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Trial Design

POSTOPERATIVE RADIOTHERAPY IMPROVES CLINICAL AND BIOCHEMICAL PROGRESSION FREE SURVIVAL AFTER RADICAL PROSTATECTOMY : FIRST RESULTS OF EORTC TRIAL 22911.

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Trial Design

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

  4. 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. 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 Trial objectives

  6. Yearly accrual

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

  8. 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. Pathological Risk factors

  10. Treatment actually received * Reasons were: ineligibility (10), post-operative complications (8), refusal (21), unspecified (2)

  11. Radiotherapy Treatment

  12. Radiation treatment * > 9 cm² square-field equivalent **  9 cm² square-field equivalent

  13. 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. Late toxicity Time to first Grade >=3 Time to first Grade >=1 100 100 At 5 years: RT: 4.2% 90 90 RT 68.0% 80 80 70 70 No RT 60 60 No RT: 2.6% 50 50 54.3% 40 40 30 30 20 20 10 10 0 0 0 1 2 3 4 5 6 7 8 9 10 11 0 1 2 3 4 5 6 7 8 9 10 11 years years More gastro-intestinal toxicity grade 1 and genito-urinary toxicity grade 1-2 are observed with RT, few grade 3 are reported

  15. Cumulative incidence of loco-regional failure 100 90 80 70 Post-operative RT: 5.4% at 5 years (98% CI: 2.7 – 8.0) 60 No further treatment: 15.4% at 5 years (98% CI: 11.2 – 19.6) 50 Gray test P<0.0001 40 30 20 10 0 (years) 0 1 2 3 4 5 6 7 8 9 10 O N Number of patients at risk : Treatment 74 503 468 404 330 268 194 128 82 44 16 Wait-and-See 25 502 465 426 362 298 228 154 107 55 14 Irradiation

  16. Clinical progression-free survival 86.3% (82.2 – 90.4) 100 90 Post-operative RT 80 70 77.1% (72.1 – 82.0 ) No further treatment 60 % 50 40 30 HR=0.61 98% CI: (0.43, 0.87) 20 Logrank P=0.0009 10 0 (years) 0 1 2 3 4 5 6 7 8 9 10 O N Number of patients at risk : 113 503 467 401 324 259 188 124 79 42 16 75 502 464 424 357 291 221 150 101 53 14

  17. Biochemical progression-free survival 100 74.0% (68.7 – 79.3) 90 80 70 Post-operative RT 60 % 50 52.6% (46.6 - 58.5 ) 40 No further treatment 30 HR=0. 48 98% CI: (0.37, 0.62) 20 Logrank P<0.0001 10 0 (years) 0 1 2 3 4 5 6 7 8 9 10 O N Number of patients at risk : 220 503 425 337 243 182 126 84 52 27 10 131 502 456 407 330 262 193 125 85 41 11

  18. Biochemical PFS by pT Events / Patients Statistics HR & CI |1-HR| Code and name Post-op RT Wawa (O-E) Var. (Post-op RT : Wawa) % ± 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 52% ±8 (26.2 %) (43.7 %) reduction 0.25 0.5 1.0 2.0 4.0 Post-op RT Wawa Test for heterogeneity better 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

  19. B-PFS Wait and See 100 90 80 70 60 50 40 30 20 Overall Wald test: p=0.0007 (df=3) 10 0 (years) 0 2 4 6 8 10 O N Number of patients at risk : Margin status 22 76 65 34 12 6 Loc - / Rev - 22 33 21 10 4 2 Loc - / Rev + 11 40 30 19 13 5 Loc + / Rev - 57 119 86 48 23 6 Loc + / Rev +

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

  21. ARO 96-02385 patients with pT3 N0 M0 4-year biochemical progression free survival 1 0,75 RT 81% 0,5 WW 60% 0,25 p = 0,0010 HR : 0,49 (IC 95 0,3-0,75) 0 0 Wiegler T et al et al ASCO 2005, abstract 4513

  22. 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. 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.

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