1. "Creating a Prostate Cancer Center of Excellence" Paul Sieber MD FACS Lancaster Urology

2. ADT Clinic Why 1. Consistency of care 2. Improved outcomes 3. Better economics What does it take 1. Discipline 2. Mid-level providers 3. Planning Who cares 1. Insurers 2. Patients How 1. Implementation

3. Bone Clinic

4. Journal of Urology February 1997 Osteoporosis after Orchiectomy for Prostate Cancer Harry W Daniell UC Davis, Department of Family Practice First article attributing orchiectomy with accelerated osteoporosis and questions risks to long term survivors.

5. ADT and Fracture Risk AuthorPopulation NFracture Incidence Time SmithPharmacy benefit 3779 15.1% 22 months OefeleinCommunity 181 20% 10 years Shahinian SEER 14,394 19.4 1-5 years Krupski Medicare 716 45.5% 7 years Melton Rochester 429 73% 15 years

6. ADT Is Associated With Fracture In men surviving at least 5 years after diagnosis: – Of those receiving ADT, 19.4% experienced a fracture – Of those NOT receiving ADT, 12.6% experienced a fracture – ADT resulted in an excess risk of fracture of 45% Shahinian VB, et al. N Engl J Med. 2005;352:154-164. No ADT (n = 32,931) GnRH agonist, 1–4 doses (n = 3763) GnRH agonist, 5–8 doses (n = 2171) GnRH agonist, 9 doses (n = 5061) Orchiectomy (n = 3399) Years After Diagnosis 23456789101 Unadjusted Fracture-Free Survival (%) 0 100 90 80 70 60 50 40 30 20 10 ADT-Related Fracture-Free Survival

7. Fractures in Men Receiving ADT and Survival Oefelein MG, et al. J Urol. 2002:168:1005-1007; Department of Health and Human Services. A report of the Surgeon General. 2004. 020406080100120140160180200 Months 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative Proportion Surviving History of fracture (n = 24) No history of fracture (n = 171) P = 0.04 In men receiving ADT for prostate cancer, median overall survival was reduced in those who sustained a skeletal fracture since diagnosis of prostate cancer (121 vs 160 months, P = 0.04) Skeletal fracture was a negative predictor of survival (Relative Death Risk = 7.4, P = 0.007)

8. Bone Clinic Protocol 1. All patients on ADT seen by mid- level at least yearly 2. All patients undergo DEXA 3. All patients have metabolic studies 4 All patients assessed/counseled for risk: FRAX,fall,glasses,smoking,EtOH consumption,calcium/vitamin D

9. Screening for Bone Loss DXA(Dual X-ray Absorptiometry) = Gold Standard Total hip, femoral neck and lumbar spine standard areas of interest Heel ultrasound, finger or forearm DXA, and quantitative CT other options but numerous weaknesses

10. Metabolic workup CMP, CBC, Vitamin D minimum Stone formers 24 hour urine Options; TSH, evaluate for GI malabsorption, Endocrine consult

12. TREATMENT DECISION 2 clinical trials with level 1 evidence of both BMD and fracture reduction Patient population included men 70 without regard to BMD NOF recommends treat osteoporosis follow FRAX for others What is risk level for osteopenics on ADT

13. BMD vs Fracture Rate & Incidence BMD

14. Minimum treatment Ensure adequate calcium/vitamin D intake 1200/800 Vitamin D >30 Reduce alcohol, smoking cessation, and weight bearing exercises Fall reduction strategies

15. Pharmacologic Therapy 1. Prolia-RANK ligand monoclonal antibody 2. Aledronate(Fosamax).Risedronate(Actone l) 2. Zoledronic acid(Zometa,Reclast) 2.Raloxifene(Evista) 3.? Teriparatide(Forteo) blackbox warning with radiation therapy 3. Calcitonin(Miacalcin) no data in men

16. Clinical Impact of Low Testosterone Levels: Two Peer-Reviewed Articles Perachino et al – BJUI. 2009 Morote et al – Urology. 2007

