Transcript Folie 1

Abstract 4091
Resectability and agreement between surgeons:
Review of CT- and MRI- scans of the CELIM study
(Multicenter randomized trial of cetuximab/FOLFOX versus
cetuximab/FOLFIRI in unresectable liver metastases).
Wolf Bechstein,1 Hauke Lang,2 Claus-Henning Köhne,3 Fabio Parisi,4
Hans-Rudolf Raab,3 Andrea Frilling,5 Ralf Konopke,6 Jürgen Weitz,7
Christian Stroszczynski,6 Gunnar Folprecht6
1University
Hospital Frankfurt, Germany, 2University Hospital Mainz, Germany,
3 Klinikum Oldenburg, Oldenburg, Germany, 4New York University, N.Y., U.S., 5University Hospital Essen, Germany,
6University Hospital Carl Gustav Carus, Dresden, Germany,
7University of Heidelberg, Dpt. of Surgery, Heidelberg, Germany
Background
• Resection of liver metastases provides favorable long-term survival
(Adam Ann Surg 2004)
• Resectability of colorectal liver metastases depends on technical
resectability and prognostic factors
• Number of liver metastases is an important prognostic factor and pts
with > 4 liver met’s were excluded from neoadjuvant trial for resectable
liver metastases (Nordlinger, Lancet 2007)
• In primary non-resectable liver metastases, resection rate correlates with
response to chemotherapy
• Few data are available on achievement of resectability due to
chemotherapy and on the agreement between surgeons regarding
resectabilty
• Cetuximab increases response rates when added to FOLFIRI or FOLFOX
(Van Cutsem NEJM 2009, Bokemeyer JCO 2009)
• The CELIM study compared tumor response and resectability rates in
patients with unresected liver metastases receiving neoadjuvant
treatment with cetuximab plus FOLFIRI or FOLFOX6
Patient selection
Patients with non-resectable colorectal liver metastases
Definition of non-resectability:
– ≥ 5 liver metastases and/or
– liver metastases that are technically non-resectable
defined by local surgeon in cooperation with local radiologist
(amount of functional liver tissue remaining, infiltration of non-resectable
structures)
Expected resectability after response to chemotherapy was not an
inclusion criterion
No extrahepatic disease
Karnofsky PS ≥ 80% and adequate hepatic, renal, and bone marrow function
Metastases histologically confirmed
Patients with simultaneous liver metastases were eligible if the primary tumor was resected
≥ 1 month prior to chemotherapy
Informed consent; no prior chemotherapy (except adjuvant chemotherapy ≥ 6 months ago); no concurrent
immunotherapy, chemotherapy or hormone therapy; no previous malignancy other than colorectal cancer,
basal cell carcinoma, or pre-invasive carcinoma of the cervix; no inflammatory bowel disease; no relevant
coronary heart disease
Patients with non-resectable colorectal liver metastases
(technically non-resectable / ≥ 5 liver metastases)
without extrahepatic metastases
Biopsy:
EGFR screening
Randomization
FOLFOX6 + cetuximab
FOLFIRI + cetuximab
EGFR IHC 0
FOLFOX6
Stratification:
technically non-resectable / ≥ 5 liver metastases
staging with PET
EGFR IHC
FOLFOX6: oxaliplatin 100 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²
FOLFIRI:
irinotecan 180 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²
Cetuximab: 400 mg/m², then 250 mg/m² weekly
5-FU, 5-fluorouracil; FA, folinic acid; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry;
PET, positron emission tomography.
Patients with non-resectable colorectal liver metastases
(technically non-resectable / ≥ 5 liver metastases)
without extrahepatic metastases
Biopsy:
EGFR screening
Randomization
FOLFOX6 + cetuximab
FOLFIRI + cetuximab
Therapy: 8 cycles (~ 4 months)
Evaluation of resectability
Technically non-resectable
Technically resectable
4 additional therapy cycles
Resection
Primary endpoint: Response
EGFR, epidermal growth factor receptor.
