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 »
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
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
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
STOCKHOLM
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