1. Association Radiothérapie-Hormonothérapie Cancers localisés et localement avancés de la prostate Michel Bolla, Camille Verry Clinique Universitaire de Cancérologie-Radiothérapie SFjRO Montpellier 8 Juin 2012

2. Risk of Relapse* -Low cT1a-T2a and Gleason 2-6 and PSA < 10ng/ml -Intermediate cT2b-T2c or Gleason 7 or PSA 10-20 ng/ml -High cT3a-b or Gleason 8-10 or PSA > 20 ng/ml -Very high cT3c-4 or any T N1 * modified from Scardino PT et al. Prostate Cancer. In L. Denis Ed. 3rd international consultation on prostate Cancer. Paris 2003; 219-47

3. To improve the loco-regional tumoral effect by reducing the number of clonogenic cells (additive or supra-additive effect) and improving the cell cycle cooperation To decrease metastases failures due to micro-metastatic disease (spatial cooperation) To decrease hypoxia by normalizing tumoral angiogenesis To synchronize the two treatments To increase overall survival

4. 1995 -2001 : 206 patients T1b – T2b N0-X M0 PSA < 40 ng Gleason > 7 (73 %) 3D-CRT : 70.35 Gy Prostate + S.V. +/- 6 months LHRHa + Flutamide 250mg TID Median follow-up : 7.6 years Overall survival : 74 % vs 61 % p = 0.01 D’Amico A.V. et al. ASCO Prostate 2008 Intermediate and high risk localized PCa Boston trial

5. Impact of comorbidity D’Amico A.V. et al. JAMA. 2008; 299(3):289-295

6. Impact of comorbidity D’Amico A.V. et al. JAMA. 2008; 299(3):289-295

7. Intermediate and high risk localized PCa RTOG 94-08 trial (1979 patients) STRATIFYSTRATIFY RANDOMIZERANDOMIZE PSA 1.<4 2.4-20 Grade (Differentiation) 1.Well 2.Moderate 3.Poor Nodal Status 1.N0 (surgical) 2.NX Arm 1 Arm 2 Neoadjuvant TAS two months before and during RT (66.6 Gy)* Radiation Therapy Alone (66.6 Gy)* *Prostate re-biopsy to be done 2 years post-treatment.

8. RTOG 94-08 10-year overall survival 62% 57%

9. RTOG 94-08 10-year overall survival

10. Intermediate risk PCa IMRT + LDR Brachytherapy +/- ADT 432 patients Median biologically effective dose : 206 Gy (142-280) ADT : 9 months (82 patients) 8-year BDFS with ADT : 92% 8-year BDFS without ADT: 92% (p = 0.4) Stock RG et al. J. Urol 2009; 183 : 546-50

11. Low, intermediate and high risk PCa IMRT +/-HDR brachytherapy IMRT (86.4 Gy) : 470 patients HDRB (21 Gy/3 fr) + IMRT (50.46 Gy) : 160 patients Median follow-up : 53 months and 47 months 5-year BDFS for intermediate-risk PCa 84 % vs 98 % (p < 0.001) Better BDFS without ADT (p= 0.0005) Deutsch I et al, Brachytherapy 2010; 9 : 313-8

12. Locally advanced PCa (415 patients) 10-year overall survival Bolla M. et al. Lancet Oncol 2010 ; 11 :1066-73 (years) 024681012141618 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 1122081781238256412293 80207185154113775126112 RTX RTX+LTAD HR=0.60 (95%CI: 0.45-0.80) Medians: 10.9 y vs 6.9 y P=0.0004 RTX RTX+LTAD 58.1% (CI: 49.2%-66.0%) 39.8% (CI: 31.9%-47.5%)

13. RTOG 86-10 : RT +/- 4-month CAB T2-4 N0-1 M0 (456 patients): 10-year results C AD-RTRT O.S*.42.6%vs33.8%p=0.12 D.S.M.23.3%vs35.6%p=0.01 D.M.34.9%vs46.9%p=0.006 B.F.R.65.1 %vs80%p<0.0001 D.F.S.11.2%vs3.4%p<0.0001 *significant difference for Gleason 2-6 Roach III M. et al. J Clin Oncol 2008; 26:585-91

14. Pilepich M.V. et al. Int. J. Radiat. Oncol. Biol. Phys. 2005 ; 61(5) :1285-90 % local failure23 vs 38 p<.00001 % distant metastases24 vs 39 p<.0001 % b NED PSA < 1,5 ng31 vs 9 p<.0001 % overall survival49 vs 39p<.002 RTOG 85-31: RT +/- LT adjuvant ADT T3-4 N0-1M0 (977 patients): 10-year results

15. RTOG 92-02: RT+neo, concomitant +/- LT ADT T2c-4 N0M0 (1554 patients): 10 years results NAHT NAHT+LTAS O.S. 51.6% p=0.36 53.9% O.S. (Gleason8-10)31.9%p=0.00645.1% D.S.S.83.9%p=0.00488.7% Horwitz E.M. J Clin Oncol 2008; 26:2497-2504 (More than 10 % of the patients with the Gleason score < 7)

16. TTROG 96-01: RT +/- neo-concom. ADT T2b-4 N0-XM0 (818 patients): 10-year results 1996-2000 T2b-c (60%), T3-4 (40%) 84% HR, 16% IR Prostate and seminal vesicles : 66 Gy Zoladex (3.6 mg) + Flutamide 3 x 250 mg 0 month (270), 3 months (265), 6 months (267) Median follow-up 10.6 years (IQR 6.9 – 11.6) Denham JW et al. Lancet Oncol 2011Epub ahead of print

