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Radiation Recurrent Prostate Cancer: Give Your Patients A Curative Treatment  Option

Radiation Recurrent Prostate Cancer: Give Your Patients A Curative Treatment  Option. Dr. Timothy C. Goodson Arkansas Urology, P.A. Radiorecurrent PCa Patient Population. 2. ?. Secondary Treatment 70% | 58,000 patients. Androgen Deprivation Therapy 90% | 22,500 patients 2,4.

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Radiation Recurrent Prostate Cancer: Give Your Patients A Curative Treatment  Option

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  1. Radiation Recurrent Prostate Cancer:Give Your Patients A Curative Treatment  Option Dr. Timothy C. Goodson Arkansas Urology, P.A.

  2. Radiorecurrent PCa Patient Population 2 ? Secondary Treatment 70% | 58,000 patients Androgen Deprivation Therapy 90%| 22,500 patients2,4 Radiorecurrent PCa Patients 60% | ~ 82,000 patients per year1 Radiation Therapy ~ 137,170 patients per year1,4 A total of > 400,000 men or ~ 3% of Medicare’s male population in the U.S. were prescribed ADT for PCa.5 Received Secondary Treatment 30%| 25,000 patients3 1. Agarwal P.K., Sadetsky A. and Carroll P.R. et. al. Treatment Failure After Primary and Salvage Therapy for Prostate Cancer. Likelihood, Patterns of Care and Outcomes. CANCER 2008;2: 307-314. 2. Grossfeld G.D., Li Y.P. and Carroll P.R. et.al. Predictors of Secondary Cancer Treatment in Patients Receiving Local Therapy for Prostate Cancer. Data from Cancer of the Prostate Strategic Urologic Research Endeavour. J Uro 2002; 116:5226-34. 3. and 4. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. EurUrol 2011, 411-412. 5. Gilbert, S., Kuo, Y., & Shahinian, V. Prevalent and Incident Use of Androgen Deprivation Therapy Among Men with Prostate Cancer in the United States. UrolOncol. 2011; 29: 647–53. Other Therapies 10% | 2,500 patients

  3. 3 Radiorecurrent PCa Patient Population • Currently, there is no consensus on when and how to detect and cure local recurrence of prostate cancer after failed RT. • Data from the CaPSURE database stated that: • 63% of prostate cancer patients who undergo radiation therapy as first line treatment for their prostate cancer will experience PSA recurrence within 10 years. • Every year ~45,000 men with prostate cancer in the USA will have a recurrence after definitive primary RT, manifested initially as an asymptomatic, increasing serum PSA level. Kimura M., Mouraviev V. and PolascikT.J. et. al. Current Salvage Methods for Recurrent Prostate Cancer after Failure of Primary Radiotherapy. BJUI 2009. 191-201.

  4. 4 Treatment Options for Recurrence after Radiation • Androgen Deprivation • Additional Radiation (i.e. Brachytherapy) • Surveillance • Salvage Radical Prostatectomy • Salvage High-Intensity Focused Ultrasound (HIFU) • Salvage Cryotherapy

  5. Use of ADT Among the Male Medicare Population 5 Analysis suggests more than 400,000 men (about 3% of the male Medicare population) in the U.S. were prescribed hormonal treatment for prostate cancer. Gilbert, S., Kuo, Y., & Shahinian, V. Prevalent and Incident Use of Androgen Deprivation Therapy Among Men with Prostate Cancer in the United States. Urol Oncol. 2011; 29: 647–53.

  6. 6 NCCN 2011 Guidelines: Hormone therapy is not endorsed for prostate biopsy-positive, non-metastatic local recurrences NCCN 2011 Guidelines Version 1.2012 Prostate Cancer

  7. 7 • NCCN Guidelines 2011 on androgen deprivation therapy (ADT) for clinically localized disease stated that1: • Adjuvant ADT given after completion of primary treatment is not a standard treatment at this time with the exception of high-risk patients treated with radiation therapy. • Low volume, high grade prostate cancer may warrant adjuvant ADT for 4-6 month but 2-3 year may be considered. • The side effects of continuous ADT increased with the duration of treatment. • The FDA (Food and Drug Administration) in 2010 issued a warning about the link between hormonal therapy and heart disease and diabetes in prostate cancer patients2. 1. NCCN 2011 Guidelines Version 1.2012 Prostate Cancer. 2. FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases. October 20, 2010.

