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High Risk disease is defined as “apparent localized cancer that has a high propensity of micro-metastatic disease” (cancer that is not visible on convention radiography, such as bone and CT ...

High Risk disease is defined as “apparent localized cancer that has a high propensity of micro-metastatic disease” (cancer that is not visible on convention radiography, such as bone and CT scans). These cancers, once removed via radiation or surgery, are likely to "return," but in fact, they were never removed in the first place because the cancer cells were outside the treated region.

Therefore, successful eradication of high risk disease requires both aggressive local control and systemic treatment with androgen deprivation therapy and extended field radiation. This lecture will review the most up-to-date data on dose-intensity radiation therapy, pelvic radiation, surgery with adjuvant radiation, and adjuvant hormone therapy. Finally, data on experimental chemotherapy and abiraterone (Zytiga) will be presented.

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  • This sets the theme for this talk which is multimodality therapy is standard and that surgery is an inferior approac
  • 1 st Group References: 1. Bahn, D et al. Targeted Cryoablation of the Prostate:7-year Outcomes in the Primary Treatment of Prostate Cancer. Urology 2002;60(Supp 2A):3-11. 2. Burri, R et al. Young Men have Equivalent Biochemical Outcomes Compared with Older Men After Treatment with Brachytherapy for Prostate Cancer. Int J Radiat Oncol Bio Phys 2010;77(5):1315-21. 3. (Open) 4. Bittner, N et al. Primary Causes of Death After Permanent Prostate Brachytherapy. Int J Radiat Oncol Bio Phys 2008;72(2):433-440. 5. Boorjian, S et al. Mayo Clinic Validation of the D'Amico Risk Group Classification for Predicting Survival Following Radical Prostatectomy. J Urology 2008;179:1354-1361. 6. Carver, B et al. Long Term Outcome following Radical Prostatectomy in Men with Clinical T3 Prostate Cancer. J Urology 2006;176:564-568. 7. Cohen, J et al. Ten-Year Biochemical Disease Control in Patients with Prostate Cancer Treated with Cryosurgery as Primary Therapy. Urology 2008;71(3):515-518. 8. Critz, F et al. 10-year Disease Survival Rates After Simultaneous Irradiation for Prostate Cancer with a Focus on Calculation Methodology. J Urology 2004;172:2232-2238. 9. Galalae, R et al. Long-term Outcome by Risk Factors Using Conformal High-Dose-Rate Brachytherapy (HDR-BT) Boost with or without Neoadjuvant Androgen Suppression for Localized Prostate Cancer . Int J Radiat Oncol Bio Phys 2004;58(4):1048-1055. 10. Kollmeier, M et al. Biochemical Outcomes After Prostate Brachytherapy with 5-year Minimal follow-up: Importance of patient Selection and implant Quality. Int J Radiat Oncol Bio Phys 2003;57(3):645-653. 11. Kuban, D et al. Long-Term Multi-Institutional Analysis of Stage T1-T2 Prostate Cancer Treated with Radiotherapy in the PSA Era. Int J Radiat Oncol Biol Phys 2003;57(4):915-928.(PSA:4-10,GS:2-6,>70 Gy) 12. Kuban, D et al. Long-Term Results of the MD Anderson Randomized Dose-Escalation Trial for Prostate Cancer. Int J Radiat Oncol Bio Phys 2008;70(1):67-74. 13. (Open) 14. (Open) 15. Loeb, S et al. Intermediate-term potency, continence & survival outcomes of radical prostatectomy for clinically high-risk or locally advanced prostate cancer . Urology 2007;69(6):1170-1175. 16. Merrick, G et al. A ndrogen deprivation therapy does not impact cause specific overall survival after permanent prostate brachytherapy. Int J Radiat Oncol Bio Phys 2006;65(3):669-77. (EBRT, Seeds, ADT) 17. Merrick, G et al. Androgen deprivation therapy does not impact cause specific overall survival after permanent prostate brachytherapy. Int j Radiat Oncol Bio Phys 2006;65(3):669-77. (EBRT & Seeds) 18. Merrick, G et al. Prognostic Significance of Perineural Invasion on Biochemical Progression-free Survival after Prostate Brachytherapy . Urology 2005;66(5):1048-1053. 