17. Trans-Tasman Radiation Oncology Group 96-01 neoadjuvant and concomitant ADT 10-year results * LF DF BDFS EFS all cause Mortality 3-month p=0.0005 p=0.55 p=0.003 p<0.0001 p=0.18 6-month p=0.0001 p=0.001 p<0.0001 p< 0.0001 p=0.0008 * Reference : RT alone group Denham JW et al. Lancet Oncol 2011 Epub ahead of print

18. EORTC 22961 equivalence trial 5-year overall survival (years) 0123456789 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 100483470452409332235122374 734874764504143542391305217 Short ADT Long ADT HR(SADT/LADT): 1.43 (96.4% CI: 1.04-1.98) P-Value: 0.6543 (H1: SADT non inferior) 85.3% (98.2% CI: 80.5-89.0) Long ADT Short ADT 80.6% (98.2% CI: 75.4-84.8) P-value: 0.0191 (H1: LADT superior) Bolla M. et al N Engl J Med 2009;360: 2516-27

19. Dose escalation

20. Dose escalation Phase III trials Authors (yr)nDose(Gy)BDFSP-value Kuban (2008)+1517873 %(10 yr)0.004 1507050 %(10 yr) Zietman (2010)19579.283%(10 yr) < 0.001 19770.267% (10 yr) Peeters (2006)*3337864 %(5 yr)0.02 3316854 %(5 yr) Dearnaley (2007)*4227471 %(5 yr)0.0007 4216460 %(5 yr) Beckendorf (2011)+3068072 % (5yr)0.036 7061 % (5yr) +Nadir+2 FFBF ; * Neoadjuvant AD < 6 months tolerated or recommended.

21. GICOR 05/99 : Dose escalation in high risk patients GICOR 05/99 : 306 patients 1995-2007 < 78 Gy p =.005 > 78 Gy NAD (4-6 months) + AAD (2 years) NAD (4-6 months) + AAD (2 years) Median dose 78 Gy (66-84.1Gy) 5 - year BDFS Zapatero A. J Int J Radiation Biol Phys 2011 ; 81:1279-1285

22. 3D-CRT +/- IMRT with dose escalation 2251 T1-3 N0-X M0 64.8 -86.4 Gy (Image guided > 81 Gy. CAB : 623 high risk (69%), 456 intermediate risk (42%) and 170 low risk (30%) Duration: 3 months (LR), 6 months (IR and HR risk patients), starting 3 months prior RT Median follow-up: 8-year. Zelefsky M et al. Eur Urol. 2011;

23. 3D-CRT +/- IMRT with dose escalation 10-year results Biochemical Disease Free Survival -Low risk : 84% (> 75.6 Gy) vs 70% (p=0.04) -Intermediate risk: 76% (> 81 Gy) vs 57% (p=0.0001) -High risk: 55% (> 81 Gy) vs 41 % (p=0.0001) -6-month ADT : 55 % versus 36% for high risk (p<0.0001). Distant Metastases Free Survival -dose > 81 Gy (p=0.027) and ADT (p=0.052) PCa mortality or overall survival, not influenced Zelefsky M et al. Eur Urol. 2011;

24. Techniques of dose escalation Image guided IMRT

26. x ray tube Accelerato r Robotic coach Robotic arm x ray tube Cylindric collimator G4 (2 ) (3 ) (1 ) (4 ) Radiotherapie stéréotaxique robotisée (Cyberknife™)

27. Axial Sagittal Planning CT TomoCT Tomotherapy Mise en correspondance Tomotherapy Mise en correspondance

28. IMRT for pelvic lymph node irradiation Lawton CAF, et al. Int J. Radiation Oncology. Biol. Phys. 2009; 74 : 377 - 82

29. Therapeutic indications Localized Prostate cancer Low risk Image guided IMRT (80Gy) IMRT (46 Gy) + Brachytherapy (low or high dose rate) Intermediate risk Image guided IMRT (78 Gy) + Complete androgen blockade (4 -6 months) High risk Image guided IMRT (78 Gy) Pelvic lymph nodes RT (56Gy) LT ADT (3 years*) *according to the number of prognostic factors

30. Locally advanced Prostate Cancer Image guided IMRT (78 Gy) Pelvic lymph nodes RT (56Gy) LT ADT (3 years)

31. Androgen deprivation therapy: iatrogenic effects Fatigue, weight gain Sexual side effects Anaemia Modification of glucide metabolism Modification of lipid metabolism Increase of incidence of cardio-vascular mortality Metabolic syndrome Bone mineral density loss

32. Cardiovascular mortality (years) 024681012141618 0 10 20 30 40 50 60 70 80 90 100 ONNumber of patients at risk : 172081781238256412293 207185154113775126112 RTX RTX+LTAD RTX+LTAD: 22 deaths HR=1.11 (95%CI: 0.59- 2.09) P>0.75 RTX: 17 deaths 10-year cumulative incidence: RTX: 5.1% (CI: 2.0%-8.2%) RTX+ LTAD: 11.1% (CI:6.1%-16.1%)

33. Cardiac event-specific mortality

34. Heidenreich A, Bellmunt J, Bolla M, et al. European Association of Urology. EAU guidelines on prostate cancer. Eur Eurol 2010 ; 59: 61-70. Evidence-based multidisciplinary approach

35. Remerciements  L. Collette Statistician (EORTC)  M. Pierart Data Manager (EORTC)  The steering committee and all the members of the EORTC ROG  Pr H. van Poppel and Pr T. de Reijke, EORTC GU Group  Pr JL Descotes, Urologist, CHU Grenoble,  Dr D. Brochon, M. Conil in charge of EORTC trials data management in Grenoble  All our gratitude to the patients included in EORTC trials 22863, 22961,22991.