  8. Radiorecurrent PCa Patient Population 8 ? Secondary Treatment 70% | 58,000 patients Androgen Deprivation Therapy 90%| 22,500 patients2,4 Radiorecurrent PCa Patients 60% | ~ 82,000 patients per year1 Radiation Therapy ~ 137,170 patients per year1,4 A total of > 400,000 men or ~ 3% of Medicare’s male population in the U.S. were prescribed ADT for PCa.5 Received Secondary Treatment 30%| 25,000 patients3 1. Agarwal P.K., Sadetsky A. and Carroll P.R. et. al. Treatment Failure After Primary and Salvage Therapy for Prostate Cancer. Likelihood, Patterns of Care and Outcomes. CANCER 2008;2: 307-314. 2. Grossfeld G.D., Li Y.P. and Carroll P.R. et.al. Predictors of Secondary Cancer Treatment in Patients Receiving Local Therapy for Prostate Cancer. Data from Cancer of the Prostate Strategic Urologic Research Endeavour. J Uro 2002; 116:5226-34. 3. and 4. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. EurUrol 2011, 411-412. 5. Gilbert, S., Kuo, Y., & Shahinian, V. Prevalent and Incident Use of Androgen Deprivation Therapy Among Men with Prostate Cancer in the United States. UrolOncol. 2011; 29: 647–53. Other Therapies 10% | 2,500 patients

  9. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. EuUrol 2011; 60: 411-412. 9 • Radiorecurrent prostate cancer is the 4th most common genitourinary cancer after primary PCa, Bladder Cancer and Kidney Cancer. • More than 90% of patients undergoing secondary therapy following radiation are treated with ADT in the CaPSURE database populationdespite: • A total lack of evidence for efficacy for ADT • The growing understanding of its own morbidity • The complete inability of ADT to cure patients who often have local recurrences that are amenable to curative local therapy • Radiorecurrentprostate cancer is often veiled by ADT which suppresses PSA level but has absolutely no chance of cure. • Covering up radiorecurrentPCa by hormones is a disservice to the growing number of men who have a potential for cure.

  10. Side Effects of Hormonal Therapy1 10 • Hot Flashes  • Bone Loss- ↑risk osteoporosis, ↑risk of fracture • Weight gain • Loss of muscle mass • Sexual side effects: ↓ libido, erectile dysfunction • Breast enlargement  • Cardiovascular side effects  • Adverse effects on lipid profile (↑cholesterol , ↑ TG) • Effect on insulin/glucose regulation  ↑fasting insulin levels • Anemia – androgens promote erythropoiesis • Cognitive impairment Schwandt A. and Garcia J.A. Complications of Androgen Deprivation Therapy in Prostate Cancer. Curr Opinion in Urol 2009; 19: 322–6. 2. FDA Drug Safety Communication: Update to Ongoing Safety Review of GnRH Agonists and Notification to Manufacturers of GnRH Agonists to Add New Safety Information to Labeling Regarding Increased Risk of Diabetes and Certain Cardiovascular Diseases. October 20, 2010.

  11. Salvage Options with Curative Intent 11 • Radiation Therapy • High-intensity Focused Ultrasound (HIFU) • Radical Prostatectomy • Cryotherapy

  12. Salvage Brachytherapy 12 • Clinical Outcomes: • The 5 year bDFS after salvage BT is broadly 20-70%.1 • Overall survival 54%-94%.2 • Disease-specific survival 74%-100%. 2 • Complications1: • Grade 3-4 genitourinary toxicities 13% (range from 0-47%) as a late complication. • Grade 3-4 gastrointestinal toxicities 5% (range 0-20%), including rectal ulcers and colostomy for rectal bleeding. • Prostatic-rectal fistula 3.4% (range from 1-12%) • Incontinence rates 4% (range 0-29%) Kimura M., Mouraviev M. and Polascik T.J. et al. Current Salvage Methods for Recurrent Prostate Cancer after Failure of Primary Radiotherapy. BJUI 2010; 105(2): 191-201. 2. Ramney S.J. and Marshall D.T. Re-irradiation for Salvage of Prostate Cancer Failures after Primary Radiotherapy. World J Urol 2012. (Ahead of print)

