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Bernard NORDLINGER M.D.
Hôpital Ambroise Paré – BoulogneAssistance Publique Hôpitaux de Paris
Treatment should start with Treatment should start with Chemotherapy before Surgery: Chemotherapy before Surgery:
Answer no 3 Answer no 3
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Case no 1
56-year old male had
resection of a T3N0M0
sigmoid colon cancer CT scan 12 months :
4 cm metachronous solitary
metastasis in left liver
Metastasis is resectable with adequat margin
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Survival after surgery of CR liver metastases
22%35%25%25%33%39%25%26%32%37%38% 34%58%41%58%
5%0%5%3%-
5%4%2%0%
2.8%0%
0.8%-
1%-
2596080
141859219280
1818204
1001235257133615190
198119861987198719881991199219921994199920002002200220032004
Foster Iwatsuki Nordlinger Adson Hughes Scheele Rosen Nordlinger - Jaeck Gayowski Fong Minigawa Ercolani Choti Adam Abdalla
5yr SurvivalOp. Mort.PatientsYearAuthors
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This patient has a « good risk » metastasis
Fong et al, Ann Surg 1999
With surgery only
- Cancer relapses in 2/3 of patients Nordlinger et al Cancer 1994
- Life expectancy
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Treatment options
Surgery first +/- post-operative chemotherapy
Chemotherapy before surgery
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Postoperative chemotherapy after resection of liver metastasis?
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Very few trials available
Hepatic arterial infusion (M. Lorenz 1998, N. Kemeny 1999, M. Kemeny 2002)
Systemic chemotherapy (Langer 2002, Portier 2006)
Most studies are underpowered ,show a trend toward a survival benefit of 5 FU based chemotherapy, combined with surgery
Post-operative chemotherapy
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Meta-analysis of the two 5FU studies
Time (months)
0 20 40 60 80
Su
rviv
al
0,0
0,2
0,4
0,6
0,8
1,0
Adjuvant chemotherapySurgery alone
DFS P=0,058
Mitry, JCO 2008
In multivariable analysis, adjuvant chemotherapy was independently associated with both progression-free survival and overall survival.
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CPT-GMA 301 Phase III study
R0 resection of liver metastases
5-FU / FA (6 months)
FOLFIRI (6 months)
R
Adjuvant chemotherapy with more active regimen than 5FU only
Ychou et al.ASCO 2008
N=324,
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1-year DFS: 63% vs. 77%2-year DFS: 46% vs. 51%
Disease-Free Survival
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
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Post-operative chemotherapy
No sufficient data to be the standard of care at the moment
We need clear results from future trials
30 to 40% of patients do not, or can not receive chemotherapy within a few weeks after surgery
Nordlinger et al. Lancet 2008
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Perioperative chemotherapy(before and after)
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EORTC 40983: Peri-operative chemotherapy
RandomiZed
SurgeryFOLFOX4 FOLFOX4
Surgery
6 cycles
(3 months)
N=364 patients
6 cycles
(3 months)
With CR UK, ALM CAO, AGITG, FFCD
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Aim of this study
To demonstrate that chemotherapy combined with surgery is a better treatment than surgery alone,
but not to compare pre vs post-operative chemotherapy
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Size of lesions after pre-operative chemotherapy *
Before 50 mm (20-255)
After 33 mm (0-230)
Relative reduction - 25.6 %
* SUM of the largest diameters
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Case no 1
- 4 cm metachronous solitary
metastasis in left liver
- Easily resectable with
adequat margin
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Progression-free survival in resected patients Nordlinger et al. Lancet 2008
HR= 0.73; CI: 0.55-0.97, p=0.025
Surgery only
Periop CT
33.2%
42.4%
+9.2%At 3 years
(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 :104 152 85 59 39 24 10
93 151 118 76 45 23 6
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Results Nordlinger et al. Lancet 2008
N ptsCT
N pts Surgery
% absolute difference
in 3-year PFS
HazardRatio
(Confidence Interval)
P-value
All patients 182 182 +7.2% (28.1% to 35.4%)
0.79(0.62-1.02)
P=0.058
All eligiblePatients
171 171 +8.1% (28.1% to 36.2%)
0.77 (0.60-1.00)
P=0.041
All resectedPatients
151 152 +9.2% (33.2% to 42.4%)
0.73(0.55-0.97)
P=0.025
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EORTC 40983: progression free survival, all patients: update May25, 2009
Progression-free survival
TreatmentPatients
(N)
ObservedEvents
(O)
Hazard Ratio
(95% CI)
P-Value(Log-Rank)
Median(95% CI)(Months)
% at 3 Year(s)(95% CI)
Surgery
182 134 1.00
0.0473
11.73 (9.63, 18.23)
29.58 (22.96, 36.48)
Pre&Postop CT
182 126 0.79 (0.62, 1.01)
18.66 (15.41, 25.76)
36.37 (29.34, 43.42)
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EORTC 40983: progression free survival, all patients: update May25, 2009
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment134 182 86 62 47 34 21 9 4
126 182 118 78 59 47 28 13 4
Surgery
Pre&Postop CT
Progression-free survival
26 May 2009 11:25
Overall Logrank test: p=0.047
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EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009
Progression free survival / irrespective of resection
TreatmentPatients
(N)
Observed
Events(O)
Hazard Ratio
(95% CI)
P-Value(Log-Rank)
Median (95% CI)(Months)
% at 3 Year(s)(95% CI)
Surgery
182 133 1.00
0.0259 14.32 (11.04, 18.76)
30.07 (23.41, 36.99)
Pre&Postop CT
182 123 0.76 (0.59,
0.97)
20.11 (16.46, 28.94)
38.50 (31.31, 45.63)
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EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment133 182 92 63 48 35 22 9 4
123 182 123 81 62 49 29 14 4
Surgery
Pre&Postop CT
Time to first prog/irrespective of resection
26 May 2009 11:25
Overall Logrank test: p=0.026
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EORTC 40983
Peri-operative chemotherapy with FOLFOX4 reduces the risk of relapse of cancer after surgery by one quarter.
