Transcript 09.40

Beleid na R1 resecties bij het
maagcarcinoom
Marcel Verheij
Afdeling Radiotherapie
Disclosure
• Roche: unconditional research grant
(CRITICS)
• KWF Kankerbestrijding: projectsubsidie
Inhoud
•
•
•
•
•
Inleiding
Chirurgie
Adjuvante therapie
R1 resecties
Conclusies
Epidemiologie van het maagcarcinoom
• USA >25.000 patiënten/jr; 16.000 overlijden
• Nederland >2.000 patiënten/jr; 1.000 overlijden
• Wereldwijd 3e doodsoorzaak t.g.v. kanker
• Afname distale tumoren; toename tumoren van de
cardia en oesofagus-maag overgang
• Proximale tumoren zijn geassocieerd met reflux
• Distale tumoren zijn geassocieerd met H. pylori
• 65% T3-T4; 85% N+; 30% lever metastasering
Overleving maagcarcinoom patiënten in Europa
Leeftijd-gestandaardiseerde 5-jaars relatieve overleving (%)
1995-1999: EUROCARE-4
1999-2007: EUROCARE-5
Sant et al. Eur J Cancer 2009
De Angelis et al. Lancet Oncol 2014
Chirurgische behandeling maagcarcinoom
15 jaar follow-up resultaten D1-D2 studie
• Uitgebreide D2 lymfklier dissectie leidt
tot minder loco-regionale recidieven en
lagere ziekte-specifieke sterfte dan een
beperkte D1 dissectie
• D2 dissectie is geassocieerd met
hogere post-operatieve morbiditeit,
mortaliteit, en aantal re-interventies
•  D2 dissectie (>15 ln) is de
aanbevolen chirurgische benadering
(zonder milt- en pancreasstaart resectie, in
specialiseerde hoog-volume centra)
• Na curatieve resectie blijft de incidentie
van loco-regionale recidieven hoog
Songun et al. Lancet Oncol 2010
Waddell et al. ESMO-ESSO-ESTRO Guidelines, Ann Oncol 2013
Recidiveringspatroon na curatieve resectie
Local / Regional - only 54%
(29-72%)
Loco-regional - total
88%
(38-94%)
Distant - only
25%
(18-35%)
Gunderson et al. 1981; Smalley et al. IJROBP 2002; Lim et al. Br J Cancer 2004
(Neo-) Adjuvante behandelingen
SWOG-Intergroup 0116 Trial
MAGIC Trial
Observation
D2 Surgery
n=275
n=253
R
R
Surgery < 6 wks
n=240
n=250
n=281
1x 5-FU
Chemoradiotherapy
2x 5-FU
45 Gy/25 fx + 5-FU/ LV
Macdonald et al. NEJM 2001; Smalley et al. JCO 2012
3x ECF
n=237
Surgery 3-6 wks
3x ECF 6-12 weeks
n=137
n=104
n=219
Cunningham et al. NEJM 2006
CRITICS
Pre-operative
Chemotherapy
(3x ECC)
Gastrectomy
+ lymph node
dissection (≥ 15)
R
Post-operative
Chemotherapy
(3x ECC)
QoL
Tissue
banking
Gastrectomy
+ lymph node
dissection (≥ 15)
Pre-operative
Chemotherapy
(3x ECC)
2 weeks
3-6 weeks
www.critics.nl
Chemoradiation
45 Gy / 25 fx
+ capecitabine
+ cisplatin
< 4-12 weeks
qr
t1
qr 200
t2 7
qr 200
t3 7
qr 200
t4 7
qr 200
t1 7
qr 200
t2 8
qr 200
t3 8
qr 200
t4 8
qr 200
t1 8
qr 200
t2 9
qr 200
t3 9
qr 200
t4 9
qr 200
t1 9
qr 201
t2 0
qr 201
t3 0
qr 201
t4 0
qr 201
t1 0
qr 201
t2 1
qr 201
t3 1
qr 201
t4 1
qr 201
t1 1
qr 201
t2 2
qr 201
t3 2
qr 201
t4 2
qr 201
t1 2
qr 201
t2 3
qr 201
t3 3
qr 201
t4 3
qr 201
t1 3
qr 201
t2 4
qr 201
t3 4
qr 201
t4 4
20
14
CRITICS studie
- inclusie -
Deelnemende centra 52
Aantal patiënten
509
inclusion per quarter
11
121
1
13
cumulative inclusion
Totaal
64
643 (nodig: 788)
estimation
800
35
700
770
30
600
643
25
500
20
400
15
300
200
10
100
0
5
0
R1 resectie maagcarcinoom
• Doel radicale chirurgie: bereiken van R0 resectie
• R1 resectie is geassocieerd met slechtere prognose
• Incidentie R1 resecties: 2-22% (NL 2002-2012: 12%, NKR)
• Factoren geassocieerd met verhoogde kans op R1
resectie:
- hoger T/N-stadium
- tumorgrootte
- histologie (diffuus type)
- totale gastrectomie
Raziee et al. Gastric Cancer 2012
Invloed radicaliteit resectiemarge op overleving
Wang et al. ASO 2009
Hartgrink et al. Lancet 2009
Bickenbach et al. Ann Surg Oncol 2013
Peri-operative chemotherapie vs. chirurgie
- MAGIC studie -
Cunningham et al. NEJM 2006
5 yr OS
“Curative
resection”
36%
69.3%
23%
66.4%
Post-operatieve chemoradiotherapie (CRT)
- overleving R0 versus R1 • 2001-2011: n=110 (AVL)
• R1 resectie was GEEN
prognostisch ongunstige
factor voor patiënten na
post-operatieve CRT
• Indicatie van voordeel?
