association radiothérapie-hormonothérapie cancers localisés et localement avancés de la prostate...
TRANSCRIPT
Association Radiothérapie-Hormonothérapie
Cancers localisés et localement avancés de la prostate
Michel Bolla, Camille Verry
Clinique Universitaire de Cancérologie-RadiothérapieSFjRO 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 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
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
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
Impact of comorbidity
D’Amico A.V. et al. JAMA. 2008; 299(3):289-295
Impact of comorbidity
D’Amico A.V. et al. JAMA. 2008; 299(3):289-295
Intermediate and high risk localized PCa
RTOG 94-08 trial (1979 patients)
STRATIFY
RANDOMIZE
PSA1. <42. 4-20
Grade (Differentiation)1. Well2. Moderate3. Poor
Nodal Status1. N0 (surgical)2. NX
Arm 1
Arm 2
Neoadjuvant TAS two months before and during RT (66.6 Gy)*
Radiation TherapyAlone (66.6 Gy)*
*Prostate re-biopsy to be done 2 years post-treatment.
RTOG 94-0810-year overall survival
62%
57%
RTOG 94-0810-year overall survival
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
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
Locally advanced PCa (415 patients) 10-year overall survival
Bolla M. et al. Lancet Oncol 2010 ; 11 :1066-73
(years)
0 2 4 6 8 10 12 14 16 18
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :112208 178 123 82 56 41 22 9 3
80 207 185 154 113 77 51 26 11 2
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%)
RTOG 86-10 : RT +/- 4-month CAB T2-4 N0-1 M0 (456 patients): 10-year results
CAD-RT RT
O.S*. 42.6% vs 33.8% p=0.12
D.S.M. 23.3% vs 35.6% p=0.01
D.M. 34.9% vs 46.9% p=0.006
B.F.R. 65.1 % vs 80% p<0.0001
D.F.S. 11.2% vs 3.4% p<0.0001
*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. 2005 ; 61(5) :1285-90
% local failure 23 vs 38 p<.00001
% distant metastases 24 vs 39 p<.0001
% b NED PSA < 1,5 ng 31 vs 9 p<.0001
% overall survival 49 vs 39 p<.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=0.36 53.9%
O.S. (Gleason8-10) 31.9% p=0.006 45.1%
D.S.S. 83.9% p=0.004 88.7%
Horwitz E.M. J Clin Oncol 2008; 26:2497-2504
(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
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
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
EORTC 22961 equivalence trial5-year overall survival
(years)0 1 2 3 4 5 6 7 8 9
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :100 483 470 452 409 332 235 122 37 473 487 476 450 414 354 239 130 52 17
Short ADTLong 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
Dose escalation
Dose escalation Phase III trials
Authors (yr) n Dose(Gy) BDFS P-value
Kuban (2008)+ 151 78 73 % (10 yr) 0.004150 70 50 % (10 yr)
Zietman (2010) 195 79.2 83% (10 yr) < 0.001
197 70.2 67% (10 yr)
Peeters (2006)* 333 78 64 % (5 yr) 0.02331 68 54 % (5 yr)
Dearnaley (2007)* 422 74 71 % (5 yr)0.0007
421 64 60 % (5 yr)
Beckendorf (2011)+ 306 80 72 % (5yr) 0.03670 61 % (5yr)
+Nadir+2 FFBF ; * Neoadjuvant AD < 6 months tolerated or recommended.
Dose escalation in high risk patients GICOR 05/99 : 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)Median dose 78 Gy (66-84.1Gy)
5 - year BDFS
Zapatero A. J Int J Radiation Biol Phys 2011 ; 81:1279-1285
3D-CRT +/- IMRT with dose escalation2251 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;
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
Accelerator
Robotic coach
Robotic arm
x ray tube
Cylindric collimator
G4
(2)
(3)
(1)
(4)
Radiotherapie stéréotaxique robotisée (Cyberknife™)
Axial
Sagittal
Planning CTTomoCT
TomotherapyMise en correspondance
TomotherapyMise en correspondance
IMRT for pelvic lymph node irradiation
Lawton CAF, et al. Int J. Radiation Oncology. Biol. Phys. 2009; 74 : 377 - 82
Therapeutic indicationsLocalized Prostate cancer
Low riskImage 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 riskImage 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)
0 2 4 6 8 10 12 14 16 18
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :17 208 178 123 82 56 41 22 9 3
22 207 185 154 113 77 51 26 11 2
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%)
Cardiac event-specific mortality
Heidenreich A, Heidenreich A,
Bellmunt J, Bolla M, Bellmunt J, Bolla M,
et al. European et al. European
Association of Association of
Urology. EAU Urology. EAU
guidelines on prostate guidelines on prostate
cancer.cancer.
Eur Eurol 2010 ; 59: Eur Eurol 2010 ; 59:
61-7061-70..
Evidence-based Evidence-based multidisciplinary multidisciplinary approachapproach
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.