1. EORTC POSTOPERATIVE RADIOTHERAPY IMPROVES CLINICAL AND BIOCHEMICAL PROGRESSION FREE SURVIVAL AFTER RADICAL PROSTATECTOMY : FIRST RESULTS OF EORTC TRIAL 22911 M. Bolla (Grenoble, France), H. van Poppel, L. Collette,P.J. van Cangh, K. Vekemans, L. Da Pozzo, R. Van Velthoven, JM Maréchal, P. Scalliet,, Th.M. de Reijke, A. Verbaeys, J.-F. Bosset, K. Haustermans, M. Piérart On behalf of the EORTC Radiotherapy and Genito-Urinary Groups

2. EORTC For pT3 patients (cancer extending beyond the capsule) the risk of local failure varies from 10 to 50%. PSA level, Gleason score and positive surgical margins are independant predictors of biochemical relapse. Post operative radiotherapy reduces significantly the local relapse and PSA failure rates without any impact on disease-free survival.

3. EORTC Trial Design RANDOMIZATION and Stratification for Institution Capsule invasion Positive margins Invasion of seminal vesicles Wait and see until local failure Post-op radiotherapy (60 Gy/6wks) SURGERYSURGERY 1005 patients recruited between end 1992 and end 2001 Median follow-up: 5 years

4. EORTC Selection Criteria Age  75 years, WHO performance status (PS) 0-1 T0-3 N0 M0 Prostate Cancer preoperatively  1 pathological risk factor of: capsule invasion positive surgical margins invasion of seminal vesicles Informed consent

5. EORTC Trial objectives The trial is planned to demonstrate an increase of 7.5% of the 5-year biochemical progression free survival with post-operative radiotherapy with 80% power (2-sided Logrank test,  =0.05) Secondary endpoints Clinical progression-free survival Local control Overall survival Acute toxicity (WHO) and late Morbidity

6. EORTC Yearly accrual

7. Israel: 8 Switzerland: 31 Italy: 115 Spain: 19 France: 84 Belgium: 597 United Kingdom: 5 The Netherlands: 146 Accrual by Country

8. EORTC Patient characteristics The characteristics were well balanced between the groups Median age 65 y (47 – 75) WHO PS 0 : 93.8% - PS1: 5.5% - PS2: 0.3% T0-1: 17.6% - T2: 65.1% - T3: 17.2% - Tx: 0.1% WHO G1: 12.5% - G2: 62.7% - G3: 23.6% - Gx: 1.2% Median PSA before surgery: 12.3 ng/ml (0.3-159.4) Median PSA after surgery: 0.2 ng/ml (0.0 - 48.7)

9. EORTC Pathological Risk factors High Risk factors Treatment Arm Total (N=1005) No RT (N=503) RT (N=502) N (%) Not pT3 0 ( 0.0) 2 ( 0.4) 2 ( 0.2) Capsule only 127 (25.2) 139 (27.7) 266 (26.5) Capsule + S.V. 40 ( 8.0) 26 ( 5.2) 66 ( 6.6) Capsule + Margin 169 (33.6) 149 (29.7) 318 (31.6) S.V. only 19 ( 3.8) 23 ( 4.6) 42 ( 4.2) S.V. + Margin 8 ( 1.6) 16 ( 3.2) 24 ( 2.4) Margin only 79 (15.7) 84 (16.7) 163 (16.2) Capsule + S.V. + margin 61 (12.1) 63 (12.5) 124 (12.3)

10. EORTC Treatment actually received No Further Trt (N=503) Post-op RT (N=502) N (%) No Further Trt 497 (98.8) 41* ( 8.2) Post-op RT 5 ( 1.0) 457 (91.0) Unknown 1 ( 0.2) 4 ( 0.8) * Reasons were: ineligibility (10), post-operative complications (8), refusal (21), unspecified (2)

11. EORTC Radiotherapy Treatment N=457 Time from Surgery to d1 of RT (days)90 (14-156) Duration of RT (days)44 (18-106) Total Dose (Gy)60.0 (50 – 74) <57 Gy 3 ( 0.7%) 57-63Gy 420 (91.9%) >63 Gy 34 ( 7.4%) Total Number of Fractions30 (26 – 39) Interruptions for toxicity14 (3.1%)

12. EORTC Radiation treatment Field size (square field-equivalent) Post-op RT (N=457) Large*-Large 247 (54.0) Large-Small** 175 (38.3) Small-Small 28 ( 6.1) Missing 7 ( 1.5) * > 9 cm² square-field equivalent **  9 cm² square-field equivalent

