assessment: • Bisphosphonate treatment for prevention of SREs • Systemic chemotherapy (docetaxel-based preferred) • Supportive care • Systemic radiotherapy: samarium or strontium ADT = Androgen-deprivation therapy; LHRH = Luteinizing hormone-releasing hormone; SREs = Skeletal-related events. National Comprehensive Cancer Network, Inc. NCCN Clinical Practice guidelines in Oncology™ Prostate Cancer. Version 1. 2007. Available at: http://www.nccn.org.

  24. BAUS Guidelines Bone metastases inpatient with HRPC Zoledronic acid Asymptomatic Symptomatic Spinal instability Monitoring Palliation Orthopedicinterventions Analgesics Radiotherapy NSAIDs Radiation Radionuclides Local/Wide field 89Sr/186Re/188Re/153Sm The British Association of Urological Surgeons. Available at: http://www.doctoronline.nhs.uk.

  25. WHO/ICUD Guidelines • Routine nuclear bone scans for staging patients with PC • Patients treated with ADT should have baseline and periodic bone densitometry scans to assess BMD for fracture risk • Consider bisphosphonate therapy if BMD decreases • Bone scan if PSA increases twice consecutively after therapy • An IV bisphosphonate (zoledronic acid) should be prescribed for HRPC patients with bone mets Nelson WG. New therapeutic targets and treatments for metastatic prostate cancer. In: McConnell J, et al. Prostate Cancer: 6ht International Consultation on New Developments in Prostate Cancer and Prostatic Diseases. Paris, France, 2006: 309-346.

  26. Bone Health Monitoring and Treatment Summary • Bone mets can contribute significantly to the disease burden • Effects on QOL, mortality • Prevention of fractures can preserve patients’ autonomy and may improve survival • Need to monitor and maintain bone health • EAU, BAUS, NCCN, and WHO/ICUD: clear consensus on use of IV bisphosphonates • Early diagnosis of bone metastases may allow for more effective treatment

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