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Transcript of Claus-Henning Köhne Klinik für Onkologie und Hämatologie ... · Learning objectives All patients...
![Page 1: Claus-Henning Köhne Klinik für Onkologie und Hämatologie ... · Learning objectives All patients with liver limited or oligometastatic disease have a potential chance for cure](https://reader030.fdocuments.in/reader030/viewer/2022040700/5d50a83e88c9936e548b64fb/html5/thumbnails/1.jpg)
Claus-Henning Köhne
Klinik für Onkologie und Hämatologie
North West German Cancer Center (NWTZ)
Unresectable or boarderline resectable disease
ESMO Preceptorship Colorectal Cancer Nov 2016 Barcelona
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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 chemotherapyare options
� In boarderline and unresectable disease the most effective andstill tolerable chemotherapy according to the molecular profileshould be used within a multidisciplinary context
� Even if surgery might not be curative it extends overall survivaland can be considered as a further line of „chemotherapy“ or a form of „maintenance“ chemotherapy
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Guidelines CRC
mut mut
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ESMO Guidelines for resectable (liver) metastases
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Liver limited disease: Patient groups
Clearly resectable
Borderline resectable
Definitely NOT resectable
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Resectable LLD but high risk of recurrence
Fong Score
� Primary tumor N +
� DFI < 12 Monate
� > 1 Metastasis
� ∅∅∅∅ > 5 cm
� CEA > 200 ng/ml
Age 51yRectal Adeno-Ca: cT3, N+Synchroneous LLD, ø 12 cmCEA 568 ng/ml
High Fong Score Estimated survival @ 5y < 10%
>12cm
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� Primary tumor N +
� DFI < 12 Monate
� > 1 Metastasis
� ∅∅∅∅ > 5 cm
� CEA > 200 ng/ml
Fong score > 2
Group 0
Resectablemetastases
Disease specific survival (DSS)
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Adjuvant systemic chemotherapy of CLM: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
ba
bili
ty
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
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Resectable Colorectal Liver Metastases
Presented By Jeanne Tie at 2016 ASCO Annual Meeting
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Neoadjuvant (perioperative) Chemotherapy in resectable CRC Liver metastases
EORTC 40983 (EPOC)
Nordlinger et al. Lancet Oncol 2013
RFSOS
FOLFOX -> OP -> FOLFOX
ROP
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Progression-free survival in eligible patients
(years)
0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :
125 171 83 57 37 22 8
115 171 115 74 43 21 5 Nordlinger et al. Lancet 2008
MOST LIKELY BENEFITBorderline resectable pts?High proliferative tumors?
MOST LIKELY NO BENEFITEasily resectable? Fong score 0-2?
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New EPOC studyNeoadjuvant FOLFOX +/- Cetuximab in LLD
Primrose et al. Lancet Oncol 2014
FOLFOX -> OP -> FOLFOX
RFOLFOX + Cetuximab -> OP -> FOLFOX + Cetuximab
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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
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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
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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 neoadjuvantchemotherapy inresectable liver metastases
Köhne JCO 2015
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Resectable : Perioperative Chemotherapy questionable
Boarderline : no restrictions in Chemo regimens including useof EGFR
Conclusions resectable & boarderline resectable disease
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Guidelines CRC unresectable (LLD)
mut mut
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Case: Male 44 y, sigmoid adenocarcinomaCase: 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
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Case: Male 44 y, Case: Male 44 y,
05/06 Base line
05/06-11/06FOLFIRI + 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
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Response and resection rates within trials
Trials withneoadjuvantfocus
Trials withpalliativefocus 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
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CELIM: Blinded surgical review
100%
50%
0%
50%
100%
| | | | | | | - | - | | | | | - - | - - | | | - | | | | | | - - -
Patient
resecta
ble
n
on
- r
esecta
ble
100%
50%
0%
50%
