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The role of the urologist in the treatment of bone metastases in genito -urinary tumours

The role of the urologist in the treatment of bone metastases in genito -urinary tumours. Theo M. de Reijke MD PhD FEBU Department of Urology Academic Medical Center Amsterdam, The Netherlands. Which genito-urinary tumours ?. Renal Bladder Prostate. 100. 80. 60. 40. 20. 0.

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The role of the urologist in the treatment of bone metastases in genito -urinary tumours

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  1. The role of the urologist in the treatment of bone metastases in genito-urinary tumours Theo M. de Reijke MD PhD FEBU Department of Urology Academic Medical Center Amsterdam, The Netherlands

  2. Whichgenito-urinarytumours? • Renal • Bladder • Prostate

  3. 100 80 60 40 20 0 “Osteophylic” cancers Incidence of bone metastases from autopsy series (%) Prostate Breast Thyroid Bladder Cervix Other Lung Kidney

  4. Role of urologist • Gatekeeper • Diagnosing • Leads multidisciplinary team • Discusses treatment modalities

  5. Role of urologist • Gatekeeper • Diagnosing • Leads multidisciplinary team • Discusses treatment modalities

  6. At first diagnosis, identification of bone metastases is essential to define the treatment strategy Localised Advanced Metastatic • Metastatic disease is treated by systemic therapy • Underdetection of M+ will • Expose patient to unjustified side-effects • Deprive patients from adapted systemic therapy • Localized and locally advanced disease are best treated by local therapies (surgery/RT) ± adjuvant therapy

  7. Diagnosis - Novel biochemical markers

  8. Diagnosis - Imaging • Plain radiography • Bone scintigraphy • SPECT • PET • MRI

  9. Prostate cancer is one of the most “osteophylic” cancers • Present at diagnosis in 5-25% of the patients in countries where PSA is used routinely • 1st cause of morbidity and mortality • > 90% osteoblastic • Most are axial

  10. Systemic progression of Pca occurs first in bone in a majority of patients. Nelson et al. Results of a phase III randomized controlled trial of the safety and efficacy of atrasentan in men with non-metastatic hormone-refractory prostate cancer (HRPC). Journal of Clinical Oncology, 25 (18S), 2007: A5018

  11. What is the problem in imaging? Tc-99m bone scan • Bone metastases are routinely diagnosed and followed-up by Tc-99m bone scan. • Tc-99 oxidronate is a marker of osteoblastic activity, not a marker of bone invasion. • Frequently requires X-Rays, CT or MRI to clarify inconsistent reading • There is a delay between bone involvement and TC-99m conversion

  12. Tc99m bonescan grossly underestimates TTP in metastatic PCa Patient enrolled in a RCT with Rank-L inhibitor Courtesy of B. Tombal

  13. Tc99m bonescan grossly underestimates TTP in metastatic PCa Patient enrolled in a RCT with Rank-L inhibitor + 3 months Courtesy of B. Tombal

  14. Tc99m BS grossly underestimates TTP in metastatic PCa Patient enrolled in a RCT with Rank-L inhibitor + 6 months Courtesy of B. Tombal

  15. Role of urologist • Gatekeeper • Diagnosing • Leads multidisciplinary team • Discusses treatment modalities

  16. Painful metastases • Surgery • Radiotherapy • Nuclear medicine

  17. Orthopedicstabilization

  18. Orthopedicstabilization

  19. Painful metastases • Surgery • Radiotherapy • Nuclear medicine

  20. Oosterhof et al Eur Urol 44:519-526, 2003

  21. Phase III ALSYMPCA results: OS Radium-223 (n=541) 100 Placebo (n=268) 80 60 % Median OS Δ: 2.8 months 40 20 0 0 3 6 9 12 15 18 21 24 27 Month Parker C, et al. Presented at EMCC 2011. Stockholm, Sweden. September 24, 2011.

  22. Role of urologist • Gatekeeper • Diagnosing • Leads multidisciplinary team • Discusses treatment modalities

  23. Adverse effects of ADT • Hot flashes • Loss of libido • Fatigue • Anemia • Obesity • Sarcopenia • Diabetes • CV disease • Osteoporosis/fractures National Osteoporosis Foundation (www.nof.org) CV, cardiovascular

  24. Estimated number needed toharm for fractures Shahinian et al N Engl J Med 352: 154–64, 2005

  25. What treatment options are available? • Bisphosphonates • Inhibit recruitment/differentiation of osteoclast precursors and attachment/survival of mature osteoclasts1,2 • Standard of care for prevention of SREs in men with PCa and bone metastases before denosumab approval2 • SERMs • Inhibit osteoclast-mediated bone resorption3 • RANKL inhibitors • Inhibits the action of RANKL – the key driver in osteoclast formation, function and survival4 • Denosumab is the only approved treatment for ADT-related bone loss5,6 RANKL, receptor activator of nuclear factor kappa-B ligand; SERM, selective oestrogen receptor modulatorSRE, skeletal-related event1. Lee et al ClinGenitourin Cancer 8:29-36, 2010 2. Rogers et al Cancer 80(8 Suppl):1652-60, 1997 3. Michael et al Br J Pharmacol151:384-95, 2007 4. Castellano et al Oncologist 16:136-45, 20115. Amgen 2011. www.amgen.com/media/media_pr_detail.jsp?releaseID=1607920;6. Amgen 2010. www.amgen.com/media/media_pr_detail.jsp?releaseID=1432232

