1. M. Wirth Department of Urology, Technical University of Dresden Adjuvant or Salvage Radiotherapy after Radical Prostatectomy

2. Adjuvant or Salvage Radiotherapy after Radical Prostatectomy: Background

3. 6- 3+4 4+38-10 0 20 40 60 80 100 0-4 ng/ml 4.1-10 ng/ml 10.1-20 ng/ml 20+ ng/ml % PSA-relapse (0.2 ng/ml) after 10 years Gleason-Score Han, Partin et al., J Urol 2003 PSA-relapse after RPE in locally advanced PCa (n=2091) preop. PSA

4. organconfined: 18 % extracapsular: 82 % cT3: MSKCC-Nomogramm: pT Stage Exampel: cT3, PSA 10 ng/ml, Gleason 4+4=8 Ohori, Kattan et al., J Urol 2004

5. cT3: MSKCC-Nomogramm:pT-Stage Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6 Ohori, Kattan et al., J Urol 2004 organconfined: 50 % extracapsular: 50 %

6. Adjuvant or Salvage Radiotherapy after Margin Positive Radical Prostatectomy Patients with R1 after RPE are at an increased risk of biochemical, local and distant failure [1]. With R1, the risk of biochemical recurrence may supersede 50 % after 10- years [2]. The associated 10-year local recurrence rate accounts for narrowly 30 % [2]. 1 EAU guidelines 2008; 2 Pfitzenmaier et al., BJU Int 2008

7. Adjuvant Radiotherapy vs. Wait-and-see after Radical Prostatectomy

8. randomised controlled trial pT3 or positive margins, pN0 age < 76 years, WHO perf. status 0-1 wait-and-see (n=503) vs. irradition (60 Gy) within 16 w. after RPE (n=502) Bolla et al., Lancet 2005 Wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 (n=1005)

9. age 65 y. (61-69) PSA: 12.4 ng/ml (7.2-20.3) PSA: 3 weeks after RPE, before RTX 0.2 (0.0-0.3) median FU 5 y. biochemical and clinical progression free survival significantly improved after ART overall survival with trend towards improvement after ART, but not (yet?) significant Bolla et al., Lancet 2005 wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911 (n=1005)

10. EORTC trial 22911 (n=1005) clinical progression free survival Bolla et al., Lancet 2005 Clinical progression-free survival

11. EORTC trial 22911 (n=1005) biochemical progression free survival Bolla et al., Lancet 2005 PSA progression-free survival

12. EORTC trial 22911 (n=1005) cumulative incidence of locoreg. failure Bolla et al., Lancet 2005 local progression-free survival

13. Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007

14. Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007 Margins ECE SV Gleason Postop. PSA

15. Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007

16. Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007 control arm

17. Patients who benefit from immediate postoperative RT – EORTC trial 22911 (n=1005) Van der Kwast, JCO 2007 immediate postoperative radiation

18. EORTC trial 22911 (n=1005) cumulative incidence of late complications Bolla et al., Lancet 2005 Late complications

19. Randomised controlled trial clinical T1/T2 preoperatively pT3 or positive margins, N0 M0 WHO perf. status 0-2 Wait-and-see (n=211) vs. Irradition (60-64 Gy, n=214) Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425)

20. Adjuvant RT in pT3 PCA (randomised study SWOG 8794, n=425) Thompson et al., JAMA 2006 100 60 80 40 20 0 Percentage

21. Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Overall survival p=0.023

22. Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Metastatic-free survival p=0.016

23. Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Metastatic-free survival, PSA 0.2 p=0.03

24. Thompson et al., J Urol 2009 Adjuvant RTX for T3N0M0 PCA – randomised SWOG trial 8794 (n=425) Summary

25. Wiegel et al., ASCO 2005 [in press as full article: J Clin Oncol 2009] adjuvant RT (60 Gy) no adjuvant RT A djuvant radiotherapy after RPE (ARO 96-02 / AUO AP 09/95, pT3R0-1, PSA 0, n=108) % PSA recurrence after 4 years 0 20 40 60 80 100 p<0.0001, hazard ratio 0.4 81 % 60 %

26. Bottke and Wiegel, Urol Int 2007 RPE with and without adjuvant RT in pT3-PCA

27. Morgan et al., Radiother Oncol 2008 Adjuvant radiotherapy following radical prostatectomy for pathologic T3 or margin-positive prostate cancer A systematic review and meta-analysis Survival Biochemical progression

28. Salvage Radiotherapy vs. Observation at PSA Failure after Radical Prostatectomy

29. no salvage treatment (n=397) vs. salvage radiotherapy (n=160) vs. salvage radiotherapy + HT (n=78) significant increase of PC-specific survival for both SRT (HR 0.32, p<0.001) and SRT+HT (HR 0.34, p=0.003) improvement limited to patients with - PSA-doubling time < 6 month - SRT within 2 y. after recurrence Trock et al., JAMA 2009 PCA specific survival following salvage RTX vs observation after RPE – survival