  13. 13 Salvage HIFU • Only few studies have been conducted in salvage setting. • Largest published salvage HIFU series (Murat et al 2009) • 167 patients • 3 year progression-free survival 53%, 42%,25% for L,I,H risk. • Complications: • Rectourethral fistula: 3 - 16% • Urinary incontinence: 10 - 50% • Retention due to urethral stricture: 18% • Erectile dysfunction: 66 - 100% • HIFU has a higher incidence of complications than salvage cryotherapy and brachytherapy. Murat F.J., PoissonnierL. and Gelet A. et al. Mid-term Results Demonstrate salvage HIFU as an Effective and Acceptably Morbid Salvage Treatment Option for Locally Radiorecurrent Prostate Cancer. EurUrol2009; 55(3): 640- 7.

  14. Salvage Radical Prostatectomy 14 • NCCN 2011 Guidelines stated that: • Salvage Radical prostatectomy (RP) is an option for highly selected patients with local recurrence after EBRT, brachytherapy, or cryotherapy in the absence of metastases, but the morbidity (incontinence, loss of erection, anastomotic stricture) is high.1 • Salvage RP is technically challenging. High volume surgeons in high volume centers generally provide better outcomes.2 • Clinical Outcomes: • 10-year bDFS rate 30-43%.3 • 10-year cancer-specific survival rates 70-77%.3 • Biopsy-proven local recurrence is between 20% to 40%.4 • Several salvage RP series reported 80% of patients have extraprostatic extension.5 • Only 25% of surveyed urologists and radiation oncologists would recommend salvage RP to a patient between 45-65 years with definitive local recurrence after RT. 3 1. and 2. NCCN 2011 Guidelines Version 1.2012 Prostate Cancer. 3. Kimura M., Mouraviev V. and Polascik T.J. et. al. Current Salvage Methods for Recurrent Prostate Cancer after Failure of Primary Radiotherapy. BJUI 2009. 191-201. 4. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. EurUrol 2011, 411-412. 5. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.

  15. Better Understanding of Salvage Cryotherapy 15 • Well-defined patient selection criteria on salvage cryotherapy: • AUA 20081 and 2009 Best Practice Guidelines.2 • NCCN 2011 Guidelines. • More clinical data is now available on salvage cryotherapy: • Salvage cryotherapy is a potential cure compared to hormones.3 • More data on lack of side-effects of cryoablation. • Advances in cryoablation technology (3rd generation). • Medicare approved salvage cryotherapy in 2001. • More data on side-effects of hormones.4 BabaianR.J., Donnelly B. and Thrasher J.B. et. al. Best Practice Statement on Cryosurgery for the Treatment of Localized Prostate Cancer. The Jour of Urol, 2008; 180: 1993-2004. Prostate-Specific Antigen Best Practice Statement: 2009 Update. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211. SchwandtA. and Garcia J.A. Complications of Androgen Deprivation Therapy in Prostate Cancer. Curr Opinion in Urol 2009; 19: 322–6.

  16. 2008 AUA Best Practice Statement of Cryosurgery 16 Well-Defined Patient Selection Criteria1: • PSA<10 ng/mL • A PSA doubling-time >16 months or more • At least a 10-year life expectancy • Absence of seminal vesicle invasion • A positive biopsy and a negative metastatic evaluation 1. Babaian R.J., Donnelly B. and Thrasher J.B. et. al. Best Practice Statement on Cryosurgery for the Treatment of Localized Prostate Cancer. The Jour of Urol, 2008; 180: 1993-2004.