Therapy continuation
for 6 cycles
(~ 3 months)
Patient characteristics
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=56
n=55
n=111
65.1
62.0
63.3
male
64%
64%
64%
wild-type
70%
71%
71%
rectal cancer
38%
51%
44%
11%
22%
16%
Median age (y.)
Sex
KRAS status (n=99)
Primary tumor site
Adjuvant chemotherapy
yes
Patient characteristics
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=56
n=55
n=111
<5
23%
31%
27%
5-10
55%
49%
52%
>10
20%
15%
17%
NA
2%
5%
4%
yes
16%
9%
13%
Number liver metastases
Prior liver resection
NA, not available
Efficacy: confirmed response
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=53
n=53
n=106
CR/PR
68%
57%
62%
95% CI
54-80%
42-70%
52-72%
SD
28%
30%
29%
PD
4%
13%
8%
Responses confirmed by 2nd CT scan according to RECIST or by resection
Chi square test for comparison between FOLFOX6+cetuximab vs FOLFIRI+cetuximab: p would be 0.23
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, CT, computed tomography
Confirmed response by subgroups
KRAS
KRAS
EGFR
EGFR
wild-type
mutant
IHC +
IHC -
n=67
n=27
n=77
n=29
CR/PR
70%
41%
60%
69%
95% CI
58-81%
22-61%
48-71%
49-85%
Responses confirmed by 2nd CT scan according to RECIST or by resection
Chi square test for comparison between KRAS wild-type vs KRAS mutant: p < 0.01
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CT, computed tomography;
EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; CI, confidence interval
Liver resections
FOLFOX6 +
FOLFIRI +
All
cetuximab
cetuximab
patients
n=53
n=53
n=106
R0 resections
38%
30%
34%
R1-resection or resection with RFA
2%
8%
5%
RFA
9%
6%
8%
Total: R0 / R1 resection / RFA
49%
43%
46%
RFA, radio frequency ablation
Resections in pts with KRAS wild-type tumors: 22/67 pts (33%)
Perioperative morbidity / mortality
Chemotherapy
+ cetuximab
n=45 (%)
All morbidity
16
(36%)
Median stay in hospital
13 days
Median stay on intensive care unit
2.0 days
Mechanical ventilation > 1 day
4
(9%)
Operative revisions
3
(7%)
Bleeding
2
(4%)
Hepatic failure
1
(2%)
Pleural effusion
6
(13%)
Wound infection
4
(9%)
Biliary leakage
2
(4%)
Renal failure
1
(2%)
Urinary tract infection
2
(4%)
Two post-operative deaths (4%):
Gram-negative sepsis –
8 days postop (right
hemihepatectomy,
FOLFOX + cetuximab arm)
Multiorgan failure –
75 days postop
(two-staged liver resection,
FOLFOX + cetuximab arm)
Blinded surgical review
CT/MRI scans
R
S
S
S
S
S
A blinded surgical review performed for CT/MRI at baseline and at 4 months:
CT / MRI scans were presented by a radiologist to 5-6 liver expert surgeons of
participating centers in two workshops.
CT, computed tomography; MRI, magnetic resonance imaging
Surgical review
- CT / MRI scans were evaluated by the surgeons without knowing when
the scan was taken (before or after chemotherapy) and without clinical
data
- Surgeons allocated scans to:
resection / exploration / chemotherapy preferred / non-resectable
- Surgeons were blinded to the votes of the other participants.
- 181 scans reviewed / 171 scans evaluable
- Paired scans (baseline and follow-up) available for 68/106 pts
Actual resection rate in this subgroup 34%, response rate 60%
- Following imaging review:
22/68 scans (32%) judged resectable at baseline
41/68 scans (60%) judged resectable at follow-up (p<0.01)
Waterfall plot of resectability at baseline
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|
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- |
- -
| | |
-
|
|
| |
| |
-
-
-
non - resectable
100%
50%
non-resectable
chemo preferred
resectable
exploration
0%
resectable
50%
100%
Patient
Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green,
“chemotherapy preferred” in yellow and for “unresectable” in red.
Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”
Waterfall plot of resectability after chemotherapy
| |
| - | | |
| - |
| - | | | - |
|
- |
| - -
|
| -
|
|
|
-
-
|
|
-
non - resectable
100%
50%
non-resectable
chemo preferred
resectable
exploration
0%
resectable
50%
Resectability according to imaging
increased by 28% (32% → 60%)
p<0.01
100%
Patient
Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green,
“chemotherapy preferred” in yellow and for “unresectable” in red.
Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-”
Patterns of voting of the individual surgeons
Votes of surgeons
60%
40%
Operation
Borderline
Non-resectab
20%
0%
Reviewer 1
Reviewer 2
Reviewer 3
Reviewer 4
Reviewer 5
Reviewer 6
Reviewer 7
Votes for “resectable”/”exploration” are in green, “chemotherapy preferred” in yellow and for “unresectable” in red.
Blinded review of patient MRI and CT scans at baseline and follow-up revealed large variation between reviewers in
the decision making process.
Reviewer
1
2
3
4
5
6
7
73%
60%
60%
61%
71%
78%
(135)
(136)
(132)
(62)
(65)
(64)
4%
64%
60%
70%
64%
67%
(135)
(166)
(161)
(69)
(89)
(86)
1
2
3%
2%
55%
56%
76%
62%
(136)
(166)
(164)
(68)
(92)
(89)
4
15%
17%
5%
76%
62%
63%
(132)
(161)
(164)
(67)
(91)
(88)
5
8%
14%
3%
18%
(62)
(69)
(68)
(67)
6
5%
2%
4%
4%
65%
(65)
(89)
(92)
(91)
(89)
7
2%
2%
2%
15%
4%
(64)
(86)
(89)
(88)
(89)
3
Agreement
Agreement and critical disagreement
“Critical” disagreement
“Agreement” (grey/green) show the percentage of agreement between two individual surgeons with the categories
“resection/exploration”, “chemotherapy preferred” and “unresectable”. Total rate in all decisions is 64.5%
“Critical disagreement” means the proportion of contrary votes (one surgeon for “resection/exploration”, the other for “unresectable”)
The total rate in all pairs is 6.8%
The numbers in brackets mean the evaluable images per surgical pair.
Conclusions
• High response rates induced by cetuximab plus either FOLFOX or FOLFIRI:
– 70% confirmed response in KRAS wild-type patients
• Resections among patients with initially non-resectable liver metastases:
– 34% R0 liver resection
– 46% R0 or R1 liver resection and/or RFA
• Perioperative morbidity/mortality comparable to experience from literature
• Resectability according to imaging review improved significantly following
treatment with cetuximab plus FOLFOX or FOLFIRI
• Cetuximab plus FOLFOX or FOLFIRI are good options for
conversional chemotherapy for KRAS wild-type patients
(Europe, not approved in U.S.)
• Although, as demonstrated here, there is heterogeneity between different
surgeons in treatment decisions, this rarely results in the need for a
surgical second opinion within experienced centers
We thank...
• All patients and their relatives
• All investigators at the study sites
University Hospital Dresden
University Hospital Vienna
University Hospital Göttingen
Klinikum Passau
University Hospital / NCT Heidelberg
University Hospital Frankfurt
University Hospital Essen
University Hospital Mannheim
Klinikum Essen-Mitte
Klinikum Oldenburg
University Hospital Tübingen
University Hospital Munich Rechts der Isar
Krankenhaus der Barmherzigen Brüder Trier
University Hospital Würzburg
Klinikum Celle
Klinikum Magdeburg
Klinikum Aschersleben
• The companies which supported this study
Merck-Serono, Sanofi-Aventis, and Pfizer