• Geen R1 controle cohort
Stiekema et al. Ann Surg Oncol 2013
Post-operatieve chemoradiotherapie verbetert
behandelresultaten t.o.v. chirurgie alleen na
R1 resectie (1)
Overall Survival
Local Recurrences
p < 0.01
p = 0.02
Chemoradiotherapy-R1
Surgery only-R1
(N=24; AVL)
(N=61; D1-D2)
Dikken et al. JCO 2010; Verheij ASTRO 2010
Post-operatieve chemoradiotherapie verbetert
behandelresultaten t.o.v. chirurgie alleen na
R1 resectie (2)
Chemoradiotherapy-R1
Surgery only-R1
Multivariate analyse:
Adjuvant CRT
HR 0.53 (95% CI 0.34 – 0.81)
Stiekema et al. ECCO 2013
(N= 40; AVL)
(N=369; NKR)
Neo-adjuvante chemoradiotherapie: fase I-II studies
Authors
Patients
RT
Chemo
Surgery
Outcome
Allal et al.
IJROBP 2005; Ann
Oncol 2003
N=19
T3-4 or N+
Median dose 38.4 Gy
(hyperfx)
2 cycles of Cisplatin (100 mg/m2) d1; 5FU
(800 mg/m2) d1-4; leucovorin (60 mg bid)
d1-4 Second cycle during RT
D2 with (sub) total
gastric resection
R0 resection 100%
pCR+pPR 47%
2yr OS 71%
Ajani et al.
JCO 2004
N=34
T2-3, Nany or
T1N1
45 Gy/25 fx
2 cycles of Cisplatin (20 mg/m 2) d 1-5; 5FU
(200 mg/m2) 21 days; leucovorin (20 mg2)
d1, 8, 15
During RT: 5FU (300 mg/m2) dd conti. iv
D2
Median number
lymph nodes
examined: 16
R0 resection 70%
pCR+pPR 54%
2yr OS 54%
Lowy et al.
Ann Surg Oncol
2001
N=24
≥T2 and/or N+
45 Gy/25 fx
10 Gy intra-operative
5FU c.i. (300 mg/m2)
83% D2
Rest PD
11% pCR
63% sign treatment effect
Ajani et al.
JCO 2005
N=41
T2-3N0-1
T1N1
45 Gy/25 fx
2 induction courses of fluorouracil,
paclitaxel and cisplatin;
5FU and paclitaxel concurrent with RT
98% S
78% R0
pCR 20%
pPR 15%
Ajani et al.
JCO 2006
N=43 assessable
[20 institutions]
T2-3N0-1
or T1N1
45 Gy/25 fx
2 induction courses with 5FU, leucovorin
and cisplatin; fluorouracil and paclitaxel
concurrent with RT
50% D2
pCR 26%
R0 77%
Med surv 23.2 m
1yr surv 72%
Wydmanski
et al. R&O 2007
N=40
TNM??
45 Gy/25 fx
4 5FU and LV based schedules (1st and
last week of RT)
80% S (D2)
R0 94%
pCR 17.5%
pPR 20%
2yr surv 63%
Saikawa et al.