30. PCA specific survival following salvage RTX vs. observation after RPE – survival Trock et al., JAMA 2009 PCA specific survival

31. PSA failure following salvage radiotherapy – CaPSURE data (retrospective study, n=194) Macdonald et al., Urol Oncol 2008

32. Radiotherapy at biochemical recurrence after RPE (retrospective study, n=162) Wiegel et al., IJROBP 2008 No biochemical recurrence

33. Radiotherapy at biochemical recurrence after RPE (retrospective study, n=162) Wiegel et al., IJROBP 2008 No biochemical recurrence

34. Radiotherapy at biochemical recurrence after RPE (retrospective study, n=162) Wiegel et al., IJROBP 2008 No biochemical recurrence

35. Salvage RTX at PSA progression: long-term efficacy Literature review Bottke and Wiegel, Urologe 2008 35-54 %

36. Arguments pro delayed radiotherapy for positive surgical margins Questionable survival advantage for immediate adjuvant RTX Sparing of side effects and costs in about 50 % of patients Improved risk stratification by monitoring of PSA value and PSA kinetics High rate of disease control with timely applied salvage therapy

37. Adjuvant vs. Salvage Radiotherapy after Radical Prostatectomy

38. Adjuvant vs. Salvage Radiotherapy Matched-control analysis (n=192) Trabulsi et al., Urology 2008 Five-year freedom from biochemical failure from end of RT

39. Adjuvant vs. Salvage Radiotherapy Matched-control analysis (n=192) Trabulsi et al., Urology 2008 Five-year freedom from biochemical failure from end of surgery

40. Adjuvant and Salvage RTX after RPE Biochemical failure free survival Jereczek-Fossa, IntJRadOncol 2008 Adjuvant RT Salvage RT n=410

41. Adjuvant and Salvage RTX after RPE Grade 2 or greater rectal and urinary toxicity Jereczek-Fossa, IntJRadOncol 2008 n=410 Adjuvant RT Salvage RT

42. Adjuvant and Salvage RTX after RPE Grade 2 or greater rectal and urinary toxicity Jereczek-Fossa, IntJRadOncol 2008 n=410

43. Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003

44. Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003 Adjuvant RT

45. Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003 Salvage RT +/- adj. androgen ablation

46. Adjuvant RTX for pN+ disease?

47. Da Pozzo et al., Eur Urol 2009 Conclusions: This study is the first to report a significant protective role for adjuvant RT in BCR-free survival and CSS of node-positive patients.

48. Adjuvant RTX for pN+ disease (retrospective study, n=250) Da Pozzo et al., Eur Urol 2009 No biochemical failure

49. Adjuvant RTX for pN+ disease (retrospective study, n=250) Da Pozzo et al., Eur Urol 2009 PCA-specific survival

50. p<0.0001 RT for PSA-Recurrence after RPE: Dosage ?(n=122) 0 3 6y No new PSA-recurrence King et al. IJROBP 2008

51. Chamie et al., AUA 2008 #393 RT in prostate cancer induces secondary malignancies (n=130.375 vs. 375.235) PCA, no RT 0 1.5 0.5 odds-ratio for secondary malignancy 1 2 1.89 (1.85-1.95) PCA, RT !

52. Risk stratification?

53. 6 % 65 % ! Biological heterogeneity of R1 disease: risk of failure after 2 years, nomogram (n=2911) Walz et al., J Urol 2009 Failure risk:

54. definite evidence for adjuvant RTX for margin-positive disease is still pending patients should be informed on the significance of the presently available results from randomized trial stratification by recurrence risk is a plausible but not yet proven concept to select patients with “temporarily delayed” RTX at PSA relapse, early onset is needed to maintain the chance of durable remission Summary

55. Adjuvant hormonal therapy?

56. Prospective randomised study: flutamide vs. control after RPE in pT3-4 pN0 (n=309) 0100200300400500600 0 20 40 60 80 100 weeks after RPE recurrence-free survival [%] log-rank-Test, p=0.0041 0100200300400500600 0 20 40 60 80 100 survival [%] log-rank-Test, p=0.92 Flutamide, n=152 control, n=157 Wirth et al., Eur Urol 2004

57. EPC program: objective progression (prospective randomised trial, n=8116, FU 7.4 y) McLeod et al., BJU Int 2006

58. EPC program: overall survival (prospective randomised trial, n=8116, FU 7.4 y)

59. Adjuvant hormonal therapy after RPE for pN+-PCa (randomised trail, n=98, FU 11.9 y) Messing et al., Lancet Oncol 2006

