treating liver limited or oligometastatic crc · 2017. 10. 26. · learning objectives all patients...
TRANSCRIPT
Claus-Henning Köhne
Klinik für Onkologie und Hämatologie
North West German Cancer Center (NWTZ)
Treating Liver Limited or Oligometastatic CRC
ESMO Preceptorship Colorectal Cancer Nov 2016 Barcelona
Learning objectives
▪ All patients with liver limited or oligometastatic disease have a
potential chance for cure
▪ A multidisciplinary aproach is essential
▪ The clinical presentation may be considered as
▪ Resectable, boarderline resectable, potentially resectable after
chemotherapy
▪ In resectable disease surgery alone or following chemotherapy
are options
▪ In boarderline and unresectable disease the most effective and
still tolerable chemotherapy according to the molecular profile
should be used within a multidisciplinary context
▪ Even if surgery might not be curative it extends overall survival
and can be considered as a further line of „chemotherapy“ or a
form of „maintenance“ chemotherapy
Guidelines CRC
mut mut
2016 - FIRE3: Blinded review for Resektability of CRC Metastases
Neumann et al, ESMO 2016
Liver limited disease: Patient groups
Clearly
resectable
Borderline
resectable
Definitely NOT
resectable
Resectable LLD but high risk of recurrence
Fong Score
▪ Primary tumor N +
▪ DFI < 12 Monate
▪ > 1 Metastasis
▪ > 5 cm
▪ CEA > 200 ng/ml
Age 51y
Rectal Adeno-Ca: cT3, N+
Synchroneous LLD, ø 12 cm
CEA 568 ng/ml
High Fong Score
Estimated survival @ 5y < 10%
>12cm
▪ Primary tumor N +
▪ DFI < 12 Monate
▪ > 1 Metastasis
▪ > 5 cm
▪ CEA > 200 ng/ml
Fong score > 2
Group 0
Resectable
metastases
Disease specific survival (DSS)
Adjuvant systemic chemotherapy of CLM:
Overall survival
Combined analysis
FFCD / EORTC trial 5-FU/FA
Mitri et al. JCO 2008
0.00
0.25
0.50
0.75
1.00
Pro
bab
ility
153 114 70 41 22LV5FUs+IRI153 95 65 44 25LV5FUs
Number at risk
0 12 24 36 48Months
LV5FUs LV5FUs+IRI
adjusted Logrank p=0.43
HR=0.89: 95%CI [0.66-1.19]
Treatment
1-year DFS: 63% vs. 77%
2-year DFS: 46% vs. 51%
Ychou et al. ASCO 2008
Overall survival
FOLFIRI
Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases
EORTC 40983 (EPOC)
Nordlinger et al. Lancet Oncol 2013
RFS
OS
FOLFOX -> OP -> FOLFOX
R
OP
Resectable : Perioperative Chemotherapy questionable
Boarderline : no restrictions in Chemo regimens including use
of EGFR
Conclusions resectable & boarderline resectable disease
Case: Male 44 y,
05/06
Base line05/06-11/06
FOLFIRI + Cetux
11/06-03/07
FOLFOX + Cetux
PS 2 PS 0 liver mets operable
primary tumor pCR
+ 5 kg
mets not operable Patient died 02/15
Response and resection rates within trials
Trials with
neoadjuvant
focus
Trials with
palliative
focus CRC
Give the most active (RR) regimen still tolerable by the patient
Folprecht G….Köhne CH et al. Ann Oncol 2005; Jones R et al. Eur J Cancer, 2014
ESMO acknowledges response parameters like early tumor shrinkage
(ETS) or depth of response (DpR) for conversion therapy
Time since start of treatment
OS
ETS
Tumor nadir
Fire-3 data
PFS
Tu
mo
rlo
ad
at
Baselin
e
Lethal tumor load
0
10
20
30
40
50
60
70
Mo
rbid
ity
No CT =<5 cycles 6-9 cycles =>10 cycles
Steatohepatitis Sinusoidal distention
Karoui Nordlinger et al, Ann.Surg. 2006
Vauthey et al. JCO 2006
Arguments disfavouring CapeOX over infusional Doublets
(FOLFOX or FOLFIRI)
Randomised trials Doublets vs. Triplets and Doublets +/- VEGF – 1st line
RASwt and RASmut disease
Trial Therapy ORR
NO16966
(n=700)
FOLFOX
+/- Beva
38% vs. 38%
n.s.
