The document discusses the history and development of cryotherapy and high-intensity focused ultrasound (HIFU) as minimally invasive treatments for localized prostate cancer. It reviews their physical mechanisms and provides data on their oncological and functional outcomes compared to other treatments like surgery and radiation therapy. Focal therapies like cryotherapy and HIFU show potential as effective partial treatment options with lower risks of side effects like incontinence and impotence compared to full gland treatments. However, long-term data from randomized controlled trials is still needed to establish them as standard options.

1. All the truth about Cryotherapy and HIFU for LPca Francois-Joseph Murat, MD Lyon, France

2. 1rst Generation 2nd Generation 3rd Generation 1964 1980‘s 1990‘s Cryotherapy :Historical considerations

3. Prototypes 1rst Generation 2nd Generation 1993-2000 2000-2005 2006- HIFU: Historical considerations

6. 1. Thermal effects Intra/extra cellular ice formation Endothelial damages: ischemia rupture of cell walls 2. Mechanical effects freezing (-40°C) and thawing process Cryotherapy: Physical aspects

7. 1. Thermal effects 2. Mechanical effects fast temperature rise (>80°C) generation of gas bubbles collaps of cavities: cavitation High Intensity Focused Ultrasound: Physical aspects

8. coagulation necrosis Early feedback (M3) on treatment efficacy 2 treatments but a unique histological aspect

9. ONCOLOGICAL RESULTS

10. Local Control: Negative Biopsy Rate « the strongest predictor of biochemical failure was post treatment biopsy status » Zelefsky et al. J Urol, April 2008

11. Local Control: Negative Biopsy Rate Cryotherapy: 76.5% - 88%* control biopsies not performed systematically after cryo * Bahn et al, 2002/ Cohen et al , 2008/ Jones et al, 2008 / Caso et al, 2010. HIFU: 73% - 93% control biopsies systematic 3-6 mo after HIFU

12. 1. Gelet et al, J Endourol. 2000; 2. Gelet et al, Eur Urol. 2001; 3. Poissonnier et al Prog Urol. 2003; 4. Poissonnier et al Eur Urol. 2007; 5. Thuroff et al J Endourol. 2003; 6. Chaussy et al Curr Urol Rep. 2003; 7. Urology. 2004; 8. Ficarra et al BJU Int. 2006;98(6):1193-8; 9. Prostate Cancer Prostatic Dis. 2006;9(4):439-43; 15. Blana et al Urology 2008;72:1329-33:Urol. 2006 Mar;13(3):228-33; 14. Blana et al European Urol 2008; 53 1194-1203;10. Blana et al Urology 2008;72:1329-33; 16. Mearini et al J Urol. 2009;181:105-112. 17. Scardino et al, NCI Monogr. 1988;(7):95-103; 18. Borghede et al, Br J Urol. 1997 Aug;80(2):247-55. 19. Crook et al, Int J Radiat Oncol Biol Phys. 2000 Sep 1;48(2):355-67; 20. Zelefsky et al, J Urol. 2001 Sep;166(3):876-81; 21. Pollack et al, Int J Radiat Oncol Biol Phys. 2002 Nov 1;54(3):677-85; 22. Zelefsky et al, J Urol. 2008 Apr;179(4):1368-73 Local Control: Negative Biopsy Rate

13. Warnings biochemical Disease Free Survival (bDFS): No validated definition ASTRO or Phenix +++ PSA thresholds (<0.2ng/ml, <0.5 ng/ml, <1ng/ml)

14. 5-year bDFS for Low risk prostate cancer (range in the literature since 2000/all definitions of bDFS) 0 40 80 100 HIFU Cryo 92% 1 77% 2 85% 3 76% 4 bDFS (%) 60 20 1., Robertson et al J Endourology 2009. 2. Blana et al Urology 2008. 3. Jones et al J Urol 2008. 4. Long et al Urology 2001.

15. 5-year bDFS for Low risk prostate cancer (range in the literature since 2000/all definitions of bDFS) 0 40 80 100 HIFU Cryo 92% 1 77% 2 85% 3 76% 4 bDFS (%) Beam RT RP 94% 7 84% 8 100% 5 55% 6 60 20 1., Robertson et al J Endourology 2009. 2. Blana et al Urology 2008. 3. Jones et al J Urol 2008. 4. Long et al Urology 2001. 5. De Meerleer et al Radiother Oncol. 2007. 6. Goldner et al Strahlenther Onkol. 2006. 7. Stokes et al Int J Radiat Oncol Biol Phys. 2000. 8. Ciezki et al Int J Radiat Oncol Biol Phys. 2004.