17. Testosterone Escapes Occur Frequently During LHRH Agonist Therapy Adapted from Morote J et al. J Urol. 2007;178:1290–5 Serum testosterone

18. Survival-Free of AIP According to Serum Testosterone Behavior Adapted from Morote J et al. J Urol. 2007;178:1290–5 Testosterone increases Group 1: <20 ng/dL Group 2: 20–50 ng/dL Group 3: >50 ng/dL 024487296120144168192216240 Months under ADT 0.0 0.2 0.4 0.6 0.8 1.0 Group 3 (72 months) Group 2 (90 months) P=0.0207 Group 1 (106 months) Cumulative survival free of PSA progression AIP, androgen-independent progression

19. Higher 6-Month Testosterone Levels Increase Risk of Death by 1.33 Times VariableCoefficient (SEM) Coefficient/SEMHazard ratio (95% CI) P value Age, years0.0359 (0.0200)1.795 1.037 (0.996–1.078) 0.08 Gleason score0.3301 (0.1002)3.295 1.391 (1.141–1.696) <0.01 Ln (6-month PSA level) 0.2690 (0.0492)5.468 1.309 (1.187–1.443) <0.01 (6-month testosterone) 2 0.2874 (0.1190)2.415 1.333 (1.053–1.687) <0.05 Predictors of survival probability (Cox regression model) Perachino M et al. B J U Int 2010; 105(5); 648-51 SEM, standard error of the mean; Ln, natural logarithm Goserelin 10.8 mg every 3 months; bone-only prostate cancer patients (N=117)

20. Bone Clinic ADT Clinic

21. Urologists Provided Most Overall Healthcare Services to Patients with Prostate Cancer Over the Course of Disease Progression 21 % Prostate Cancer Health Services Initial Care Continuing Care End of Life Care Overall Care *Medical oncology and hematology/oncology Internal medicine, family practice and general practice Skolarus 2010 J Urol 184:2279-2284 Initial care: first 12 months after diagnosis Continuing care: between initial and end of life End of life care: final 12 months of life Initial care: first 12 months after diagnosis Continuing care: between initial and end of life End of life care: final 12 months of life

22. Abbreviation: LHRH=luteinizing hormone-releasing hormone. Natural History of Prostate Cancer Typical presentation of patients as they move through the different stages. The line represents level burden of disease. Time is not proportional Under the care of ONCOLOGIST Castration Sensitive Asymptomatic Non Metastatic Castration Resistant Metastatic Symptomatic Local Therapy Androgen Deprivation Therapies After LHRH Agonists and Antiandrogen Chemotherapy Post Chemo Death

23. New Paradigms 1.Bone Agents Xgeva ?Radium 223 2. Provenge 3. Abiraterone 4. Enzulutamide

24. Metastatic Disease Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. Yu EY J Urol July 2012 Yu EY 31% of men with apparent M0 disease were M1

25. Bone Metastasis Denosumab and bone-metastasis-free survival in men with castration- resistant prostate cancer: results of a phase 3, randomised, placebo- controlled trial. Smith MR et al Lancet Jan 2012 396 23% of men with apparent MO disease were M1

26. Provenge Survival Baseline PSA <22.1>22.1-50.1>50.1- 134.1 >134.1 Provenge OS41.3mon27.1mon20.4mon18.4mon Control OS28.3mon20.1mon15.0mon15.6mon Chodak G ASCO 2012 Abstract 4648

27. Prior SRE Associated with Greater Risk of Subsequent SRE Saad F Clin GU Cancer 5:390-6

28. ADT Clinic Bone Clinic plus 1. ROS for side effects 2. Additional labs include annual CBC,CMP,HgbA1c,Lipid profile 3. PSA doubling time if appropriate 4. Update to PCP

29. Keys to Success Physician champion Motivated mid-level as well Group Buy-in Make it easy for group members

30. William Penn Liberty without discipline equals chaos Discipline without liberty equals slavery