(n=700) CAPOX
+/- Beva
38% vs. 38%
n.s.
ITACA
(n=376)
FOLFOX or
FOLFIRI
+/- Beva
48% vs. 49%
n.s.
EORTC
requestFOLFIRI +/- Bev not done
Saltz et al. JCO 2008, Cassidy BJC 2007, Passardi Ann Oncol 2015
Van Cutsem NEJM,
CTx +/- VEGF
Trial Therapy ORR
GONO
(n=244)
FOLFIRI
+/- Oxaliplatin
41% vs.
66%
TRIBE
(n=700)
FOLFIRI / BEV
+/- Oxaliplatin
53% vs.
65%
Austria
(n=80)
FOLFOX / Bev
+/- Irinotecan
62% vs.
81%
AIO
(n=242)
FOLFOX / Bev
+/- Irinotecan
60% vs.
79%
DOUBLET vs. TRIPLET
Randomisierte Studien mit EGFR AK – 1. Linie k-ras exon 2 wt
Europäische & Asiatische Erfahrungen
Trial Therapy ORR
Infusional 5FU
CRYSTAL
(n=666) FOLFIRI +/- Cetux
40% vs. 57%
Chinese*
(n=138)FOLFIRI or FOLFOX+/- Cetux 40% vs. 57%
PRIME
(n=656) FOLFOX +/- Pani
48% vs. 57%
OPUS
(n=197) FOLFOX +/- Cetux
34% vs. 57%
Tailor
(n=380)FOLFOX +/- Cetux 34% vs. 56%
VOLFI all RASwt
(n=99) 2:1FOLFOXIRI +/- Pani 61% vs. 86%
Bolus 5FU
Cape
COIN
(n=729) XELOX/FOLFOX +/- Cetux
57% vs. 64%
NORDIC
(n=194)FLOX +/- Cetxu 47 vs. 46%
Chinese randomized trial in patients with non resectable
k-ras exon 2 wt CRC LLD
Chemotherapy +/- Cetuximab
Ye et al. JCO 2013
CELIM: R0 Resection as a surgical „maintenance therapy“
in the continuum of care
R0 resected: 15.495%CI: 11.3-19.5
Not R0 res.: 8.995%CI: 6.7-11.0
HR 2.10 [1.37-3.20]
p<0.001
R0 resected: 53.995%CI: 35.9-71.9
Not R0 res.: 27.395%CI: 21.1-33.4
HR 2.25 [1.34-3.78],
p=0.002
5y-OS: 45.8%
Overall survivalProgression free survival
Update CELIM 12/2012, ASCO 2013
few patients
without relaps
Theo Ruers et al, ASCO 2015
EORTC CLOCC trial
EORTC CLOCC trial
N=152
Theo Ruers et al, ASCO 2015
Arm Resection Resection
+RFA
RFA
only
CT 12%
CT+RFA 47% 6%
Liver limited / dominant diesase
Clearly
resectable
Borderline
resectable
Definitely NOT
resectable
Surgery! ➢ Adjuvant to chemotherapy
➢ Maintenance or an additional
line of chemotherapy to
chemotherapy
Chemotherapy ?• adjuvant to surgery
S
U
R
G
E
R
Y
C
H
E
M
O
OPEN QUESTIONS
• Right / Left
• RASmut
• BRAFmut
Overall response rate left & right
JY Douillard & JP Pignon ESMO 2016
24
EVALUATION OF RESPONSE SIDEDNES
mFOLFOXIRI +
panitumumab
mFOLFOXIRI +
panitumumab
FOLFOXIRIFOLFOXIRI
left right
ORR (%)
10
20
30
40
50
60
70
80
90
100
90,6
68,0
60,0
37,5
OR 4.518
(1.29-15.71)
P=0.0210
OR 2.500
(0.37-16.88)
P=0.6372
N=78 N=18
Geissler et al. ESMO 2017
Treatment for RASmut or BRAFmut Disease ?
