The document discusses prostate cancer treatments including HIFU (high-intensity focused ultrasound). HIFU uses ultrasound waves to coagulate prostate tissue without direct contact, allowing treatment in a single session without incisions. Studies show HIFU achieves negative biopsy results in 90% of low-risk prostate cancer patients within 6 months with few side effects and good long-term cancer control and survival rates. HIFU is presented as a minimally-invasive alternative to surgery or radiation for localized prostate cancer.

3. American Cancer Society , Cancer Facts & Figures 2005 Annual Percentage of Change 1975-87 +0.9% 1987-91 +3.0% 1994-01 -4.1%

4. PSA Screening Program and Its Effect on Tyrol’s Prostate Cancer Mortality Rate Horninger W, MD et al Am J Urol Review 2005 Apr 3:4, 172-175 1993 Mass screening project launched in Tyrol, Austria, offers PSA testing free to all men ages 45-75; 65,123 enrolled Treatment for Tyrol subjects with: Elevated PSA levels  advised to undergo DRE and biopsies Organ-confined lesions  RRP or EBR T3 lesions  EBR only Metastases  ADT No organized screening in the rest of Austria. Treatments varied. WJC

5. American Cancer Society , Cancer Facts & Figures 2005 Relative Survival Rates Survival in relation to men who do not have prostate cancer 1995-2005 stage at diagnosis 90% localized 5% distant

7. Changes in Relative 5-Year Survival Rates

11. Typical Pathology Diagrams of Prostates with Cancers in 1991 PSA Level: 2.5 2mm 3 15mm 3 PSA Level: 17.5 urethra urethra

12. Typical Pathology Diagrams of Prostates with Cancers in 2005 PSA Level: 2.5 2mm 3 PSA Level: 6.0 2mm 3 urethra urethra

13. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. 7% 10% 17% 24% 27% 1% 1% 2% 5% 7% 0 5 10 15 20 25 30 ? 0-0.5 0.6-1.0 1.1-2.0 2.1-3.0 3.1-4.0 PSA Level (ng/ml) % of Men with Prostate Cancer and High- Grade Disease Percent with Prostate Cancer Percent with Gleason > 7 Disease Thompson IM, et al. N Engl J Med. 2004 May 27;350(22):2239-46. (13%) (10%) (12%) (19%) (25%) Relationship of the PSA Level to the Prevalence of Prostate Cancer and High-Grade Disease

15. Simple, non-invasive urine specimen collected post-DRE Groskopf J, et al. Clin Chem 2006;52:1089-95

16. What is measured in the urine post-DRE ?

17. Measuring PCA3 mRNA to calculate the PCA3 Score Quantitative PCA3 Score PCA3 Assay Using transcription-mediated amplification technology, PCA3 mRNA molecules are amplified

18. PCA3 is 66-fold over-expressed in malignant prostate tissue Tissue type PCA3 mRNA copies/  g tissue (x 10 5 ): range PCA3 mRNA copies/  g tissue (x 10 5 ): median Fold over-expression: median BPH (n=12) 0.2-10.1 2.4 1 < 10% PCa (n=13) 6.6-166.0 25.3 11 > 10% PCa (n=27) 7.0-994.0 158.4 66

20. Studies in men scheduled for repeat biopsy

22. A PCA3 Score cut-off of 35 provides the greatest diagnostic accuracy for repeat biopsy US study (n=233) Sensitivity: 58% Specificity: 72% European study (n=199) Sensitivity: 57% Specificity: 73% AUC ROC Serum PSA: 0.524 PCA3 Score: 0.678 AUC ROC % free PSA: 0.572 PCA3 Score: 0.698

23. The higher the PCA3 Score, the greater the likelihood of a positive repeat biopsy PCA3 Score PCA3 Score US study (n=233) 27% positive Bx European study (n=199) 25% positive Bx Enrollment complete/560 cases

24. How do PROGENSA PCA3 reports look like?

26. The PCA3 Score in low volume /low grade PCa is significantly lower than in significant PCa Low volume: tumour volume < 0.5 mL; Low grade: Gleason Score  6 Nakanishi H, et al. ASCO 2007 Prostate Cancer Symposium: abs. 354

29. HIFU= H IGH I NTENSITY F OCUSED U LTRASOUND

34. HIFU device evolution First prototype: 1993 -1995 Second prototype: 1995-2000 First generation ABLATHERM « maxis »: 2000-2005 Last generation « Integrated Imaging »: 2006- 1993 1995 2000 2006 Study period

35. POSIZIONE DEL PAZIENTE

36. Posizione di imaging Le onde ultrasonore ad alta energia vengono focalizzate attraverso la parete rettale sul bersaglio Il volume prostatico bersaglio viene localizzato con la sonda ecografica biplana Posizione di fuoco Le due posizioni del trasduttore

