1Amiens, 22 novembre 2014

Centre Antoine Lacassagne

Nice

J.P. GERARD

Radiothérapie et

cancer du rectum

Protocoles et Indications

2

DISCLOSURE

Ariane Medical SystemsTM (UK)

Contact Brachytherapy X Ray 50 kV

"Papillon 50"

J.P. GERARD

Medical Advisor

Philips

RT 50

20091971

PLAN

• les techniques de Radiothérapie (externe- curie)

• Traitements neo-adjuvants : Phase III (rationel)

• Les protocoles ( TNCD – thésaurus )

• Les Essais en cours (et à venir)

• 1970

Linear accelerator

X 10-18 MV

. 1995

Digital -Computer

RC 3D - IMRT

Contouring : GTV -

CTV and OAR

3D CT scan

simulation

CTV

GTV

OAR

6

Nice

Total dose

50 Gy

44 + 6

(boost)

T2 N0

Overview

Treatment

Plan

Isodose

Display

44 Gy

7

RT+

Loc Recurrence Green : pN0, Red : pN1

J Nijkamp, IJROBP 2010 Dutch TME below S2/S3

Treatment room

Positionning : laser

Image guided

Dynamic arc

1

2 3

- Multi leaf collimator (1)

- Conformal 3D RT (2)

- Intensity modulated RT (3)

(IMRT : concave)

IGRT : Image guided

Adaptive

Radiotherapy

Novalis

KV.KV - cone beam CT

TomoTherapy

Field Matching DRR vs kV image : Lateral Field

CyberknifeTomotherapy Linac

Vero Novalis – Gama Knife

radiotherapy machines

EDGE

V Mat

1313/2009 13/2009

"CAP 50“ French Standard 2012

RXTherapy 50Gy / 25fractions / 5 weeks

2Gy/fraction

field shrincking after 44 Gy

Capecitabine 1.600 mg/m2/day

(800 mg bid) (825)

on RXT days (not W.E.)

RT Dose/volume Effect - « small volume »

Marie Curie and Albert Einstein

Lac Leman, Suisse 1925

Radium

Discovery

Curietherapy

BRACHYtherapy

/2009 15

interstitial HDR

Brachytherapy Ir192

1

/2009 16

1

2

BRACHYTERAPY

1) Contact X Ray

Brachytherapy

X 50 Kv

CXBP 50

2) Endoluminal

HDR Brachy

Iridium 192

17

Contact x-ray 50 kv Papillon technique

Philips

CXB

50 Kv

1968

1971

cCR

30 Gy

2mn

30 Gy

/2009 18

CXB unique RT = high precision with eye guided

into Small Volume (5cm3) : HIGH DOSE / Fraction

30.Gy

2 min.

Transanal Endoscopic radiotherapy

19

T1

T3LEGRAND tm

KNEE - CHEST

CCR

Rectoscope

disposable

RECTOSCOPY + DRE in KNEE CHEST POSITION

« BIOPROBE »

20

Rectosope : 2,5 cm de diamètre

Legrand Paris info@a-legrand.com

Papillon50TM

Transanal Endoscopic

Contact X Ray

brachytherapy 50 kv

CXB

2009

Papillon 50 TM Transanal Endoscopic CXBAccurate Targeting . Ambulatory . Any age

1) Scope-Target 2) Fixation 3) Irradiation

/2009 23

Local excision (TEM) or

T2-3 Nxcombined CBX+EBRT

Watch / Wait

EBRTCBX 50kV +

24

uT3N0

Day 1

Day 21 7 years

1992

25

Mr W.

74 y

Oct. 2010

T2N0CXB

110 Gy

CAP 50

CCR

07/2014 :

Loc Cont

D1 : 35Gy

D28 : after 65Gy D35 : CCR

/2009 26/2009 26

Mr Boe 84 y Card. Ins.

ADK uT3 N0 3cm diam. low R.

March 2009 : CBX (100 Gy)

CAP 50 = Jan. 2014 : NED

1995

C

C

CC : Cure : 50%

C : Conservative

C : Cost effective

Radiotherapy

3 C

Relevance of Radiotherapy

« 3 C »

Cure : 50 % of patients treated with RXT

Conservative : eye, larynx, breast, rectum etc…

Cost – effective : France Health : 200 B €

Cancer : 20 B € - Radiotherapy : < 2 B €

RT many various –complex techniques

“Tailored treatment” - “sur mesure”

/2009/2009

SURGERY : main treatment Rectal Kc

• TME : sharp dissection/ visual control (R0, nerve)

• ISR Inter-sphinteric : bowel function ?