IJROBP 2008
N=29 evaluable
40 Gy/20 fx
S1 (60 mg/m2/d) and
Cisplatin (6 mg/m2/d)
33% S D2;
> 10 months
R0: 100%
pCR: 4/30 (13.3%)
Med surv 25 m
Trip et al. 2013
N=25
II-IV (M0)
45 Gy/25 fx
weekly carboplatin and paclitaxel
concurrent with RT
84% D1+
R0: 72%
pCR: 16%
Combined
19 - 43 pts
40 - 45 Gy
5FU/cis-/carboplatin/
paclitaxel
D2
R0: 70 - 100%
pCR: 11 - 26%
Neo-adjuvante chemoradiatie bij het maagcarcinoom
Voordelen
• beperkte bestralingsvelden door betere definitie doelgebied
• downstaging/-sizing; grotere kans op radicale R0 resectie
• goede tolerantie
• vroege indicatie van therapie sensitiviteit
Nadelen
• geen informatie over histologie, lymfklier status
• toxiciteit kan leiden tot uitstel definitieve chirurgie
Beslisboom behandeling maagcarcinoom
EMR
ConsiderConsider
EMR
Operable
or limited
or limited
Surgery
Stage >T1N0
resection
resection
Operable
Operable
Stage >T1N0
Stage >T1N0
Re-assess ?
Consider EMR
Pre-operative
Pre-operative
or limited
chemotherapy
chemotherapy
resection
Inoperable
or
Inoperable
or
Metastatic
Metastatic
Operable
Inoperable
or
Stage >T1N0
Metastatic
Re-assess
?
Re-assess
?
Best supportive
Inoperable
or
Pre-operative
Palliative
care
Surgery Surgery
Surgery
Metastatic
chemotherapy
chemotherapy
if unfit for
treatment
Re-assess ?
Inoperable or
Metastatic
Best supportive
Best supportive
care
care
Palliative
if unfit for
if chemotherapy
unfit for
treatment
treatment
Best supportive
care
if unfit for
treatment
Her-2 negative:
Her-2 negative:
Her-2 negative:
Best supportive
HER-2 positive: Consider
HER-2 positive:
HER-2
positive:
HER-2 positive:
Consider
clinical
clinical
Consider
clinical care
Platinum
+
Platinum
+
Platinum +
Platinum +
Adjuvant Palliative
Adjuvant
Adjuvant
Adjuvant
Adjuvant
Adjuvant
Surgery
Surgery
of trials
novel of novel
Surgery
trials of novelifFluoropyrimidineTrastuzumab trials
FluoropyrimidineTrastuzumab
FluoropyrimidineTrastuzumab
chemotherapy
unfitchemotherapy
forFluoropyrimidine- Trastuzumab
chemoradiation
chemotherapy
chemoradiation
chemotherapy
chemoradiation
agents
agents
agents treatment
+ CF/CX
+ CF/CX
based doublet
or
+ CF/CX
based doublet
or
based
doublet
or
+ CF/CX
based doublet or
triplet regimen
triplet regimen
triplet regimen
triplet regimen
Consider clinical
trials of novel
agents
Palliative
Palliative
chemotherapy
chemotherapy
Re-assess ?
Her-2 negative:
tive Adjuvant
rapy
chemoradiation
ative
rapy
Gastric Cancer
(Adenocarcinoma) (Adenocarcinoma)
(Adenocarcinoma)
Operable
Operable
Gastric Cancer Operable
Stage
T1N0
Stage T1N0
Stage T1N0
(Adenocarcinoma)
Operable
tage >T1N0
y
Gastric Gastric
Cancer Cancer
Gastric Cancer
(Adenocarcinoma)
Adjuvant
Surgery
chemotherapy
Adjuvant
chemoradiation
Her-2 negative:
nd
HER-2 positive:
Platinum + 2 line single
Adjuvant
Post-operative
Post-operative
Post-operative
agent Trastuzumab
Fluoropyrimidinechemotherapy
chemotherapy
chemotherapy
chemotherapy
/ trials if
+ CF/CX
based doublet chemo
or
triplet regimen adequate PS
Consider clinical
trials of novel
agents
2nd line single
2nd line single
agent agent
chemo /chemo
trials if/ trials if
adequate
PS
adequate
PS
2nd line single
agent
chemo / trials if
adequate PS
2nd line single
agent
chemo / trials if
adequate PS
Gebaseerd op:
Waddell et al. ESMO-ESSO-ESTRO Guidelines, Ann Oncol 2013
Beslisboom behandeling maagcarcinoom
EMR
ConsiderConsider
EMR
Operable
or limited
or limited
Surgery
Stage >T1N0
resection
resection
Operable
Operable
Stage >T1N0
Stage >T1N0
Re-assess ?