60. no difference benefitflutamidepT3- 4pN0 Wirth et al., 2004 no difference benefitbicaluta- mide T1b-T4Mc Leod et al., 2006 no data available benefitLHRH- analog stage CPrayer-Galetti et al., 2000 benefit orchiectomy or LHRH- analog pN+Messing et al., 1999, 2003 survivalprogressionregimenstageauthor, year Adjuvant hormonal therapy after RPE

63. BACKUP

64. M. Wirth Klinik und Poliklinik für Urologie Adjuvant or Salvage Radiotherapy after Radical Prostatectomy

65. 6- 3+4 4+38-10 0 20 40 60 80 100 0-4 ng/ml 4.1-10 ng/ml 10.1-20 ng/ml 20+ ng/ml % PSA-relapse (0.2 ng/ml) after 10 years Gleason-Score Han, Partin et al., J Urol 2003 PSA-relapse after RPE in locally advanced PCa (n=2091) preop. PSA

66. organconfined: 18 % extracapsular: 82 % cT3: MSKCC-Nomogramm: pT Stage Exampel: cT3, PSA 10 ng/ml, Gleason 4+4=8 Ohori, Kattan et al., J Urol 2004

67. cT3: MSKCC-Nomogramm:pT-Stage Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6 Ohori, Kattan et al., J Urol 2004 organconfined: 50 % extracapsular: 50 %

68. Bottke and Wiegel, Urol Int 2007 RPE with and without adjuvant RT in pT3-PCA

69. Randomised controlled trial clinical T1/T2 preoperatively pT3 or positive margins, N0 M0 WHO perf. status 0-2 Wait-and-see (n=211) vs. Irradition (60-64 Gy, n=214) Thompson et al., JUrol 2009 Adjuvant RTX for T3N0M0 PCA – SWOG 8794

70. Thompson et al., JUrol 2009 Adjuvant RTX for T3N0M0 PCA – SWOG 8794

71. Adjuvant RT in pT3 PCA (randomised study, n=425) Thompson et al., JAMA 2006 100 60 80 40 20 0 Percentage

72. Thompson et al., JAMA 2006 Adjuvant RT in pT3 PCA (randomised study, n=425)

73. Randomised controlled trial pT3 or positive margins, pN0 age < 76 years, WHO perf. status 0-1 Wait-and-see (n=503) vs. Irradiation (60 Gy) within 16 w. after RPE (n=502) Bolla et al., Lancet 2005 wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911

74. Age 65 y. (61-69) PSA: 12.4 ng/ml (7.2-20.3) PSA: 3 weeks after RPE, before RTX 0.2 (0.0-0.3) median FU 5 y. biochemical and clinical progression free survival significantly improved after ART overall survival with trend towards improvement after ART, but not (yet?) significant Bolla et al., Lancet 2005 wait-and-see vs. immediate postoperative radiotherapy - EORTC trial 22911

75. EORTC trial 22911 clinical progression free survival Bolla et al., Lancet 2005

76. EORTC trial 22911 biochemical progression free survival Bolla et al., Lancet 2005

77. EORTC trial 22911 cumulative incidence of locoreg. failure Bolla et al., Lancet 2005

78. Patients who benefit from immediate postoperative RT – EORTC trial 22911 Van der Kwast, JCO 2007

79. EORTC trial 22911 cumulative incidence of late complications Bolla et al., Lancet 2005

80. Wiegel et al., ASCO 2005 adjuvant RT (60 Gy) no adjuvant RT A djuvant Radiotherapy after RPE (ARO 96-02 / AUO AP 09/95, pT3R0-1, PSA 0, n=108) % PSA recurrence after 4 years 0 20 40 60 80 100 p<0.0001, hazard ratio 0.4 81 % 60 %

81. PSA Recurrence after RPE: Salvage Radiotherapy vs. Observation

82. Salvage radiotherapy within 2 years of biochemical recurrence was associated with a significant increase in CaP– specific survival among men with a PSA doubling time <6 months, independent of pathological stage or Gleason score. JAMA 2008

83. PCA specific survival following salvage RTX vs observation after RPE – survival Trock et al., JAMA 2009

84. no salvage treatment (n=397) vs. salvage radiotherapy (n=160) vs. salvage radiotherapy + HT (n=78) significant increase of PC-specific survival for both SRT (HR 0.32, p<0.001) and SRT+HT (HR 0.34, p=0.003) improvement limited to patients with - PSA-doubling time < 6 month - SRT within 2 y. after recurrence Trock et al., JAMA 2009 PCA specific survival following salvage RTX vs observation after RPE – survival