Cremolini et al. Lancet Oncol 2015
Cremolini et al. Lancet Oncol 2015
Triplette nicht besser als Doublette Group Events/No. OS (95% CI), months
RAS/BRAF WT (Arm
A)51/79 25.2 (20.8-29.8)
RAS/BRAF WT (Arm
B)40/79 32.2 (26.1-46.1)
RAS MT (Arm A) 68/97 21.3 (19.6-23.0)
RAS MT (Arm B) 65/97 23.2 (18.1-28.4)
BRAF MT (Arm A) 11/12 12.4 (10.2-20.2)
BRAF MT (Arm B) 8/10 7.8 (4.7-13.5)
Doublette nicht besser als FP+Bev
Welches ist die beste therapie für RASmut Erkrankung?
FOLFIRI/Bev +/- Oxaliplation FP/Bev +/- Irinotecan
Modest et al. ESMO 2017
Jones et al. et al. JCO 2017
Prognosis of BRAFmut Disease
mFOLFOXIRI +
panitumumab
mFOLFOXIRI +
panitumumab
FOLFOXIRIFOLFOXIRI
super wild-type
ORR (%)
BRAF mutation
10
20
30
40
50
60
70
80
90
100
86,0
64,7
71,4
22,2
Geissler et al. ESMO 2017
Triplett +/- Panitumumab
CELIM 2
PI Gunnar Folprecht Dresden
Liver limited / dominant diesase
Clearly
resectable
Borderline
resectable
Definitely NOT
resectable
Surgery! ➢ Adjuvant to chemotherapy
➢ Maintenance or an additional
line of chemotherapy to
chemotherapy
Chemotherapy ?• adjuvant to surgery
S
U
R
G
E
R
Y
C
H
E
M
O
Learning objectives
▪ All patients with liver limited or oligometastatic disease have a
curative chance
▪ A multidisciplinary aproach is essential
▪ Clinical presentation may be considered as
▪ Resectable, boarderline resectable, potentially resectable after
chemotherapy
▪ In resectable disease surgery alone or following chemotherapy
are options
▪ In boarderline and unresectable disease the most effective and
still tolerable chemotherapy according to the molecular profile
should be used within a multidisciplinary context
▪ Even if surgery is not curative it extends overall survival and can
be considered as a line of „chemotherapy“ or a form of
„maintenance“ chemotherapy
Thank you for
your attention!
Metastatic disease including
locoregional treatment
FOXFIRE (n=1103, 3 Studies)
Slide 12
Presented By Ricky Sharma at 2017 ASCO Annual Meeting
FOXFIRE (n=1103, 3 Studies)
HR: 1.04
P=0.6
HR: 0.90
P=0.1
Best radiological response by study
Presented By Ricky Sharma at 2017 ASCO Annual Meeting
FOXFIRE (n=1103, 3 Studies)
CALGB/SWOG 80405: Baseline Characteristics
Resected Patients
Characteristic
Kras WT codons 12/13
n=1137
Resected Pts
n=180
Chemo + Bev
n=559
Chemo + Cetux
n=578
Chemo + Bev
n=75
Chemo + Cetux
n=105
Age, years
Median (range) 59 (21–85) 59 (20–89) 55 (24–82) 55 (21–79)
Male, % 62.3 60.4 64.0 60.0
Non-Caucasian, % 14.6 16.5 9.3 20.0
FOLFOX, %* 73 74 77 81
Prior Radiation, %* 14.5 13.7 8.0 6.7
Prior Adjuvant Chemotherapy, %* 8.9 9.0 6.7 9.5
Palliative intent, % 86.4 82.5 62.7 60.0
Primary in place, % 28 27 30 20
Liver metastases only, % 29.3 39.8 53.3 50.0*Stratification Factor
Achieve NED: 132
/180