• LAPAROSCOPIC Surgery (« health capital »)

• Robotic surgery (17 M € ) ?

Anesthesiology- Intensive Care :

60 days post – op mortality < 2% +++

/2009/2009

TME SURGERY : APE

Extra-Levator A P E

APE :

T3 bad - T4

Distal rectum

R0 : CRM −

Waist

Courtesy

Ph Quirke

/2009/2009

- Surgery ("TME") main treatment.

Neo (adjuvant )treatment benefit ?

Evidence Based Medecine

ONLY RANDOMIZED TRIALS

/2009/2009

Neo (adjuvant) phase III – O verview

- NIH ( JAMA 1999) : Postop chemoRT Standard

- 2004 : German / Sweden: preop > post op

- 2006 : FFCD-EORTC : chemoRT > RT alone

- 2010 : ACCORD12 : RT dose 50 Gy > 45

- 2012 : STAR-NSABP- PETACC6 : no Conc. oxalipt.

- 2003 : Dutch + CRO7 : 5x5 useful with TME

/2009/2009

Benefit of neoadjuvant CRT : modest

• Local control : YES ….. « TME surgery »

• Survival : NO

• Toxicity : Post-op death , anesthes. Volume RT !

• Conservative treatment ?

- Bujko : Rad. Oncol. 2006;8:4.

- Gérard : Crit. Rev. Hem. Oncol. 2012,81:28

34/2009 3430/05/2009

Does rectal cancer shrinkage induced

by preoperative RT (chemo) increase

the likelihood of anterior resection ?

References

K. Bujko – Radioth Oncol 2006; 8:

4-12

Gerard - Crit Rev Hemat onco 2012

JP Gérard Crit Rev Onc. Hem. 2012 Jan;81(1):21-8

Sph

Spincter

Saving

36

SEOUL : Rectum T3-4 M0 Ph III – pre vs post CRT

Preop 107 Postop 113

LAR 80 % 72 % (NS)

ypT0 21 % 0 %

Loc. Rec. (4y) 4 % 6 %

DFS (3y) 77 % 73 %

Late Toxicity G3-4 8 % 3 %

Med Age : 55 - Distal R : 52 % "CAP 50"

Park – Cancer 2011 ;117:3703

37/2009 3730/05/2009

Does rectal cancer downsizing induced

by preoperative RT (chemo) increase

the likelihood of

Sphincter preservation anterior resection?

References

K. Bujko – Radioth Oncol 2006; 8: 4-12

Gerard - Crit Rev Hemat onco 2012 ;81:8

NO ! ! WHY ?

/200930/05/2009

Adenocarcinoma rectum : radioresistantRadiation Dose-Response Model (EQD 2)

A Appelt-Jakobsen Int J R OBP 2013 ; 85: 74

T3 rectal ADKypCR

Veijle : 222 ptsEBRT + Brachy Ir

D 50% = 92 Gy[79- 145 ] 95 % CI

39/2009 39

INTERVAL : LYON R 90-01 Phase III

(François; Gérard JCO 1999; 17: 2396)

Short2 (2w) Int (99) Long (6w) Int (102)

Yp CR 7% 14% (0.1)

Sphinter preserv. 69% 79% (NS)

" (<6 cm) 23% 41%

Post-op death 3% 4%

Loc. rec. (5 yrs) 13% 10%

Ov. Surv (5 yrs) 68% 66%

Cracow : 5x5 short vs long interv. 154 pts : pCR: 0% vs 10% no diff in SSS (2012)

4040

15 year follow-up

Overall survival :

