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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