19. Merrick, G et al. Impact of Supplemental External Beam Radiotherapy and/or Androgen Deprivation Therapy on Biochemical Outcome After Permanent Prostate Brachytherapy. Int J Radiat Oncol Bio Phys 2005;61(1):32-43. (EBRT & Seeds) 20. Merrick, G et al. Impact of Supplemental External Beam Radiotherapy and/or Androgen Deprivation Therapy on Biochemical Outcome After Permanent Prostate Brachytherapy. Int J Radiat Oncol Bio Phys 2005;61(1):32-43. (EBRT, Seeds, ADT) 21. Mian, B et al . Outcome of Patients w/ Gleason score 8 or Higher Prostate Cancer following Radical Prostatectomy alone . J Urology 2002;167:1675-1680. 22. Pellizzon, A et al . The Relationship Between the Biochemical Control Outcomes and the Quality of Planning of HDR as a Boost to External Beam Radiotherapy for locally and locally advanced Prostate Cancer using the RTOG-ASTRO Phoenix definition. Int J Med Sci 2008;5:113-120. 23. Stokes, S et al. Comparison of biochemical disease-free survival of patients with localized carcinoma of the prostate undergoing radical prostatectomy, transperineal ultrasound-guided radioactive seed implantation, or definitive external beam irradiation Int J Radiat Oncol Bio Phys 2000;47(1):129-136. (EBRT) 24. Potters, L et al. 12-Year Outcomes Following Permanent Prostate Brachytherapy in Patients With Clinically Localized Prostate Cancer. J Urology 2005;173:1562-1566. 25. Stokes, S et al. Comparison of biochemical disease-free survival of patients with localized carcinoma of the prostate undergoing radical prostatectomy, transperineal ultrasound-guided radioactive seed implantation, or definitive external beam irradiation Int J Radiat Oncol Bio Phys 2000;47(1):129-136. (RP) 26. Sylvester, J et al. Ten Year Biochemical Relapse Free Survival After External Beam Radiation and Brachytherapy for Localized Prostate Cancer: The Seattle Experience. Int J Radiat Oncol Bio Phys 2003;57(4):944-952. 27. (Open) 28. (Open) 29. Thames, H et al. Increasing External Beam Dose for T1-T2 Prostate Cancer: Effect on Risk Groups. Int J Radiat Oncol Bio Phys 2006; 65(4):975-981. 30. Ward, J et al. Radical Prostatectomy for Clinically Advanced (cT3) Prostate Cancer since the advent of PSA testing: 15 year outcome. BJU Int 2005; 95:751-6. 31. Zelefsky, M et al. Multi-Institutional Analysis of Long-Term Outcome for T1-T2 Prostate Cancer Treated with Permanent Seed Implantation. Int J Radiat Oncol Bio Phys 2007;67(2):327-333. 32. Zelefsky, M et al. Long Term Outcome of High Dose Intensity Modulated Radiation Therapy for Patients With Clinically Localized Prostate Cancer. J Urology 2006;176:1415-19. (81 Gy) 33. Zelefsky, M et al. Long-term Results of Conformal Radiotherapy for prostate Cancer: Impact of Dose Escalation in Biochemical Tumor control and distant Metastases-free Survival Outcomes. Int j Radiat Oncol Bio Phys 2008;71(4):1028-33. (81 Gy) 34. Zelefsky, M et al. Long-term Results of Conformal Radiotherapy for prostate Cancer: Impact of Dose Escalation in Biochemical Tumor Control and distant Metastases-free Survival Outcomes. Int j Radiat Oncol bio Phys 2008;71(4):1028-33. (86 Gy) 35. Zelefsky, M et al. High Dose Radiation Delivered by Intensity Modulated Conformal Radiotherapy Improves the Outcome of Localized Prostate Cancer. J Urology 2001;166:876-881. (75 Gy) 36. Zelefsky, M et al. High Dose Radiation Delivered by Intensity Modulated Conformal Radiotherapy Improves the Outcome of Localized Prostate Cancer. J Urology 2001;166:876-881. (81 Gy) 37. Dattoli, M et al. Long-term Outcomes After Treatment with Brachytherapy and Supplemental Conformal Radiation for Prostate Cancer Patients Having Intermediate and High-Risk Features. Cancer 2007;110(3):551-555. 38. Moyad, M et al. Statins, especially Atorvastatin, may Favorable Influence Clinical Presentation and Biochemical Progression-free Survival after Brachytherapy for Clinically Localized Prostate Cancer. Urology 2005;66(6):1150-1154. 39. Zelefsky, M et al . Long Term Outcome Following Three dimensional Conformal/IMRT for Clinical Stage T3 Prostate Cancer. Eurr Urol 2008; 53:1172-79. 40. (Open) 41. Galalae R et al. Hypofractionated Conformal HDR Brachytherapy in Hormone Naïve Men with Localized Prostate Cancer . Strahlenther Onkol 2006;182(3):135-141. 42. Demanes, DJ et al. Excellent Results from High Dose Rate Brachytherapy and External Beam Radiation Therapy for Prostate Cancer are Not Imroved by Androgen Deprivation. Amer J Clin Oncol 2009;32(4):342-347. 43. Stock, R et al. Outcomes for patients with High-Grade Prostate Cancer Treated with a Combination of Brachytherapy, EBRT and Hormone therapy. BJU Int 2009;104:1631-1636. 