37. Effetto termico + Cavitazione = lesione tissutale Lesione L = 19 - 24 mm max D = 1.7 mm min HIFU – Meccanismo d’azione 3L/4 L/4 D

38. Posizionamento preciso della lesione Risparmio del tessuto circostante HIFU – Meccanismo d’azione

40. Reperti istologici Pre HIFU

41. Reperti istologici 48 hours 3 months Completa distruzione del tessuto ghiandolare dovuto alla necrosi coagulativa che raggiunge la capsula e il grasso periprostatico Il tessuto prostatico necrotico viene sostituito da un tessuto fibroso (che include la capsula)

42. 6 months Reperti istologici

48. Ablatherm ® efficiency on long-term results Overall survival * 90% at 5 years 83% at 8 years (p = 0.23) No death related to HIFU treatment * time of death, regardless of cause

49. Ablatherm ® efficiency on long-term results Prostate cancer-specific survival * 100% at 5 years 98% at 8 years * time of death from prostate cancer

50. Ablatherm ® efficiency on long-term results Salvage treatment-free survival * 86% at 5 years 79% at 8 years (p = 0.006) 89% 69% * time of a salvage treatment introduction

51. Ablatherm ® efficiency on long-term results Biochemical failure-free survival * 73% at 5 years 69% at 6 years (p = 0.086) *PSA < PSA nadir +2 ng/ml (ASTRO 2005)

53. Ablatherm ® efficiency on long-term results Biochemical failure-free survival at 5 years Katz AE and Rewcastle JC. Current Oncology Reports 5(3) pp. 231–238 (2003) 77%

54. Ablatherm ® efficiency on long-term results Biochemical failure-free survival at 5 years Katz AE and Rewcastle JC. Current Oncology Reports 5(3) pp. 231–238 (2003) 71%

57. PSA Nadir following EBRT: 34% 0% 40% (1.0-2.0 ng/ml) >1.0ng/mls 17% >2.0ng/ml 55% 26% 52% 0.6-1.0ng/ml 90% 93% 75% <0.5ng/ml Zietman et al n=314 5yr f/u Critz et al n=660 5yr f/u Ray et al n=4833 8yr f/u nPSA

59. Definitions of biochemical failure Post HIFU Therapy?

62. Baseline patients characteristics (used as covariates in the adjusted Cox proportional hazards models) Age 69.4 68.2 71.4 NS PSA value 6.1 6.6 8.5 p<0.02 Gleason score 4.8 5.2 5.5 NS Prostate AP  22.3 28.2 29.0 p<0.001 Prostate volume 22.7 28.3 35.4 p<0.001 Median time to nadir (weeks) 12.1 13.4 12.7 NS ≤ 0.2 0.21–1 >1 p-value

63. Results Actuarial survival rates at 5 years for the variables: Biological failure free 86% 65% 20% Biochemical (ASTRO 2005) 86% 85% 24% Salvage-free treatment 94% 91% 60% Disease free 83% 62% 19% ≤ 0.2 0.2–1.0 >1.0

64. Disease-free survival p<0.001 (Log rank) Nadir PSA ≤ 0.2 ng/ml Nadir PSA 0.21-1,0 ng/ml Nadir > 1,0 ng/ml

88. Salvage HIFU after EBRT : stratified DFSR(*) by pre-EBRT risk level (*) ASTRO 2005:negative biopsy & no adjuvant therapy & last PSA < nadir+ 2ng low risk:53% high risk:25% inter risk:42% High =T2c-T3a or PSA>20ng/ml or Gleason>7 Low = T1-T2a & PSA≤10ng/ml & Gleason<7 Inter=T2b or PSA10-20 or Gleason=7

89. Salvage HIFU after EBRT : stratified DFSR (*) by pre HIFU PSA (*) ASTRO 2005:negative biopsy & no adjuvant therapy& PSA < nadir+ 2ng

90. Salvage HIFU after EBRT : stratified DFR(*) by pre HIFU Gleason (*) ASTRO 2005:negative biopsy & no adjuvant therapy& PSA < nadir+ 2ng

91. Salvage HIFU after EBRT : Complications % Non specific treatment parameters (n=56, 1995-2002) Specific treatment parameters (n=111, 2002-today)

92. Salvage HIFU after EBRT : Uretro-rectal fistula No more uretro-rectal fistulas with the specific RBT failure treatment protocol %

94. HIFU in Europa: riproducibilità dei risultati 0,1 87,5 % Como 0,0 88,9 % Monaco 0,1 86 % Lyon 0,1 87,2 % Studio multicentrico PSA nadir Biopsie negative

96. Grazie per l’attenzione