Consider EMR
Pre-operative
Pre-operative
or limited
chemotherapy
chemotherapy
resection
Inoperable
or
Inoperable
or
Metastatic
Metastatic
Operable
Inoperable
or
Stage >T1N0
Metastatic
Re-assess
?
Re-assess
?
Best supportive
Inoperable
or
Pre-operative
Palliative
care
Surgery Surgery
Surgery
Metastatic
chemotherapy
chemotherapy
if unfit for
treatment
Re-assess ?
Inoperable or
Metastatic
Best supportive
Best supportive
care
care
Palliative
if unfit for
if chemotherapy
unfit for
treatment
treatment
Best supportive
care
if unfit for
treatment
Her-2 negative:
Her-2 negative:
Her-2 negative:
Best supportive
HER-2 positive: Consider
HER-2 positive:
HER-2
positive:
HER-2 positive:
Consider
clinical
clinical
Consider
clinical care
Platinum
+
Platinum
+
Platinum +
Platinum +
Adjuvant Palliative
Adjuvant
Adjuvant
Adjuvant
Adjuvant
Adjuvant
Surgery
Surgery
of trials
novel of novel
Surgery
trials of novelifFluoropyrimidineTrastuzumab trials
FluoropyrimidineTrastuzumab
FluoropyrimidineTrastuzumab
chemotherapy
unfitchemotherapy
forFluoropyrimidine- Trastuzumab
chemoradiation
chemotherapy
chemoradiation
chemotherapy
chemoradiation
agents
agents
agents treatment
+ CF/CX
+ CF/CX
based doublet
or
+ CF/CX
based doublet
or
based
doublet
or
+ CF/CX
based doublet or
triplet regimen
triplet regimen
triplet regimen
triplet regimen
Consider clinical
trials of novel
agents
Palliative
Palliative
chemotherapy
chemotherapy
R1
Re-assess ?
Her-2 negative:
tive Adjuvant
rapy
chemoradiation
ative
rapy
Gastric Cancer
(Adenocarcinoma) (Adenocarcinoma)
(Adenocarcinoma)
Operable
Operable
Gastric Cancer Operable
Stage
T1N0
Stage T1N0
Stage T1N0
(Adenocarcinoma)
Operable
tage >T1N0
y
Gastric Gastric
Cancer Cancer
Gastric Cancer
(Adenocarcinoma)
Adjuvant
Surgery
chemotherapy
Adjuvant
chemoradiation
R1
Her-2 negative:
nd
HER-2 positive:
Platinum + 2 line single
Adjuvant
Post-operative
Post-operative
Post-operative
agent Trastuzumab
Fluoropyrimidinechemotherapy
chemotherapy
chemotherapy
chemotherapy
/ trials if
+ CF/CX
based doublet chemo
or
triplet regimen adequate PS
Consider clinical
trials of novel
agents
2nd line single
2nd line single
agent agent
chemo /chemo
trials if/ trials if
adequate
PS
adequate
PS
2nd line single
agent
chemo / trials if
adequate PS
2nd line single
agent
chemo / trials if
adequate PS
Gebaseerd op:
Waddell et al. ESMO-ESSO-ESTRO Guidelines, Ann Oncol 2013
Samenvatting
• Maagcarcinoom heeft een slechte prognose
• Ondanks adequate chirurgie zijn LR recidieven frequent
• Peri-operatieve chemotherapie en post-operatieve
chemoradiotherapie verbeteren de overleving
• R1 resecties is prognostisch (zeer) ongunstige factor
• Post-operatieve chemoradiotherapie verbetert mogelijk
prognose na R1 resectie
• Pre-operatieve chemoradiotherapie lijkt veelbelovend
Met dank aan
Edwin Jansen
Anouk Trip
Jurriën Stiekema
Steven Vanhoutvin
Johan Dikken
Johanna van Sandick
Elma Meershoek-Klein Kranenbarg
Henk Boot
Nicole van Grieken
Cornelis van de Velde
Annemieke Cats
Marianne Nordsmark
Pehr Lind