44. Stone, N et al . Local Control following Permanent Prostate Brachytherapy: Effect of High Biologically Effective Dose on Biopsy Results and Oncologic Outcomes. Int J Radiat Oncol Bio Phys 2010;7 6(2):355-360. 45. Bittner, N et al. Whole Pelvis Radiotherapy in Combination with Interstitial Brachytherapy: Does Coverage of the Pelvic Lymph Nodes Improve Treatment Outcome in High Risk Prostate Cancer? Int J Radiat Oncol Bio Phys 2010;76(4):1078-1084. 46. Rubio-Briones, J et al . Metastatic Progression, Cancer Specific Mortality and Need for Secondary Treatments in Patients with Clinically High Risk Prostate Cancer Treated Initially with Radical Prostatectomy. Actas Urologicas Esanolas 2010; 34(7):610-617. 47. Dattoli, M et al . Long Term Outcomes for Patients with Prostate Cancer Having Intermediate and High Risk Disease, Treated with Combination External Beam Irradiation and Brachytherapy. J Oncology 2010;2010(Article Id 471375):6 pages. 48. Menon, M et al . Biochemical Recurrence Following Robot Assisted Radical Prostatectomy: Analysis of 1384 patients with a median 5 year follow-up. Eurr Urol 2010;58:838-46. 49. Pierorazio, P et al. Long Term Survival after Radical Prostatectomy for Men with High Gleason Sum in Pathologic Specimen. Urology 2010;76(3):715-21. 100. (Open) 101. Deger, S et al . (Germany) High Dose Rate (HDR) Brachytherapy with Conformal Radiation Therapy for Localized Prostate Cancer. Eurr Urology 2005;47:441-448. 102. Magheli A et al . (Johns Hopkins) Importance of Tumor Location in Patients with High Preoperative PSA Levels ( greater than 20 ng/ml treated with Radical Prostatectomy . J Urology 2007;178:1311-15. 103. Kupelian P, et al. Improved Biochemical Relapse-Free Survival With Increased Radiation Doses in Patients With Localized Prostate Cancer: The Combined Experience of Nine Institutions in 1994 and 1995. Int J Radiat Oncol Bio Phys 2005;61(2):415-419. 104. Sylvester, J et al. 15-Year Biochemical Relapse Free Survival in Clinical Stage T1-T3 Prostate Cancer Following Combined External Beam Radiotherapy and Brachytherapy: Seattle Experience. Int J Radiat Oncol Bio Phys 2007;67(1):57-64. 105. Hinnen, K et al. (Netherlands) Long Term Biochemical and Survival Outcome of 921 Patients Treated with I-125 Permanent Prostate Brachytherapy. Int J Radiat Oncol Biol Phys 2010; 76(5):1433-1438. 106. Hsu, C et al . Comparing Results After Surgery in Patients with Clinical Unilateral T3a Prostate Cnacer Treated with or without neoadjuvent Androgen-Deprivation Therapy . BJU Int 2006;99:311-314. 107. Roehl, K et al. Cancer Progression and Survival Rates Following Anatomical Radical Prostatectomy in 3,478 Consecutive Patients: Long Term Results. J Urology 2004;172:910-914. 108. Merrick, G et al. Prostate Cancer Death is Unlikely in High Risk Patients Following Quality Permanent Seed Implantation. BJU Int 2010;107:226-233. (No ADT) 109. Merrick, G et al. Prostate Cancer Death is Unlikely in High Risk Patients Following Quality Permanent Seed Implantation. BJU Int 2010;107:226-233. (Plus ADT) 2 nd Group References: 50. Aizer A, et al. Radical Prostatectomy vs Intensity-Modulated Radiation Therapy in the Management of Localized Prostate Adenocarcinoma. Radiotherapy and Oncology 2009;93:185-191. 51. Battermann J , et al . Results of permanent prostate brachytherapy, 13 years of experience at a single institution. Radiotherapy & Oncology 2004;71:23-28. 52. Berglund R, et al. Limited Pelvic Lymph Node Dissection at the Time of Radical Prostatectomy Does Not Affect 5-Year Failure Rates for Low, Intermediate and High Risk Prostate Cancer: Results From CaPSURE. J Urology 2007;177:526-530. 53. Beyer D, et al. Relative influence of gleason score and pretreatment PSA in predicting survival following brachytherapy for prostate cancer . Brachytherapy 2003;2:77-84. 54. Cahlon O, et al. Ultra high dose (86.4Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int J Radiat Oncol Bio Phys 2008;71(2):330-337. 55. Copp H, et al. Tumor Control Outcomes of Patients Treated With Trimodality Therapy For Locally Advanced Prostate Cancer . Urology 2005;65(6):1146-1151. 56. Crouzet S , et al . Multicentric Oncologic Outcomes of High-Intensity Focused Ultrasound for Localized Prostate Cancer in 803 patients. Eurr Urol 2010;58:559-566. 