85. PSA Recurrence after RPE: Salvage Radiotherapy vs. Observation: Timing?

86. Radiotherapy for PSA-Recurrence (n=1540) Stephenson et al., JCO 2007 bis 0.5 ng/ml 0.51-1.0 ng/ml 1.01-1.50 ng/ml 1.51+ ng/ml

87. PSA Failure following Salvage Radiotherapy – CaPSURE data Macdonald et al., UrolOncolSemOrigInv 2008

88. Adjuvant Radiotherapy or after PSA- Recurrence (n=162) Wiegel et al., IJROBP 2009

89. Radiotherapy at Biochemical Recurrence after RPE (n=162) Wiegel et al., IJROBOP 2008

90. Adjuvant and Salvage RTX after RPE Biochemical failure free survival Jereczek-Fossa, IntJRadOncolBiolPhys 2008 Adjuvant RT Salvage RT

91. Adjuvant and Salvage RTX after RPE Biochemical failure free survival Taylor et al., IntJRadOncBiolPhys 2003

92. p<0.0001 RT for PSA-Recurrence after RPE: Dosage ?(n=122) 0 3 6 Jahre No new PSA-recurrence King et al. IJROBP 2008

93. Radiotherapy for PSA-Recurrence (n=1540) Stephenson et al., JCO 2007

94. adjuvant and Salvage-RT after RPE both improve recurrance free survival and offer a second chance of cure adjuvant RT should be considered in patients with positive margins Summary (I)

95. Salvage-RT should be performed at a low PSA-level << 1.0 ng/ml postoperative RT has a limited effect on patients with pN+ optimal radiation dose unclear Summary (II)

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97. adjuvant and salvage-RT after RPE both improve recurrance free survival and offer a second chance of cure adjuvant RT should be considered in patients with positive margins Summary (I)

98. salvage-RT should be performed at a low PSA-level << 1.0 ng/ml postoperative RT has a limited effect on patients with pN+ optimal radiation dose unclear Summary (II)

99. Radiotherapy + HT vs. hormonal Therapy alone

100. Thompson et al., JAMA 2006 Adjuvant RT in pT3 PCA (randomised study SWOG 8794, n=425)

101. RT + hormonal therapy* vs. hormonal therapy* alone in locally advanced PCA (n=875) *flutamide 3x250 mg/d Widmark et al., Lancet 2009 P<0.0001 PSA recurrence (%)

102. RT + Hormonal Therapy* vs. Hormonal Therapy* alone in lokally advanced PCA (n=875) P=0.004 Hormonal Therapy alone Radiotherapy + Hormonal Therapy *flutamide 3x250 mg/d Widmark et al., Lancet 2009

103. Adjuvant HT* after RT in organ confined high risk tumor *6 mo., n=206 D‘Amico et al., JAMA 2008

104. Short vs. long* adjuvant ADT after RT *3 years vs. 6 months Bolla et al., ASCO 2007 Overall survival

105. AuthorsStagesRegimenProgressionSurvival Bolla et al., 1997, 2002T1-T4N0-xLHRH analogues advantage Pilepich et al., 1997, Lawton et al., 2001, Pilepich et al., 2003 stage C or D1LHRH analogues advantage Granfors et al., 1998, 2006T1-4N0-1orchiectomyadvantageadvantage in N1 subgroup Hanks et al., 2003T2b-T4, PSA<150 ng/ml LHRH analogues plus flutamide advantageadvantage in Gleason score 8-10 subgroup D’Amico et al., 2004Gleason score 7+, cT3-4 or PSA>10 ng/ml LHRH analogues advantage Wirth et al., 2001, McLeod et al., 2006 T1b-T4 N0-1M0 bicalutamideadvantageadvantage in locally advanced disease D’Amico et al., 2006 Localized or locally advanced, PSA velocity >2ng/ml/y Not specifiedadvantage Adjuvant hormonal treatment after RTX for locally advanced prostate cancer

106. Increased cardiovascular mortality at hormonal therapy after RPE (n=3262) Tsai et al., JNCI 2007 <65 Jahre65+ Jahre HR: 2.6; 95% CI: 1.4-4.7; p =0.002

107. D‘Amico et al., JAMA 2008 Negative consequences of androgen suppression in men with comorbidities and RT in high-risk PCA (randomised trial, n=206)

108. After RPE adjuvant hormonal therapy is not necessary! After radiotherapy an adjuvant hormonal therapy is recommended(side effects!) for at least 3 years.

109. good results after RPE adjuvant / early RT after RPE improves recurrance free survival and offers a second chance of cure neoadjuvant hormonal therapy after RPE not necessary Summary (I)

110. adjuvant hormonal therapy after RPE is not necessary – no survival benefit radiotherapy + hormonal therapy is recommended best concept of hormonal therapy adjuvant to radiotherapy is unclear Summary (II)