CALGB/SWOG 80405: Baseline Characteristics
Resected Patients
Characteristic
Kras WT codons 12/13
n=1137
Resected Pts
n=180
Chemo + Bev
n=559
Chemo + Cetux
n=578
Chemo + Bev
n=75
Chemo + Cetux
n=105
Age, years
Median (range) 59 (21–85) 59 (20–89) 55 (24–82) 55 (21–79)
Male, % 62.3 60.4 64.0 60.0
Non-Caucasian, % 14.6 16.5 9.3 20.0
FOLFOX, %* 73 74 77 81
Prior Radiation, %* 14.5 13.7 8.0 6.7
Prior Adjuvant Chemotherapy, %* 8.9 9.0 6.7 9.5
Palliative intent, % 86.4 82.5 62.7 60.0
Primary in place, % 28 27 30 20
Liver metastases only, % 29.3 39.8 53.3 50.0*Stratification Factor
CALGB/SWOG 80405: Baseline Characteristics
Resected Patients
Characteristic
Kras WT codons 12/13
n=1137
Resected Pts
n=180
Chemo + Bev
n=559
Chemo + Cetux
n=578
Chemo + Bev
n=75
Chemo + Cetux
n=105
Palliative intent, % 86.4 82.5 62.7 60.0
curative intent % 13.6% 17.5%
curative intent N 76 101
Resected NED (R0) N Pat 45 66 45 66
Resected NED (R0) % 8.0% 11.4% 60.0% 62.8%
Primary in place, % 28 27 30 20
Liver metastases only, % 29.3 39.8 53.3 50.0
*Stratification Factor
Discrepance of numbers:
Resected NED =111; Resected achieved NED=132
CALGB/SWOG 80405: Overall Survival (KRAS wild type, NED Post-Surgery, N=132)
ArmN
(Events)
Median
(95% CI)
HR
(95% CI)p
Chemo +
Bev50(15)
67.4
(50.6-NA) 1.2
(0.6-2.2)
0.56
Chemo +
Cetux82(30)
64.1
(51.1-78.9)
Most pts were resectable
upfront, thus surgery is
the main driver or
survival rather than pre-
op chemotherapy
Resectable Colorectal Liver Metastases
Presented By Jeanne Tie at 2016 ASCO Annual Meeting
Neumann et al, ESMO 2016
2016 - FIRE3: Blinded review for Resektability of CRC Metastases
Jones et al, BJS 2012
Patients treated with palliative Chemotherapy in a regional Center in UK
Guidelines CRC
unresectable (LLD)
mut mut
Case: Male 44 y, sigmoid adenocarcinoma
well until 4 months ago, PS 2
weight loss ~ 5 Kg within last 3 months
grossly enlarged palpable liver
abdominal US:
difuse hypodensic liver leasons
CT scans:
Synchroneous diffuse liver metastases
LDH elevated, WBC 12.000 /dl
Bilirubin normal, LFT < 4x ULN
Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases
EORTC 40983 (EPOC) and new EPOC
Nordlinger et al. Lancet Oncol 2013
Primrose et al. Lancet Oncol 2014
RFS
OS
OS
RFS
FOLFOX -> OP -> FOLFOX
R
OP
FOLFOX -> OP -> FOLFOX
R
+Cet -> OP -> +Cet
Liver limited diesase: Patient selection
EPOC New EPOC
Surgery Chemo Chemo
Inclusion Definitely resectable Definitely and
„suboptimal“
resectable
N Lesions Maximum 4 unlimited
unresectable 10% 4% 12-19%
Köhne JCO 2015
Visible on CT/MRI
Non - visible on CT/MRI, potentially visible during operation
CT/MRI prior chemoCT/MRI after chemo
prior surgery
Potential disadvantage of effective neoadjuvant
chemotherapy inresectable liver metastases
Köhne JCO 2015