57. Demanes D, et al. High-Dose-Rate Intensity Modulated Brachytherapy With External Beam Radiotherapy for Prostate Cancer: California Endocurietherapy's 10-Year Results. Int J Radiat Oncol Bio Phys 2005;61(5):1306-1316. 58. Donohue J, et al. Poorly Differentiated Prostate Cancer Treated With Radical Prostatectomy: Long-Term Outcome and Incidence of Pathological Downgrading. J Urology 2006;176(3):991-995. 59. Ellis R, et al. Biochemical disease free survival rates following definitive low-dose-rate prostate brachytherapy with dose escalation to biologic target volumes identified with SPECT/CT capromab pendetide. Brachytherapy 2007;6:16-25. 60. Freedland S, et al. Radical Prostatectomy for Clinical Stage T3a Disease . Cancer 2007;109(7):1273-1278. 61. Henry A, et al. Outcomes Following Iodine-125 Monotherapy for localized Prostate Cancer: The results of Leeds 10-year single-center brachytherapy experience . Int J Radiat Oncol Bio Phys 2010;76(1):50-56. 62. Hernandez D, et al . Contemporary Evaluation of the D’Amico risk classification of Prostate Cancer. J Urol 2007;70(5):931-935. 63. Hong S, et al . Predictions of Outcomes after Radical Prostatectomy in Patients Diagnosed with Prostate Cancer of Biopsy GS > 8 via Contemporary multi ( > 12)-core prostate biopsy. BJU Int 2011;108(2):217-222. 64. Hull G, et al. Cancer control with radical prostatectomy alone in 1000 consecutive patients. J Urology 2002;167:528-534. 65. Khaksar S, et al. Interstitial low dose rate brachytherapy for prostate cancer-a focus on intermediate & high risk disease. Clinical Oncology 2006;18:513-518. 66. Khuntia D, et al. Recurrence-free survival rates after external-beam radiotherapy for patients with clinical T1-T3 prostate carcinoma in prostate specific antigen era . Cancer 2004;100(6):1283-1292. 67. Koontz B, et al. Morbidity and Prostate Specific Antigen Control of External Beam Radiation Therapy plus Low Dose Rate Brachytherapy Boost for Low ,Intermediate and High Risk Prostate Cancer. Brachytherapy 2009;8:191-196. 68. Kupelian P , et al . Hypofractionated Intensity-Modulated Radiotherapy (70Gy at 2.5Gy per fraction) for Localized Prostate Cancer: Cleveland Clinic Experience. Int J Radiat Oncol Bio Phys 2007; 68(5):1424-1430. 69. Kwok Y, et al. Risk Group stratification in patients undergoing permanent I-125 prostate brachytherapy as monotherapy. Int J Radiat Oncol Bio Phys 2002;53(3):588-594. 70. Lederman G, et al. Retrospective Stratification of a Consecutive Cohort of Prostate Cancer Patients Treated with a Combined Regimen of External-beam Radiotherapy and Brachytherapy. Int J Radiat Oncol Bio Phys 2001;49(5):1297-1303. 71. Lee L, et al. Role of Hormonal therapy in the management of intermediate to high risk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Bio Phys 2002;52(2):444-452. 72. Liauw S, et al. Dose-escalated radiotherapy for hight-risk prostate cancer: outcomes in modern ear with short termandrogen deprivation therapy. Int J Radiat Oncol Bio Phys 2010;77(1):125-130. 73. Livsey J, et al. Hypofractionated Conformal Radiotherapy in Carcinoma of the Prostate: five-Year Outcome Analysis. Int J Radiat Oncol Bio Phys 2003;57(5):1254-1259. 74. Nobes J, et al. Biochemical Relapse-Free Survival in 400 Patients Treated with I-125 Prostate Brachytherapy: the Guildford Experience. Prostate Ca & Prostatic Disease 2009;12:61-66. 75. Phan T, et al. High dose rate brachytherapy as a boost for the treatment of localized prostate cancer. J Urology 2007;177:123-127. Prada P, et al. High-dose-rate intensity modulated brachytherapy with external-beam radiotherapy improves local and biochemical control in patients with high risk prostate cancer. Clin Transl Oncol 2008;10:415-421. Sathya J, et al. Randomized Trial comparing Iridium implants plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate. J Clin Oncol 2005;23(5):1192-1199. Stock, R. et al. Combined Modality Treatment in the Management of High Risk Prostate Cancer . Int J Radiat Oncol Bio Phys 2004;59(5):1352-1359. Stone N, et al. Multicenter Analysis of Effect of High Biologic Effective dose on Biochemical Failure and Survival Outcomes in Patients with Gleason 7-10 Prostate cancer Treated with Permanent Prostate Bracyhhterapy. Int J Radiat Oncol Bio Phys 2009;73(2):341-346. Stone N, et al. Customized