  26. Therapeutic area is characterized by an exciting portfolio in bone targeted therapies • Bisphosphonates • Zoledronate • Clodronate • Ibandronate • Rank-L inhibitor • Denosumab • Endothelin R inhibitor • Atrasentan • ZD4054

  27. Bisphosphonates for the relief of painsecondary to bone metastases • 30 randomized, controlled studies • N=3682 Evidence for some pain relief Insufficient evidence to recommend as first line therapy Insufficient evidence for most effective BP Reserve as second line therapy Wong & Wiffen The Cochrane Library, 2004

  28. Renal Cell Cancer: Percent of patients with each SRE Zoledronic acid consistently reduces all types of SREs

  29. Denosumabfracture prevention study Denosumab q6 months for 3 years R A N D O M I Z E Current ADT forprostate cancer; Age >70 or T score <-1.0 (n=1,468) Placebo q6 months for 3 years • Primary Endpoint: change in lumbar spine BMD • Key Secondary Endpoint: new vertebral fractures Smith et al N Engl J Med 361:745–55, 2009

  30. Denosumab increased BMD at all skeletal sites Smith et al N Engl J Med 361:745–55, 2009

  31. Practical recommendations ̶ Osteoporosis Screening • BMD testing for all men on ADT • Test at baseline, after 1 year of ADT, then every 2 years Treatment • Supplemental calcium (≥1,200 mg daily) and vitamin D (800–1,000 IU daily) for all • Drug therapy if age ≥50 and any of: • Personal history of hip or vertebral fracture, OR • T-score ≤−2.5 at the femoral neck or spine, OR • WHO algorithm: • 10-year probability of a hip fracture ≥3% OR • 10-year probability of a major osteoporosis fracture ≥20% Saylor et al J Gen Intern Med 24(Suppl 2):S389–94, 2009

  32. WHO/FRAX risk assessment http://www.shef.ac.uk/FRAX/

  33. Denosumab for the treatment ofbone metastases Denosumab 120 mg sc q 4 weeks R A N D O M I S E Castrate-resistantPCa and bone metastasis; No prior bisphosphonate (n=1,904) Zoledronic acid 4 mg ivq 4 weeks • Primary endpoint: time to first SRE Fizazi et al Lancet 377:813-822, 2011

  34. Denosumab significantly prolongs time to first on-study SRE Fizazi et al Lancet 377:813-822, 2011

  35. Current treatment options for advanced PCa MDV3100 (H2: 2012) Custirsen (H1: 2013) Ipilimumab (H1: 2013) TAK-700 (H2: 2013) Alpharadin XL-184 2nd Line Therapy Jevtana (approved June 2010) Zytiga (approved April 2011) Afibercept (H2: 2012) Sprycel (H1: 2013) Revlimid (H2: 2013) Custirsen (H1: 2014) 1st Line Chemotherapy Taxotere Ipilimumab (H1: 2014) MDV3100 (H2: 2014) TAK-700 (H2: 2014) PROSTVAC (H1: 2015) Provenge (Approved April 2010) mCRPC Estrogen (off-label) Non-Metastatic CRPC (Secondary Hormone Therapy) Ketoconazole (off-label) Casodex Combined Androgen Blockade LHRH agonists / GnRH antagonist Androgen Deprivation Therapy (ADT) Surgery and Radiation GnRH, gonadotropin releasing hormone; LHRH, luteinizing hormone-releasing hormone; PCa, prostate cancer

  36. A suggested treatment paradigm for mCRPC • Clinical trial (preferred) • Observation • Secondary HT Progression to M1 M0 CRPC Maintain castrate testosterone levels • Abiraterone • Cabazitaxel • Salvage chemotherapy • Docetaxel rechallenge • Mitoxantrone • Other secondary HT • Clinical trial • Docetaxel • Mitoxantrone • Abiraterone (2B) • Palliative RT • Clinical trial Symptomatic Denosumab or zoledronic acid (bone metastases) M1 CRPC • Sipuleucel-Ta • Secondary HT • Clinical trial Asymptomatic aApproved in US only All recommendations Category 1 or 2A unless specified (1, high-level evidence;2A, lower-level evidence; 2B, lower-level evidence and non-uniform NCCN consensus) HT, hormonal therapy; NCCN, National Comprehensive Cancer Network PSA, prostate-specific antigen;RT, radiotherapyNCCN Guidelines™ Prostate Cancer, v4.2011, www.nccn.org/professionals/physician_gls/f_guidelines.asp

  37. The role of the urologist in the treatment of bone metastases in genito-urinary tumours • The urologistshouldbe gatekeeper • Provided he/she has knowledge on • different treatments • Multidisciplinary approach is essential

  38. Thankyouforyour attention

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