Association Radiothérapie-Hormonothérapie Cancers localisés et localement avancés de la prostate Michel Bolla, Camille Verry Clinique Universitaire de.

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.