dose Prescription for Permanent Prostate Brachytherapy: Insights From a Multicenter Analysis of Dosimetry Outcomes. Int J Radiat Oncol Bio Phys 2007;69(5):1472-1477. Yamada Y, et al. Favorable Clinical Outcomes of 3-D Computer Optimized High Dose Rate Prostate Brachytherapy in the management of Localized Prostate cancer. Brachytherapy 2006;5:157-164. Yossepowitch O, et al . Radical Prostatectomy for Clinically Localized High Risk Prostate Cancer: Critical Analysis of Risk Assessment Methods. J Urology 2007;178:493-499. (Def. #1) Yossepowitch O, et al . Radical Prostatectomy for Clinically Localized High Risk Prostate Cancer: Critical Analysis of Risk Assessment Methods. J Urology 2007;178:493-499. (Def. #2) Yossepowitch O, et al . Radical Prostatectomy for Clinically Localized High Risk Prostate Cancer: Critical Analysis of Risk Assessment Methods. J Urology 2007;178:493-499. (Def. #3) Zwahlen D , et al. High Dose Rate Brachytherapy in Combination with Conformal External Beam Radiotherapy in the Treatment of Prostate Cancer. Brachytherapy 2010;9:27-35. D’Amico A, et al. Biochemical outcomes after Radical Prostatectomy or External Beam Radiation Therapy for patients with clinically localized prostate carcinoma in the Prostate Specific Antigen Era. Cancer 2002;95(2):281-286. (RP) D’Amico A, et al. Biochemical outcomes after Radical Prostatectomy or External Beam Radiation Therapy for patients with clinically localized prostate carcinoma in the Prostate Specific Antigen Era. Cancer 2002;95(2):281-286. (EBRT) Stokes S, et al. Comparison of biochemical disease-free survival of patients with localized carcinoma of the prostate undergoing radical prostatectomy, transperineal ultrasound-guided radioactive seed implantation, or definitive external beam irradiation. Int J Radiat Oncol Bio Phys 2000;47(1):129-136. (seeds) Yossepowitch O, et al . Radical Prostatectomy for Clinically Localized High Risk Prostate Cancer: Critical Analysis of Risk Assessment Methods. J Urology 2007;178:493-499. (Def. #4)

DrLam HighRiskProstateCancer(Azure) Presentation Transcript

  • 1. Richard Lam, MDProstate Oncology Specialists September 8 2012
  • 2. Definition: High-RiskLocalized cancer with a high likelihood of microscopic spread and therefore relapse.CT and bone scans are normal.High-risk features (any one of the below)  PSA > 20  Gleason score = 8-10  Stage > T2b  Two or three Intermediate-Risk FactorsAn even more serious form of High-Risk:  Any Gleason grade 5 (Gleason score 9 or 10)  Seminal vesicle invasion  Pelvic lymph node metastases diagnosed at surgery
  • 3. Examples of High Risk Prostate CancerT1c, Gleason 4+5= 9, PSA=6.0T3, Gleason 4+3=7, PSA=18.0 The differing profile of High Risk disease in research studies is highly era-dependent and continues to be a problem in comparing treatment outcomes today. Trend for High Risk category today is lower volume disease but high grade
  • 4. High Risk Cancer DemographicsApproximately 15% of the 220,000 men who are diagnosed annually (33,000 men) are High-RiskCancer specific mortality at 10 years for High-Risk disease averages between 5% and 15%There is some consensus among experts about treatment: 1. Treat aggressively 2. Radiation + Androgen Deprivation Therapy (ADT) is generally better than Prostatectomy alone
  • 5. Staging Studies: High RiskStandard: Bone Scan to look for possible bone metastasis CT scan (or MRI ) of abdomen and pelvis to look for possible abdominal and pelvic node metastasesNew Methods (not approved): Endorectal MRI to evaluate for possible seminal vesicle invasion C-11 PET scan Na-Fluoride bone scan
  • 6. Advanced Disease
  • 7. Treatment for High Risk Disease: Multi-pronged AttackSurgery Add Radiation? Add Androgen Deprivation Therapy? Lymph Node Dissection? Add new drugs (abiraterone?)External Beam Radiation Therapy Add Androgen Deprivation Therapy? Add Brachytherapy (Seeds)? Add Chemotherapy?
  • 8. Surgery or Radiation Head-to-Head No good studies exist directly comparing the 2 treatments.  Mostly retrospective single institution studies.  Radiation patients are usually less healthy (ie not surgery candidates).  Surgery patients often get radiation after surgery.  Radiation patients often get ADT.  Surgical and radiation techniques constantly improving (moving target phenomenon).