48 %

NO Difference

pCR is a marker of

good prognosis not

a cause

2nd primary cancer

9%

Wang PMH : 13 weeks - Dutch: 11 weeks

Traitement conservateur - Essais

• GRECCAR 6 T3 T4 Phase III Endpoint : ypCR

délai 7 semaines

délai 12 semaines

End Point : ypCR

jeremie.lefebvre@sat.aphp.fr

RRCT preop

42

Cumulative incidence local recurrence

Time in month

Cu

mu

lati

ve

in

cid

en

ce

RT

CT-RT

FFCD 9203 JCO 2006

60 120

Chemo-Radiotherapy 5-FU

43

ACCORD 12 – RT dose effectGérard et al. J Clin Oncol 2010, 28: 1638

Cap 45 (287) Capox 50 (287)

Toxicity G3-4 11 % 25 % <0.001

Ant Resect 74 % 76 %

Death 60 days 0.3 % 0.3 %

Dworak ypCR 13.9 % 19.2 % 0.09

No + few residual

cells

29 % 39 % 0.002

CRM + 1 mm 12 % 7 % 0.17

CRM + 2 mm 19 % 10 % 0.02

/2009/2009

SAFE Radiation Dose escalation : EVIDENCE

PHASE III Lyon R96-02

• T2-3 < 1/2 circumf 6 cm Anal Verge (distal rectum)

R

EBRT (39 Gy/4w)

Cont X Brachy (90 Gy/3) + EBRT

Gérard : J Clin Oncol 2004; 22 : 2404

• End Point : sphincter preservation : 40% 70 %

• 1996 – 2001 : 88 pts randomized

45

Lyon R96-02 - Results- EVIDENCE

CBX : median dose : 85 Gy/3F Median interval : 5 weeks

No chemotherapy - Operable Patients

EBRT (43) CXB+EBRT (45)

cCR 1 (2%) 11 (29 %) p<0.05

APE 24 (56%) 11 (24%)

Sph. Saving Tt 19 (44%) 34 (76%) p=0.004

RT alone (Org) 0 7 (cCR : 7)

Loc. Exc. (Pre) 0 3 (cCR : 2)22%

Gerard JCO 2004;22: 2404

46

Lyon R 96-02 - 10 years Fol.up

EBRT (43) CXB 90 Gy + EBRT (45)

cCR 2 % 29 % < 0.05

Sph. Sav. Sgy 44 % 76 % < 0.05

Organ preserv. 0 10 (3+7) < 0.05

10 y stomy free 29% 61% <

0.05

Loc. Rec. (10 y) 16 % 11 %

Ov. Surv. (10 y) 55 % 55 %Gérard : JCO 2004 ;22:2404 - Ortholan : IJROBP 2012 ; 83: e165

/200947/2009 47/2009/2009 47

Day 1

uT2N0

Day 70

pT0N0 14 years

1999

cCR

Lyon R96.2 – Phase III – 10 years : Good Evidence

Safe dose escalation with CXB 50 kV

- Increases 30% clinical complete response

- higher rate 30% sphincter preservation

May provide organ preservation

Surgeon may reappraise the strategy

No perirectal Lymph Node relapse

C. Ortholan – J.P. Gérard

Dis Colon Rectum 2006 ; 49 : 1-9

Clinial Complete Response cCR

The CLINICAL complete response hypothesis

Radioresistance

PR

« clinical complete response is defined :

- total disappearance of the tumor,

- normal supple mucosa and rectal wall

on digital and rectoscopic examination »

Int. J Rad Onc Biol Phys 1996 ;34:775-83

/2009/2009

Cancer du rectum

Radiothérapie

Indications

TNCD :Thésaurus National de Cancérologie Digestive

- Promoteur : SNFGE

- Groupe de travail

analyse littérature – rédaction

- Groupe de relecture

modification – correction – discussion

- Comité de pilotage : SNFGE – FFCD – GERCOR

FNCLCC – SFCO – SFRO

arbritage – validation (E. Dorval)

- www.tncd.org

53STRATEGIE

54

STRATEGIE

/2009/2009

Cancer du rectum

Radiothérapie :

