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

Risk of Relapse* -Low cT1a-T2a and Gleason 2-6 and PSA < 10ng/ml -Intermediate cT2b-T2c or Gleason 7 or PSA 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;

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

: 206 patients T1b – T2b N0-X M0 PSA < 40 ng Gleason > 7 (73 %) 3D-CRT : 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

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

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

Intermediate and high risk localized PCa RTOG trial (1979 patients) STRATIFYSTRATIFY RANDOMIZERANDOMIZE PSA 1.< 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.

RTOG year overall survival 62% 57%

RTOG year overall survival

Intermediate risk PCa IMRT + LDR Brachytherapy +/- ADT 432 patients Median biologically effective dose : 206 Gy ( ) 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 :

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= ) Deutsch I et al, Brachytherapy 2010; 9 : 313-8

Locally advanced PCa (415 patients) 10-year overall survival Bolla M. et al. Lancet Oncol 2010 ; 11 : (years) ONNumber of patients at risk : RTX RTX+LTAD HR=0.60 (95%CI: ) Medians: 10.9 y vs 6.9 y P= RTX RTX+LTAD 58.1% (CI: 49.2%-66.0%) 39.8% (CI: 31.9%-47.5%)

RTOG : 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< D.F.S.11.2%vs3.4%p< *significant difference for Gleason 2-6 Roach III M. et al. J Clin Oncol 2008; 26:585-91

Pilepich M.V. et al. Int. J. Radiat. Oncol. Biol. Phys ; 61(5) : % local failure23 vs 38 p< % 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

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

TTROG 96-01: RT +/- neo-concom. ADT T2b-4 N0-XM0 (818 patients): 10-year results 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

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

EORTC equivalence trial 5-year overall survival (years) ONNumber of patients at risk : Short ADT Long ADT HR(SADT/LADT): 1.43 (96.4% CI: ) P-Value: (H1: SADT non inferior) 85.3% (98.2% CI: ) Long ADT Short ADT 80.6% (98.2% CI: ) P-value: (H1: LADT superior) Bolla M. et al N Engl J Med 2009;360:

Dose escalation

Dose escalation Phase III trials Authors (yr)nDose(Gy)BDFSP-value Kuban (2008) %(10 yr) %(10 yr) Zietman (2010) %(10 yr) < % (10 yr) Peeters (2006)* %(5 yr) %(5 yr) Dearnaley (2007)* %(5 yr) %(5 yr) Beckendorf (2011) % (5yr) % (5yr) +Nadir+2 FFBF ; * Neoadjuvant AD < 6 months tolerated or recommended.

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

3D-CRT +/- IMRT with dose escalation 2251 T1-3 N0-X M 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;

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;

Techniques of dose escalation Image guided IMRT

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

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

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

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

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

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

Cardiovascular mortality (years) ONNumber of patients at risk : RTX RTX+LTAD RTX+LTAD: 22 deaths HR=1.11 (95%CI: ) 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%)

Cardiac event-specific mortality

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

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.