16. 5-year bDFS for Intermediate risk prostate cancer (Range in the literature since 2000/all definitions of bDFS) 0 40 80 100 87% 1 77% 2 89% 3 71% 4 bDFS (%) 60 20 1. Robertson et al J Endourol 2009. 2. Blana et al Urology 2008. 3. Bahn et al Urology 2002. 4. Long et al Urology 2001. HIFU Cryo

17. 0 40 80 100 87% 1 77% 2 89% 3 71% 4 bDFS (%) 87% 7 72% 8 94% 5 40% 6 60 20 1. Robertson et al J Endourol 2009. 2. Blana et al Urology 2008. 3. Bahn et al Urology 2002. 4. Long et al Urology 2001. 5. De Meerleer et al Radiother Oncol. 2007. 6. Goldner et al Strahlenther Onkol. 2006. 7. Stokes et al Int J Radiat Oncol Biol Phys. 2000. 8. Ciezki et al Int J Radiat Oncol Biol Phys. 2004. HIFU Cryo Beam RT RP 5-year bDFS for Intermediate risk prostate cancer (Range in the literature since 2000/all definitions of bDFS)

18. TOXICITY ?

19. Incontinence 0 10 20 30 7% 1 2.3% 2 49% 3 5% 4 Incidence (%) 1% 12 8% 11 † excluding grade I, ‡pad rate. 1. Ficarra et al, BJU Int. 2006 Dec;98(6):1193-8. 2. Chaussy and Thuroff Curr Urol Rep. 2003;4(3):248-52. 3. Steineck et al, N Engl J Med. 2002 Sep 12;347(11):790-6; 4. Abou-Elela et al, Eur J Surg Oncol. 2007; 33:96-101; 5. Reis et al, Int Urol Nephrol. 2004;36(2):187-90; 6. Feigenberg et al, Int J Radiat Oncol Biol Phys. 2005 Jul 15;62(4):956-64; 7. Matalinska et al, J Clin Oncol. 2001 Mar 15;19(6):1619-28; 8. Potosky et al, J Natl Cancer Inst. 2000 Oct 4;92(19):1582-92; 9. Zelefsky et al, Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1111-6; 10. Brabbins et al, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):400-8. 11. Long et al, Urology. 2001 Mar;57(3):518-23; 12. Donnelly et al, Urology. 2002 Oct;60(4):645-9; 10% 5 1% 6 7% 7 4% 8 0% 10 15% 9 HIFU RP Cryo Brachy EBRT IMRT

20. Rectal Complications 0 1 2 3 4 5 RT Occurence (%) 0 10 20 30 40 50 HIFU RT 43% 0% Occurence (%) None reported Severe (fistula – requiring surgery) Minor (blood, diarrhea…) ≤ 0.6 % 2 0% ≤ 0.5 % 1 HIFU Cryo Cryo 0% ≤ 0.5 % 3 None reported 1. Poissonnier et al Prog Urol. 2003; 2. Chrouser et al J Urol 2005; 3. Bahn et al,Urology. 2002.

21. Bladder Outlet Obstruction 1. Uchida et al, BJU Int. 2006; 2. Poissonier et al, Eur Urol. 2007; 3. Elliot et al, J Urol. 2007; 4. Benoit et al, Urology. 2000; 5. Zefelsky et al, J Clin Oncol 1999; 6. Zefelsky et al, J Urol. 2006; 7. Shelley et al, Cochrane Database Syst Rev. 2007. 0 20 40 60 80 100 Incidence (%) 27% 1 6% 2 25.7% 3 2.7% 3 2% 7 55% 7 12% 4 8% 5 1.73 3 / 3% 6 Not reported HIFU RP Cryo Brachy EBRT IMRT

22. Impotence ?

23. Impotence 1. Blana et al Urology. 2004. 2. Thuroff et al. J Endourol. 2003. 3. Langenhuisen et al Eur Urol 2008. 4. Finley et al Urol Clin N Am 2010. 5. Matalinska et al, J Clin Oncol. 2001. 6. Walsh et al, J Urol. 2000. 7. Incrocci et al, Acta Oncol. 2005. 8. Incrocci et al, Acta Oncol. 2005. 9 Potosky et al, J Natl Cancer Inst. 2000. 10. Matalinska et al, J Clin Oncol. 2001. 0 20 40 60 80 100 Incidence (%) 53% 1 13% 2 91% 5 14% 6 50% 4 90% 3 51% 7 5% 8 63% 9 41% 10 Not reported HIFU RP Cryo Brachy EBRT IMRT

27. Different Focal strategies Cryo or HIFU allow different kind of focal strategies Hemiablation Nerve Sparing Zonal

28. Focal therapy : From Outsiders to winners ! Effective in tissue destruction Ability to partial treatment Minimally invasive treatment No dose limitation: perfect repeatability The lower the treated volume, the lower the complication rate HIFU Cryo HIFU Brachy Cryo HIF U Brachy Cryo HIFU Surgery/EBRT Brachy/HIFU Cryo/PDT Proven partial Treatment capacity Minimal invasiveness Repeatability

29. Focal therapy: the winner is ???? Cryo ? HIFU ?

30. 1. Bahn et al. J Endourol, 2006; 2. Onik et al. Urol Oncol, 2008; 3. Truesdale et al. Cancer Journal, 2010; 4. Van Velthoven personnal communication. 5. French association of urology, current multicenter trial. FOCAL THERAPY CRYO HIFU Study 1 2 3 4 5 Pts 31 48 77 24 140 Fup (Mo) 70 54 24 20 9 bDFS 93% 94% 73% 82.6% NA Potency (%) 89 90 93 NA 100 Continence (%) 100 100 100 100 100