100%| | | - | | | | - | | - | | | - | | - | | - - | | - | | | - - | | -
Patient
rese
cta
ble
n
on
- r
es
ecta
ble
60%, p<0.0132%
Baseline Follow-up
Folprecht G….Köhne CH et al. Lancet Oncol 2010
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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
Morb
idity
No CT =<5 cycles 6-9 cycles =>10 cycles
Steatohepatitis Sinusoidal distention
Karoui Nordlinger et al, Ann.Surg. 2006
Vauthey et al. JCO 2006
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FOLFIRI vs. FOFOXIRI
Regimen N RR Author
FOLFIRI 122 41% Falcone
FOLFOXIRI 122 66% JCO 2007
FOLFIRI+Bev 256 53% Falcone
FOLFOXIRI+Bev 252 65% NEJM 2015
• FOLFOXIRI more effective than FOLFIRI• Unproven role of bevacizumab
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Randomised trials of EGFR antibodies – 1st line k-ras exon 2 wt onlyEuropean & Asian experience
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%
Bolus 5FU
Cape
COIN
(n=729) XELOX/FOLFOX +/- Cetux 57% vs. 64%
NORDIC
(n=194)FLOX +/- Cetxu 47 vs. 46%
sig. diff; (clinically relevant not statist. Sig); no sig. diff * LLD only
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Chinese randomized trial in patients with non resectable
k-ras exon 2 wt CRC LLDChemotherapy +/- Cetuximab
Ye et al. JCO 2013
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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
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Randomized trials in patients withnon resectable k-ras exon 2 wt CRC LLD
Chemotherapy +/- Cetuximab
METHEP Chinese study CELIM OLIVIA
FOLFIRI/F
OLFOX
~30
FOLFOXIRI
N=30
FOLFIRI/FOL
FOX
N=68
CT + Cet
N=70
FOLFIRI/F
OLFOX +
Cet
N=67
FOLFOX
+ Bev
N=39
FOLFOXIRI
+ Bev
N=41
RR ~60 73% 40% 57% 70% 62% 81%
R0 resection ~23 30% 7% 26% 33% 31% 54%
OS all pts
(mo)~29 48.8 21.0 30.9 35.7 32.2 NR
OS resected
pts (mo)- - 36.0 46.4 53.9 - -
Ychou Ann Surg Oncol 2013; Ye et al. JCO 2013; Folprecht...Köhne Lancet Oncol 2010; Gruenberger Ann Oncol 2015
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Jones, Folprecht Eur J Cancer 2014
Response and resection rates within trials
Trials withpalliativefocus CRC
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2016 - FIRE3: Blinded review for resectability
Neumann et al, ESMO 2016
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2016 - FIRE3: Blinded review for resectability
Neumann et al, ESMO 2016
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2016 - FIRE3: Blinded review for resectability
Neumann et al, ESMO 2016
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Jones et al, BJS 2012
Patients treated with palliative chemoat a regional oncology centre
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Overall response rate left & right
JY Douillard & JP Pignon ESMO 2016
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Duration of response � 1st line: in most arms duration of response appears to be longer in left-sided disease
� 2nd line: not enough responses in right-sided disease to calculate duration of response
Left, n Right, n Median DoR (95% CI), months
Actual treatment
Responder
s Progressed
Responder
s Progressed Left Right
PRIME
(1st line)
Pmab + FOLFOX 114 72 16 6 11.8 (9.6–14.8) 9.7 (3.9–13.3)
FOLFOX alone 82 56 16 14 9.3 (7.7–11.0) 7.6 (4.2–9.4)
PEAK
(1st line)
Pmab + FOLFOX 34 28 14 13 16.1 (11.1–20.9) 8.7 (3.7–14.2)
Beva + FOLFOX 31 29 7 7 9.5 (7.9–13.8) 9.2 (5.9–16.6)
Left, n Right , n Median DoR (95% CI), months
Actual treatment Responders Progressed Responders Progressed Left Right
181
(2nd
line)
Pmab + FOLFIRI 73 56 4 1 7.7 (6.1–9.5) NE (9.5–NE)
FOLFIRI alone 19 12 1 0 9.3 (5.7–12.3) NE (NE–NE)
Beva, bevacizumab; CI, confidence interval; DoR, duration of response; NE, not evaluable; Pmab,
panitumumab
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Liver limited / dominant diesase
Clearly resectable
Borderline resectable
Definitely NOT resectable
Surgery! � Adjuvant to chemotherapy� Maintenance or an additional
line of chemotherapy tochemotherapy
Chemotherapy ?• adjuvant to surgery
SURGERY
CHEMO
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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 chemotherapyare options
� In boarderline and unresectable disease the most effective andstill tolerable chemotherapy according to the molecular profileshould be used within a multidisciplinary context
� Even if surgery is not curative it extends overall survival and canbe considered as a line of „chemotherapy“ or a form of„maintenance“ chemotherapy
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Thank you for your attention!
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