Pr Gilles Créhange, MD, PhD 1,2

Départements d ’Oncolog ie Radiothérapie

1. Centre Georges François Leclerc, DIJON2. CHRU Jean Min joz Besançon

Radiothérapie et cancer du rectum :

5 vs 25 séances?

13èmeBiennaledeCancérologiedeMonaco

2Février2018

Liens d’intérêtLiens d’intérêt

CentreGeorgesFrançoisLeclerc,DijonUniversitédeBourgogne

CHRUJeanMinjoz,Besançon

Expert,Consultant

JanssenIpsenAstellasTakedaBayerSanofiQualimedisGalderma

Post-op Pre-op p5-y outcome (n=394) (n=405)

Survival % 74 76 0.80LF % 13 6 0.006

acute toxicity 40 27 0.001(Diarrhées)

chronic toxicity 24 14 0.01(Sténoses anastomotiques)

Rodel C et al., NEJM 2004

RCT étalée sur 5 semaines CAO/ARO/AIO-94

TME SURGERY

CAO/ARO/AIO-94

declared to sphincter-savingrequire APR surgery

Post 78 19 % (15/78)

Pre 116 39 % (45/116) p 0.004

XRT-CT préopératoire Impact sur la conservation sphinctérienne

Rodel C et al., NEJM 2004

5-y LR, %

RT RT + CT

EORTC 17 8

FFCD 16 8

Bosset, NEJM 2006; Gerard, JCO 2006

Rôle de la chimiothérapie concomitante préop

Schémasuédois(5X5Gy)sansTME

StockholmI: 1980-1986, 849patients•RéductiondutauxdeRLde50%•AugmentationsignificativeDCpostop8%vs2%

SRCSGCancer1990,66:49-55

StockholmII: 1987-1993, 557patients•RéductiondutauxdeRLde56%• SG(aprèschircurative)etDCliésaucancerrectalréduitsaprèsRT5X5(p<0.001)

MartlingA.Cancer2001,92:896-902

RT 5X5Gy (Swedish Rectal Cancer trial) : 13-y FU

Folkesson J et al., JCO 2005

Rechutes locales Survie Globale

Tous les pts

Tous les pts

Stade I

Stade I

Stade IIStade II

Stade IIIStade III

P= 0.008 P= 0.31

P= 0.27 P= 0.18

25 Gy, 45 Gy, 50.4 Gy …

BujkoK.etal.RadiotherOncol2008

RT courte 5X5Gy + «TME»

Dutch TME trial

cm from 2-y LR, %anal verge RT+TME TME p

0-5 5.8 10 0.055-10 1.0 10.1 <0.001

10-15 1.3 3.8 0.17

Marijnen C et al., NEJM 2001

RT 5X5Gy (TME trial) : 12-y FU

Van Gijn W et al., Lancet Oncol 2011

RL : ( 50% à 12 ans (5% vs. 11%)

SG : pas d’impact sauf…

Stade III, CRM- : SG 10 ans : 40% vs. 50% (p= 0.032)

Décès par second cancer 14% vs. 9%

Dutch trial Résultats fonctionnels à 14 ans du 5X5

Chen TYT, Clin colorect Cancer 2015

Pooledanalisys:CAO-ARO,EORTC,Swedishtrials,Polishtrial

Variable HR 95% CI p-valueDistance <0.001

≤ 5 cm 1.005-10 cm 0.84 0.67 – 1.06 0.15> 10 cm 0.44 0.30 – 0.64 <0.001

N status <0.001N0 1.00N+ 2.31 1.89 – 2.83

CRM <0.001Negative 1.00Positive 3.12 2.22 – 4.40 <0.001Unknown 1.24 0.77 – 1.99 0.38

*Modeladjustedfortrial,arm,sex,age,surgicalprocedure,numberofexaminedLNandanastomotiqueleakage DenDulkM.,EJC2007

Polish trial• 5 X 5 vs. 25 X 1.8 +CT

•N = 312 pts

•FU = 4 ans

P= 0.960 P= 0.32

Bujko, K et al., BJS 2006

Short- termradiotherapyversusconventionallyfractionatedchemoradiation

5X5Gyversus 50.4Gywith 2cycles5FU-Lv

409eligible patients,164excluded

5x5 CRTRth– S 8d 78d

Complete CR 2% 13% p<0.001

Micro CR 1% 16% p<0.001

Positive CRM 13% 4% p=0.017

Sphincter PR 62% 58% p=0.57

BujkoK.RadiotherOncol2004;75:15-24

RA

ND

OM

ISAT

ION TM

E

TME4-8 w

d3-7

25Gy/5fx

50Gy/25fx5-FUc + bolus

Schémas court vs. LongTROG 01-04

Ngan S. et al., JCO 2012

N= 326 T3 IRMFU Median = 5.9 ans

5-FU hebdo X 6

5-FU hebdo X 4

Downstaging

ypT0 1% vs. 15%

ypT0-2 28% vs. 45% (p= 0.003)

ypT3 (SD) 67% vs. 52% (p= 0.002)

ypN0 60% vs. 65% (p= 0.50)

Chir

AAP vs. RRA (N.S.)