  • 9. Surgery vs. Radiation for High-RiskArcangeli et al (RedJournal 75:975, 2009)  162 men EBRT + ADT vs. 122 men treated with RP (+/-EBRT)  3-year relapse rate was 13% for the radiation patients vs. 30% for the RP patients.Boojian et al (Cancer: 2883, 2011)  609 men RP vs. 344 men EBRT+ADT  88% of RP group received EBRT and/or ADT afterwards.  Prostate cancer deaths were equivalentAizer er al (GreenJournal 93:185, 2009)  204 men RP vs. 352 IMRT  In the high risk subset, PSA relapse free survival was 38.4% in RP group vs 62.2% in the IMRT +ADT group
  • 10. Are You Ready for Your Prostatectomy?
  • 11. 5-Year Surgery Relapse Rates for High-Risk # Patients % Relapsed Reference 110 55% Nguyen, J Urol 181:75, 2009 206 48% Yossepowitch, J Urol 178:493, 2007 957 32% Spahn, EurUrol 58:1 2010 712 35% Ward, BJU 95:751, 2005 1179 53% Matti, Eur Urol 53:118, 2008 188 29% Zwergel, Eur Urol 52: 1058, 2007 42% Average Relapse Rate @ 5 years
  • 12. Surgery Outcomes for Gleason 8-10 Disease Epstein, Urology 76:715, 20109300 men with median: PSA of 7.5 and stage T280% recurrence rate at 15 years70% had extra capsular diseaseAn even worse outcome was associated with any: Gleason grade 5 Seminal vesicle invasion Positive lymph nodesTake home message: Surgical cure rates are low withhigh Gleason score, especially when there is apalpable abnormality on digital rectal examination
  • 13. How to Improve Surgery Results?Androgen Deprivation (ADT)Radiation to the Prostate BedRadiation to the PelvisLymph node dissection
  • 14. Does ADT Improve Surgery Outcomes? Retrospective review by the Mayo Clinic suggested improved remission rates and survival (Zincke, JUrol 166: 2208, 2001) Two years of ADT consisting of Zoladex plus Casodex resulted in surprisingly low relapse rate in 481 men with High-Risk disease (Dorff, JCO 29:2040, 2011) Relapse rate @ 5 years was only 7.5% However, there is no prospective data supporting the routine use of ADT for all high risk patients after prostatectomy. Side Effects of ADT may negate the benefits.
  • 15. ADT after Surgery Improves Outcomes in Men with Lymph Node Metastasis98 Men with Positive Nodes Detected at Surgery: 47 Men received Immediate ADT 51 Men received Delayed ADT at relapseDeaths @ 7 years: 15% for ADT group vs 40%(Messing, NEJM, 341:1781, 1999)
  • 16. Radiation after ProstatectomyEORTC 22911 Trial first reported an advantange to immediate radiation vs wait-and-see approach (Bolla et al. Lancet 366: 572, 2005)  74% vs 52.6% 5-year relapse free survival.  Update in 2011 showed no survival benefit.  Only treat younger patients?  Treat immediately at PSA relapse (early salvage)?ARO 96-02 Trial (Wiegel et al. JCO 27: 2924, 2009)  72% vs 54% 5-year relapse free survival.SWOG-8794 Trial (Thompson et al. JUrol 181: 956, 2009)  72% vs 42% 10-yr relapse free survival.  Less metastasis with adjuvant radiation  Longer survival with adjuvant radiation: 15.2 vs. 13.3 years.
  • 17. Adjuvant Radiation Side EffectsEORTC 22911 Trial: used older radiation techniques  Grade 3 Urinary and Bowel Toxicities:  Radiation Grp: 4.2% vs. Observation Grp: 2.6%SWOG-8794 Trial: used older radiation techniques  Strictures:  Radiation: 17.8% vs. Observation: 9.5%  Rectal Complications:  Radiation: 3.3% vs. Observation: 0.0%ARO 96-02 Trial: used 3D conformal and IMRT radiation  Grade 3 Urinary and Bowel Toxicities: 0.3%Impotence>80%
  • 18. Extensive Lymph Node Removal May BeCurative for Small Volume Metastatic DiseaseBader (JUrol 2003; 169:849): If 1 lymph node involved, 39% remained cancer free at 45 months.Von Bodman (JUrol 2010; 184:143): If 1 lymph node involved, 79% was relapse free at 24 months.Side effects of extensive lymph node dissection More bleeding More scar tissue in the pelvis More leg swelling Longer operating time
  • 19. Rationale for Pelvic RadiationLymph nodes are the first place of cancer metastasisHistorically, pelvic radiation is incorporated as standard in all successful randomized prospective trials of High-Risk diseaseStill controversial Mack Roach showed improved disease free survival at 5 years with pelvic radiation Pascal Pommier showed no benefitModern IMRT radiation is far less toxic that older radiation technology
  • 20. Role of Pelvic Radiation after Surgery for High Risk Disease (Spiotto, IJROBP 2007)Retrospective Study at Stanford114 men with high risk disease 72 men underwent whole pelvis + prostate bed radiation 42 men underwent prostate bed radiation only5 year PSA relapse free survival 47% in whole pelvis radiation group 21% in prostate bed radiation only group