Radiothérapie de Contact

Organ Preservation

-

56

Day 1

T1N0

CXB

Day 21

Day 7

8 years

/2009 57

Rectal cancer T1 N0 - Contact

• Local Excision FIRST ++

• CXB 50 Kv adjuvant

+ postop RXT

Selection +++ (path specimen)

endoscopic submucosal dissection ESD gastroenterologist

Full thickness trans anal Exc. TEM surgeon

Cortesy

P O Toole

No risk (< 5%) : surveillance

Risk in tumor bed only : CXB alone

Total Dose : 50 Gy / 3 Fr / 3 w

Risk in T + N ≥ 10% : CXB + EBRT± Chemo

CXB : 30 Gy/ 2 Fr + CAP 50

APE should be exceptional in pT1

Pathological report - Decision

Papillon50TM

intraluminal

Contact brachy X 50

kv

/2009 61

Day 1

Day 21

Adjuvant

Contact X B

50 Gy/3 fr. 3weeks

Applic: 3 cm

T1 N0Local Excision

Adverse Pathology

Acta Oncol

Jp Gérard et al

Nov 2014

Local excision + adjvuant CXB ± EBRT

Ref N° pt pTis pT1 pT2 Loc Cont OS 5 y

Lyon

1980-1995 43 4 34 5 93% 80%

Nice

2004-2012 20 2 15 3 96% 82%

Total 63 6 49 8 95% 84%

Gérard Gastroent. Cl. Biol. 2000;24:430 Gérard IJROBP 2006

NO isolated lymph node relapse

64

T2 T3 : Organ preservation Rectum

1- Papillon

CXB:

T1: 90% contrôle local

2- Habr Gama

Chimioradiothérapie

Watch and Wait

« Early T2 -3 »: 40% contrôle

/2009/2009

A. Habr Gama – R. Perez – Sao Paulo (1991-2011)

T2-3 N0-1 Rectal cancer (≤ 7 cm AV) : 183 pts

CRT : 50-54 Gy (1.8) + 5FU : delay 8 weeks (Med Fup : 5y)

- cCR : 49% 90/183

- Local recurrence : 31% (28/90) (17 E + 11 late)

- Salvage : 79% 22/28 (primary T)

- 5y DFS : 68%

- 5y loc control : 94%

- Dist Met : 14% (13/90)

- Organ preservation : 78% (70/90) 39% : 70/183

Habr Gama Int J rad Onc B Phys 2014;13:360

/2009/2009

GRECCAR II – T2T3 < 4 cm- Phase III 2007-12

195 Pts T2 -3 < 4cm N0-1 ≤ 8cm AV

CAP 50 : if T < 2 cm : R. TME vs L.E.

145 pts random : 71% responders < 2 cm

71 TME : 40% pCR - ypT1: 21%

74 LE : 26 « salvage » TME (ypT2-R1)

48 pts : organ preservation (38%)

ypT0-1 all pN0 - Loc Rec ??

Local Excision (fat) : always even cCR

Vendrely Rullier Rouanet IJROBP 2014;90 abst 34

Acta Oncol

Jp Gérard et al

Nov 2014

T2 T3 CXB + EBRT : 120 Pts - Results

Ref N° pt age T2 T 3 cCR Loc Rec Sp S 5 y

Lyon

1986-2001 80 73 52 28 94% 27% 72 %

Nice

2002-2012 40 81 22 18 95% 12% 70 %

Total 120 76 74 46 94% 20% 71 %

Gérard IJROBP 2002 ; 54: 142 - Gérard Acta Oncol Nov 2014

NO isolated lymph node relapse

Clatterbridge - Liverpool

The Papillon ClinicPr A. Sun Myint

Papillon Clinic

/2009

Clatterbridge – Liverpool – A. Sun Mynt combined nCRT +

CBX elderly patient

- 2006-2011 : 132 pts m. Age : 74

- T2 : 79 T3 : 53

- Cap 45 Gy + CBX 90 Gy/3F

- Median Fol-up : 3 years

- CCR : T2 : 84% T3 : 72%

- Loc. Rec. after cCR : 4% (4/107)

Neoadjuvant Treatment and cCR

cCR : 30-50% cCR : 60-85%

Escalating RT dose with endocavitary boost (XRB – HDR)

increases cCR by 30% with acceptable toxicity.