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Potential negative impacts
Risk that metastases progress during chemotherapy
Liver damage induced by chemotherapy
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Progressive disease 12/182 pts (7%) 4 were resected 8 were not resected
4: appearance of new lesions: preoperative chemotherapy permitted to avoid unnecessary surgery
4: progression of known metastases (2%)…
Risk of progression during pre-operative chemotherapy: EORTC 40983
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Outcome after resection when metastases
progress during chemotherapy
30%37%
Stabilization: 39
Progression: 34
Downstaging: 58
Log–rank: p<0.000120
40
60
80
100
0 1 2 3 4 5
63%
12%8%
44%
95%
55%
Years
92%
Updated from: Adam R, et al. Ann Surg 2004;240:644–658
Su
rviv
al (
%)
Survival according to response to neoadjuvant CT (multiple metastases)
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Risk of progression during pre-operative CT
Risk is low ( total: 7%; known metastases: 2%)
It is better to know before surgery because this is a biological marker for poor prognosis
Indication for second line chemotherapy,
Before surgery
Evaluate every 3 cycles
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Risk of liver damage induced by chemotherapy
The type of liver injury depends on the drug administered
Vascular lesions : Oxaliplatin
(Rubbia-Brandt et al, 2004)
Steatosis : 5FU, Irinotecan ?
(Parikh et al, 2003)
Steatohepatitis : Irinotecan
(Vauthey et al, 2006)
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Clinical significance: impact on surgery
•Karoui Nordlinger et al, Ann.Surg. 2006
0
10
20
30
40
50
60
70
Mor
bidi
ty
No CT =<5 cycles 6-9 cycles =>10 cycles
•Aloia Adam et al, Ann.Surg. 2006 : Morbidity increased after 12 cycles •Nakano Jaeck et al, Ann.Surg. 2008 : Morbidity increased after 6 cycles
Mortality rate not increased
Morbidity rate related to the number of cycles of CT
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EORTC 40983 : complications of surgery
Peri-op CT Surgery
Reversible complications (pts) *
40 /159 (25%)
27 / 170 (16%)
Cardio-pulmonary failure 3 2
Bleeding 3 3
Biliary Fistula 13 7
(Incl Output > 100ml/d, >10d) (9) (2)
Hepatic Failure 11 8
(Incl. Bilirubin>10mg/dl, >3d) (10) (5)
Wound infection 5 4
Intra-abdominal infection 11 4
Need for reoperation 5 3
Other (lung, urinary, ascites, etc…) 20
10
Post-operative deaths 1 patient 2 patients
*P=0.04 Nordlinger et al., Lancet 2008
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Liver damage
• Damage induced to liver by neoadjuvant chemotherapy is limited and has few clinical consequences if patients are not overtreated
• Damage induced to tumor has a major impact on survival
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Complete pathological response after preoperative chemotherapy
Tumor is replaced by fibrosis
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Impact of pathological response after chemotherapy on survival
Complete response : 29/738 (4%)Adam et al, JCO 2008
Complete response : 25/271 (9%)Blazer et al, JCO 2008
75%
56%
33%
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Preoperative treatment of GI cancers in general: the present and the future
- Benefits outweigh potential disadvantages
- Has become the standard of care for most patients with cancers of the rectum
- Prolongs survival in patients with stomach cancer Cunningham,NEJM,2006.
- Reduces the risk of relapse after resection of colorectal cancer liver metastases.
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The patient
Received FOLFOX4 6 cycles before surgery and 6 cycles after surgery
Post-operative course was uneventful
Pathologic examination showed:
- major response : 15% residual cancer cells
- large part of tumor was replaced by major fibrosis reflecting the effect of chemotherapy
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Future trials can go two ways
1- Simplify treatment: make it easier for patients - Compare preop CT to postop CT
- Reduce the number of cycles of CT given before surgery
2- Intensify treatment to further reduce the risk of relapse of cancer
- Combine cytotoxics and targeted agents - Combine several cytotoxics
-
Perspectives
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FOLFOX + EGFR blocker
R
ResectableLiver
Metastases from CRC n < 10
KRAS WT
+/-Lung Mets
< 2
FOLFOX+ VEGF inhibitor
FOLFOX
+ EGFR blocker
FOLFOX
+ VEGF inhibitor
follow up
follow up
SU
RG
ER
YS
UR
GE
RY
EORTC 40091:BOS2 (Biologics,Oxaliplatin,Surgery)
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Previously untreated patients with resectable mCRC KRAS WT
2 weeks preoperative
12 weeks postoperative
CRUK phase III study: CRC liver metastases:
Randomized
(expected n=340)
Oxaliplatin +
fluoropyrimidine
Oxaliplatin +
fluoropyrimidine
+ CetuximabPFS