13. EORTC Data Maturity The median follow-up is 5 years for both arms A total of 351 of the 478 events of biochemical/ clinical progression-free survival needed per protocol were observed (73.4%) The EORTC Independent Data Monitoring Committee recommended the early release of the results in December 2003 It is too early to assess the impact on time to distant metastases or survival (only 89 patients have died)

14. EORTC Late toxicity More gastro-intestinal toxicity grade 1 and genito-urinary toxicity grade 1-2 are observed with RT, few grade 3 are reported years 01234567891011 0 10 20 30 40 50 60 70 80 90 100 Time to first Grade >=1 01234567891011 0 10 20 30 40 50 60 70 80 90 100 Time to first Grade >=3 54.3% 68.0% years No RT RT No RT: 2.6% At 5 years: RT: 4.2%

15. (years) 012345678910 0 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk :Treatment 74503468404330268194128824416 255024654263622982281541075514 Wait-and-See Irradiation Cumulative incidence of loco-regional failure Gray test P<0.0001 No further treatment: 15.4% at 5 years (98% CI: 11.2 – 19.6) Post-operative RT: 5.4% at 5 years (98% CI: 2.7 – 8.0)

16. Clinical progression-free survival (years) 012345678910 0 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 113503467401324259188124794216 755024644243572912211501015314 % 86.3% (82.2 – 90.4) 77.1% (72.1 – 82.0 ) HR=0.61 98% CI: (0.43, 0.87) Logrank P=0.0009 No further treatment Post-operative RT

17. Biochemical progression-free survival (years) 012345678910 0 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 22050342533724318212684522710 131502456407330262193125854111 % HR=0. 48 98% CI: (0.37, 0.62) Logrank P<0.0001 No further treatment Post-operative RT 74.0% (68.7 – 79.3) 52.6% (46.6 - 58.5 )

18. EORTC Code and name Events / Patients Post-op RTWawa Statistics (O-E)Var. HR & CI :(Post-op RTWawa) |1-HR| % ± SD SM+, ECE- 13 / 84 27 / 79 -9.7 9.8 SM-, ECE+ 34 / 139 40 / 127 -6.2 18.3 SM+, ECE- 33 / 149 74 / 169 -24.1 26.5 SV+ 51 / 128 79 / 128 -22.9 30.9 Total 131/500 220/503 -63 85.5 (26.2 %)(43.7 %) 52% ±8 reduction 0.250.51.02.04.0 Post-op RTWawa Test for heterogeneity better Chi-square=4.41, df=3: p=0.2 Treatment effect: p=0.00000 Test for trend Chi-square=0.06, df=1: p=0.8 Biochemical PFS by pT

19. EORTC (years) 0246810 0 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk :Margin status 22766534126 2233211042 11403019135 571198648236 Loc - / Rev - Loc - / Rev + Loc + / Rev - Loc + / Rev + B-PFS Wait and See Overall Wald test: p=0.0007 (df=3) Margin status Patients (N) Observed Events (O) % at 5 Year(s) (95% CI) Local - / Review - 76 2265.60 (50.89, 76.86) Local - / Review + 33 2245.27 (25.84, 62.88) Local + / Review - 40 1169.75 (50.34, 82.78) Local + / Review + 119 5749.44 (39.38, 58.72)

20. EORTC ARO 96-02 : 385 patients Southwest Oncology Group Trial : 431 patients Other randomized studies

21. EORTC ARO 96-02 385 patients with pT3 N0 M0 1 0,75 0,5 0,25 0 0 p = 0,0010 HR : 0,49 (IC 95 0,3-0,75) RT 81% 4-year biochemical progression free survival Wiegler T et al et al ASCO 2005, abstract 4513 WW 60%

22. EORTC SWOG 8794 1988-1995 - 473 pts pT3 prostate cancer randomized to RT - 60-64Gy or observation only Thompson et al. AUA 2005 Abstract #1665

23. EORTC Conclusion Post-operative radiotherapy results in improved biochemical and clinical progression-free survival. Today, T1c stages are most common and the rate of SM(+) is far lower as well as the median PSA before surgery. The results of RP and immediate RT for pT3 R0-1 N0 might be improved by : i) accruing patients with a negative post-operative PSA, ii) replacing conventional RT by 3D-CRT, iii) promoting dose escalation.