  • 21. Role of Pelvic Radiation after Surgery for High Risk Disease (Briganti, Eur Urol 2011)Retrospective study in Milan Italy364 men node positive after surgery 117 men had ADT plus pelvic radiation vs. 247 men had ADT only10-year cancer specific survival 86% pelvic radiation + ADT group 70% with ADT alone group
  • 22. ADT Plus Pelvic Radiation Roach, IJROBP 69:646, 20071500 patients randomized between pelvic radiation vs. no radiation.Also randomized between ADT for 4 months, starting 2 months before radiation vs. 4 months ADT starting after radiationMedian PSA was 22, 73% of men had Gleason 7 or more, 2/3 of men were stage T2c, T3 or T4Conclusion: Node radiation improved cure rates. However, the improvement was only seen when TIP was started 2 months before radiation
  • 23. Pelvic Radiation Ineffective? Pommier, JCO 25:5366, 2007444 patientsPelvic node radiation 46 Gy (instead of 50Gy)Smaller radiation field than the Roach studyInitial dose to prostate only 66 GyMany patients were NOT at high risk for relapseConclusion: No difference in cure rates at 5 years but study was seriously underpowered to detect a difference
  • 24. Toxicity from Node Radiation?Deville IJROBP 78:763, 2010 30 patients treated with IMRT 79 Gy 30 patient treated IMRT 79 Gy and 45 Gy to pelvis At 24 months no “late” GI or GU toxicityDeville IJROBP 82:1389, 2012 31 patients IMRT 70.2 Gy (to fossa after surgery) 36 patients IMRT 70.2 to fossa & 45 Gy to pelvis No significant difference in “late” toxicity at 25 months
  • 25. Is Surgery Appropriate for High Risk? Consider the following: If cure rates with surgery alone are poor… If men need radiation after surgery anyway… If men need ADT after surgery anyway… Why not skip prostatectomy and proceed straight to radiation?
  • 26. How to Improve Radiation Results for High Risk Disease?Radiation to the pelvisIncrease the dosage directed to the prostate via: Seeds Image-guided technologyAndrogen Deprivation Therapy (ADT) to treatsystemic diseaseChemotherapy (?)
  • 27. Rationale for Seed Implant BoostHigher dose, more conformal radiation treatment is attained when seed implant are added to EBRTStudies incorporating seed implant boost show excellent relapse free survival rates
  • 28. Sculpting Radiation Doses with Seeds
  • 29. Remission Rates with EBRT + HDR seedsMayo Clin Proc 83: 1364, 2008
  • 30. Remission Rates with EBRT + Seeds vs RPOncology 22: 995, 2008
  • 31. Remission Rates with EBRT + Seeds vs RPOncology 22: 995, 2008
  • 32. Very High Risk Disease Treated with Seeds + EBRT + ADT 131 patients, median age 68 yr.  T3  PSA > 40  Gleason 10  Gleason 8-9 with >50% + bx cores  Gleason 8-9 with PSA > 20 12 year results  Overall survival: 61%  Cause-specific survival: 88%  PSA progression free: 71% Cause of death  Prostate cancer: 8.3%  Heart disease: 22.2% *Bittner N, Merrick GS, Butler WM, et al. Brachytherapy 11(2012) 250-255
  • 33. Relapse Rates: High-Risk >40 months follow-up 65 81 20 20 16 16 45 109 109 Brachy 19 18 45 80 19 18 4 74 4 108 108 EBRT & ADT 78 38 22 22 67 67 17 55 75 EBRT & Seeds 72 54 85 43 76 43 37 37 72 54 34 34 44 32 32 47 47 Hypo EBRT 66 9 41 66 9 41 68 44 2 57 104 71 6436 68 71 6436 79 48 59 48 59 2 10 104 10 42 42 50 50 56 11 56 12 12 24 24 53 25 8 61 8 61 25 89 89 101 101 EBRT 62 106 62 106 70 70 33 21 33 21 5 39 5 39 11 11 60 60 103 103 83 7 82 26 83 7 82 26 35 35 63 66 Protonsss ecc uS t ne maer T 52 63 52 84 84 73 31 30 58 77 46 73 46 31 30 58 88 88 86 87 86 87 107 107 102 15 102 15 HDR t 51 51 105 105 EBRT Seeds + r g or P AS P % 23 29 Surgery 29 ← Years from 23 Treatment 69 69 49 49 ADT → Robot RP • Prostate Cancer Results Study Group HIFU • Numbers within symbols refer to references 09/14/12 40 Prostate Cancer Center of Seattle
  • 34. ADT + Radiation Better than Radiation AloneEORTC 22863 (Bolla et al. Lancet 11: 1066,2010) showed that adding 36 months of ADT to radiation resulted in: Less likelihood of dying from cancer at 10 years: 10% vs 30%. Improved overall survival: 58% vs 40%.D’Amico study (JAMA 292: 821,2004) showed that adding 6 months of ADT to radiation resulted in: Less likelihood of dying from cancer at 4 years: 0% vs 6%. Improved overall survival: 88% vs 78%. Intermediate risk
  • 35. ADT + EBRT is than EBRT AloneRTOG 94-08 (NEJM 365: 107,2011) showed that adding 4 months of ADT resulted in:  Less likelihood of dying from cancer at 9 years: 4% vs 8%.  Improved overall survival: 62% vs 57%.  Intermediate risk men.Pilepich study (RTOG 86-10) showed that adding 4 months of ADT resulted in:  Less likelihood of dying from cancer at 10 years: 23% vs 36%.  Bulky tumors.RTOG 92-02 (JCO 26: 2497, 2008) showed that 28 months was superior to 4 month for Gleason 8-10 cancers.  10-year survival was 45 vs 32 months.