  17. 17 Patient Selection Criteria for Salvage Cryotherapy Rising PSA after radiation therapy: • How long ago was the primary procedure? • How high is the PSA? • How fast is PSA increasing? (PSA doubling time) • Difficult to justify salvage cryotherapyif PSA >10ng/ml Biopsy proven recurrence: • Unilateral or bilateral disease ? • Often high grade. Number of cores involved • Biopsy proximal portion of each seminal vesicle • Is patient eligible for a focal salvage procedure? Work-Up: • IPSS and IIEF scores • Rectal examination • Transrectal USS assessment Staging investigations: • Endorectal MRI (unless brachytherapy was performed) • CT abdomen-pelvis / pelvic lymphadenopathy • Bone scan

  18. Predictors of Salvage Success 18 • The best predictor identified so far is PSA1. • PSA<10 ng/mL = most likely to be effective. • Even better results if PSA< 5ng/mL2. • Cryotherapy is cytocidal without regard to tumor differentiation2. • Highly differentiated cancer may still be cured even if radiation was not successful and if the persistent disease is localized to an area suitable for cryo2. The Key Issue Early Intervention is Key. Salvage therapy must be administered before cancer advances beyond where local treatment can reach. • Wenske S., Quarrier S., Katz AE. Salvage Cryosurgery of the Prostate for Failure After Primary Radiotherapy or Cryosurgery: Long-term Clinical, Functional, and Oncologic Outcomes in a Large Cohort at a Tertiary Referral Centre. Eu Urol. 2012. Ahead of Print. • Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. EurUrol 2011, 411-412. • Williams AK and Chin JL. Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven • Radio-Recurrent Prostate Cancer. E Urology 2011; 60: 405-410. • 4. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer • Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.

  19. Benefits of Salvage Cryotherapy 19 • Potentially curative without the side effect of hormones • Low side effect profile compared to salvage surgery • Usually single treatment. Repeatable if necessary • Regional anesthesia • No major blood loss • Salvage (nerve sparing) procedure is possible • Minimal postoperative discomfort • Very low risk of DVTs , PEs, urinary sepsis • Patients with co-morbidities tolerate procedure • No steep trendelenburg • Patients with LUTs who are not suitable for brachy • Can treat extracapsular disease • Caution re TURP + radiation + cryo patients

  20. Growing Body of Data on Salvage Cryotherapy 20 • 5-year bDFSsurvival 50%-70% (3rd generation technology).1 • Complications1: • Perineal pain: 4-14% • Mild-moderate incontinence: 6-13% • Severe incontinence: 2-4% • Urinary retention: 2-21% • Rectourethral fistula formation: 1-2% • Urinary incontinence: <1% • Erectile function can be preserved using nerve sparing techniques.2 • Local control is high with only 17.6% positive post salvage biopsy.3 • The ability to freeze beyond the capsule into periprostatic tissues (including proximal portions of the seminal vesicles) is a recognized advantage of cryotherapy.4 Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211. Wenske S., Quarrier S., Katz AE. Salvage Cryosurgery of the Prostate for Failure After Primary Radiotherapy or Cryosurgery: Long-term Clinical, Functional, and Oncologic Outcomes in a Large Cohort at a Tertiary Referral Centre. Eu Urol. 2012. Ahead of Print. Williams AK and Chin JL. Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven Radio-Recurrent Prostate Cancer. E Urology 2011; 60: 405-410. Jones J.S. Radiorecurrent Prostate Cancer: An Emerging and Largely Mismanaged Epidemic. EurUrol 2011, 411-412.

  21. Growing Body of Data on Salvage Cryotherapy 21 Pre-radiation PSA, pre-salvage PSA, a pre-salvage Gleason are factors correlated with recurrences. Post-salvage PSA nadir are factors correlated with recurrences. Williams AK and Chin JL. Disease-Free Survival Following Salvage Cryotherapy for Biopsy-Proven Radio-Recurrent Prostate Cancer. E Urology 2011; 60: 405-410.

  22. Advances in Cryotherapy Technology 22 • The incontinence rates decreased to <5% in recently reported Salvage Cryoablation (SCA) series : • Because of the use of Multi-thermal sensors (MTS) which allows precise thermal control of the freezing process around the external sphincter; and hence, • Optimizes the likelihood of preserving urinary continence following treatment. • Currently, SCA is a feasible option due to: • More precise prostate ice ball formation and • The flexibility to place additional cryoneedles where needed to selectively target a site of tumor recurrence. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.

  23. The Bottom Line 23 Salvage cryotherapyis supported for carefully selected men whose cancer recurrence is identified, while localized to an area that can potentially be cured. Mouraviev V., Spiess P.E. and Jones S.J. Salvage Cryoablation for Locally Recurrent Prostate Cancer Following Primary Radiotherapy. Eu Urology 2012; 61:1204-1211.

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