Schémas court vs. LongTROG 01-04

Ngan S. et al., JCO 2012Distal vs. prox: HR= 1.59;95%CI, 0.58 to 4.34; P=0.31LC vs. SC: HR= 0.75; 95% CI, 0.32 to 1.77; P= .66

STOCKHOLM IIIRA

NDO

MIS

ATIO

N TME

TME

TME

4-8 w

4-8 w

1 w

25Gy/5fx

50Gy/25fx

25Gy/5fx

ARM 1

ARM 2

ARM 3

STOCKHOLM III

Erlandsson J et al., Lancet Oncol 2017

CT Suivi médian

T aigues T tardives Complications postop

TROG 0104 LC 3 ans LC < SC - LC = SCPOLISH I LC 4 ans LC < SC LC = SC LC = SCPOLISH II LC + SC 3 ans - LC = SC LC = SCSTOCKHOLM III - 5 ans LC<SC LC = SC LC = SC

Toxicités / Complications postop

Ansari N, Ann Surg 2017Bujko K, BJS 2006Bujko K, Ann Oncol 2017Erlandsson J, Lancet Oncol 2017

CRM evaluation

NagtegaalI.JCO2008;26:303-312

Impact of neoadjuvant therapy

• A positive CRM is a more powerful predictor of local recurrence– From 1% to 28 %

–Neoadjuvant therapy• Dutch Trial: 5 X 5 does not influence the percentage of positive margins

• Polish trial: 25 Gy versus 50.4 Gy: there is a difference: 13% vs 4%

• EORTC 22921: The addition of 5FU based chemotherapy did not decrease the number of positive margins (more dowstaging but no difference in CRM positivity)

RCT préop : Réponse T2-w IRM vs path (n= 119)

Median FU = 62 mos

5-y OS 62.2 (CRM-) vs 42.2% (CRM+)

HR= 1.97 (95% CI, 1.27 to 3.04; P .01)

5-y DFS was 67.2% (95% CI, 61.4% to 73%)

(CRM-) vs. 47.3% (95% CI, 33.7% to 60.9%) (CRM+)

HR=1.65 (95% CI, 1.01 to 2.69; P .05)

LR HR= 3.50 (95% CI, 1.53 to 8.00; P .05) (CRM+)

MVA : MRI-based CRM LR+, DFS+, OS+

MERCURY study : 5-y results

Taylor FGM, JCO 2014

MRI-based good prognosis patients (MERCURY study)

Taylor FGM, Ann Surg 2011

MRI-directed therapy« Le Bon, la brute et le truand »

Blomqvist L, Glimelius B. Acta Oncol 2008

POLISH IISC + 3 FOLFOX-4 vs LC 5FU-based

Bujko K, Ann Oncol 2017

SG 3 ans = 73% vs 65%, p= 0.046 RL 3 ans = 22% vs 21%, p= 0.82

Tx Mets (22% vs 21%), p=NSDFS (53% vs 52%), p= NS

5X5 + mFOLFOX6 preop

Markovina S et al. IJROBP 2017

RAPIDO trial (Radiotherapy And Preoperative Induction therapy followed by Dedicated Operation)

2 arms (1:1)

Primary objective =

3-y DFS from 50% to 60% (HR= 0.737)

Sample size 885 pts

• 2 standards XRT courte (25/5) XRT longue (45/25)

• XRT-CT (45/25) : pCR, LR, DFS, (SG et décès/second K?)

• XRT courte (25/5), recul + long : LR, SG (St III, CRM-)

• MAIS…qualité de vie << si anus conservé

• Rétablissements de continuité << vs RT étalée

• XRT courte non recommandée si T4, CRM+, ≤5cm (RTCT étalée)

• XRT courte et intervalle avec la chirurgie + long = Nouvelle option valide

• Futurs enjeux : QDV et les rechutes M+ (30-35%)

CONCLUSIONS