  • 36. ADT Side Effects
  • 37. Common Side Effects Associated with Androgen Deprivation Therapy (ADT)Osteoporosis GynecomastiaAnemia DepressionHot flashes Memory LossLoss of Libido Weakness/FatiguePenile Atrophy Gastrointestinal ToxicityMuscle Wasting
  • 38. Adjuvant ChemotherapyRationale: Treat hormone resistant micro-metastatic cells while still vulnerable to eradicationProven benefit in other tumor types such as breast, colon and lung cancerEarly trials in the 1980-90’s for prostate cancer were negativeProblems: inadequate trial participation, inadequate medicines
  • 39. Adjuvant Chemotherapy StudiesMitoxantroneVinorelbine + EstramustineEtoposide + EstramustineDoxetaxelNab-PaclitaxelDoxetaxel + Capecitabine
  • 40. Adjuvant Mitoxantrone Wang, BJU 86:675, 200038 men with locally advanced diseaseAll given with Lupron / Flutamide indefinitely19 men randomly allocated to 4 cycles of mitoxantrone (this is the only randomized trial of adjuvant chemotherapy in existance)Kaplan-Meier survival curve shows significantly prolonged survival in the men administered mitoxantrone.Study was too small.
  • 41. Adjuvant Mitoxantrone Mitoxantrone No Mitoxantrone
  • 42. Adjuvant Taxotere Kibel, J Urol 177:1777, 200777 men treated with surgery most who had seminal vesicle invasion and high Gleason scoresThe median time to relapse for this group of patients based on their stage, Gleason score and PSA was predicted to be 10 months by a Kattan NomogramAll 77 men were administered weekly Taxotere for 6 mo.Actual median time to relapse was improved by 50% (to 15.7 months)
  • 43. Radiation + Hormones + Taxotere DiBiase IJROP 81:732,201142 patients 75 % grade 4 + 3 or higher Median PSA 17.8Treatment Pelvic radiation Brachytherapy boost Lupron for two years Weekly Taxotere for 3 monthsOutcome: 70% disease free after 7 years
  • 44. (Zelefsky et al, RedJournal 84: 125, 2012)
  • 45. AbirateroneAbiraterone is a potent, selective, and irreversible inhibitor of CYP17A1Blocking CYP17A1 further shuts down testosterone production“Super Lupron”
  • 46. Abiraterone 6 2 Testosterone Androstenedione 5 4 nmol/l ng/dl Lower limit of 3 sensitivity 1 No rise at 2 progression No rise at progression 1 0.07 0 01 Start of 10 20 60 70 At Start of 28 56 At treatment Days progression Days progression treatment 12.5 12.5 DHEA Estradiol 10.0 10.0 ρmol/lnmol/l 7.5 7.5 No rise at 5.0 progression 5.0 2.5 2.5 0 0 28 56 At 10 20 30 40 50 60 Start of treatment Days progression Days post treatment
  • 47. Abiraterone + ADT Pre-Prostatectomy29 men with high risk disease  All received abiraterone and Lupron for 24 weeks  All men then underwent prostatectomyBefore surgery, 26 men had a PSA < or =0.2At surgery  7 men (24%): <5mm of cancer in the removed prostate  3 men (10%): no cancer seen.This great response has never been reported.Provocative, but more studies needed.Taplin et al. JCO 30:2012 (abstr 4521)
  • 48. The Best Treatment for High-Risk is Multimodality TherapyLocal Therapy: Prostatectomy + Radiation Radiation + Seed Implant BoostRegional Therapy: Pelvic radiationSystemic Therapy: ADT for 2 years, to be started a couple months before radiation Chemotherapy in selected patients (investigational)