EBRT EBRT + boost endocavitary

T2 – T3 – CCR : ↑ 30% CRT + XRBHabr Gama Mass, Beets Gérard Sun Myint

CRT alone

30-50%

CRT + contact XRB boost

60-85%cCR :

Thésaurus TNCD

- Consensus au « temps t »

- Evolutif (internet / marbre)

- Aide à la décision pratique en RCP

- L’avenir : Les essais cliniques

snfge.org TNCD – rectum 2013

7474

France – Phase III – 2014 : SURVIE

• Prodige 23 : T3-4 M0 (≤ 75 y) (T Conroy)

CAP50 – 6w – TME

Folfirinox (4 cycles/2 months)

CAP50 – 6 w – TME

End point : 3 year DFS 75% vs 85% 460 pts

R

75

RAPIDO (Sweden)

• Inclusion : MRI : "T3 c-d" – T4 (N2 ?) CRM+

CRT (8w) TME – Xelox (4 months)

5 x 5 Xelox (5m) (8w) TME

• End point : 3y DFS

• Stat : 3y DFS : 50% 60%

880 pts (SW - NL - It …)

Dutch M1 : 5 x 5 – Xelox – BVZ : 50pts : 26% pCR

R

76

Trial : Local ontrol – Phase III - 2014

• GRECCAR 4 : T3c-T4 MRI (Ph Rouanet)

Folfirinox 4 cycles – Response MRI (CRM)

Poor CAP 50 – TME

Response CAP 60 – TME

AIM : reduce R0 rate – increase cCR and AR

R

ACCORD 12 – Phase III

T3-T4 M0 : Cap 50 (Capecitabine + 50 Gy)

Age < 70y (442) Age ≥ 70y (142)

PS 0-1 99.8% 99.2%

RXT-stop 1.4% 4.2% 0.03

Surgery 99 % 95 % 0.008

Stoma 23 % 33 % 0.01

Death 6 months 6 % 12 % n.s.

Gérard JCO 2012 François Rad Onc 2014

78

Prodige T3-4 TOXICITY ≥ 75 years (2015)

• Aim : reduce toxicity – increase surgery

CAP50 + TME

25 Gy/5 + TME

• End point : - surgery performed

- 2 y DFS –Toxicity- Q o Life

R

eric.francois@nice.unicance.fr

79

the Complete

Response

Revolution

Clinical Complete Response : cCR

for ORGAN PRESERVATION

FICARE

Sao Paulo

Nov 2013

W Heald

80

« upcoming » GRECCAR 12

Goal : Increase Loc Excision : organ preservation

Inclusion : T2-3 < 4cm Distal- middle Rectum

Cap50 - W 12 : LE or TME

Folfirinox (4)- CAP 50 : LE or TME

Loc Excision if T ≤ 2cm if pT2-3 : TME

End point : Organ preservation at 1 year

Hypothesis : 40 % vs 60 %

R

/2009/2009

T 2-3a-b < 5 cm N0-1 M0 Operable ; low-mid rectum

RCRT + EBRT : 9 Gy

CRT + Cont X B :90 Gy

OPERA : Phase III 0rgan Preservation Early Rectal Adenocarcinoma

W 14

End point : organ (rectal) preservation 3 years

Hypothesis : 20 % to 40 % : 236 pts (dec 2019?)

Clinical

response

Resp

Partial : TME

cCR : Watch/ Wait or Loc Excision

Rectal adenocarcinoma T2 T3 a-b

OPERA randomized trial

4- 2014 M 69y MRI :T3a N0

90 Gy/3f CXB+ CAP 50

cCR 8-2014 - Loc Exc

ypT0

D1

D28

84

OPERA – Europe : promotion CAL Nice• UK : 4 ( 7 )

•France : 3 ( 4 ) Nice - Lyon villeurb - Mâcon

•DK : 2

Sweden : 1 Suisse : 1 ?

Start : February 2015 (CPP-ANSM- PHRC)

10 units (32) : 80 patients / year (60 -80-100)

Results December 2019 : Organ preseerved 40% T2-3ab

85

1971

Clinical Approach

Tumor Evaluation ++

Before treat t - During + - After

Clinical Tumor Response

cCR - Local Control (loc rec)

DRE - Rectoscopy - Imaging

86

Gina Brown

performing Proctoscopy

Back to the CLINIC !

87

ROENTGEN

26 décembre 1895 DESPEIGNES 1896

Observation

concernant un cas de

cancer de l’estomac

traité par les rayons

Roentgen

par le Docteur Victor

Despeignes,

Lyon Médical

July 1896: 428

1902 1912

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