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
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
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
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
Treatment options
Surgery first +/- post-operative chemotherapy
Chemotherapy before surgery
Postoperative chemotherapy after resection of liver metastasis?
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
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.
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,
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
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
Perioperative chemotherapy(before and after)
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
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
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
Case no 1
- 4 cm metachronous solitary
metastasis in left liver
- Easily resectable with
adequat margin
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
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
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)
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
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)
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
EORTC 40983
Peri-operative chemotherapy with FOLFOX4 reduces the risk of relapse of cancer after surgery by one quarter.
Potential negative impacts
Risk that metastases progress during chemotherapy
Liver damage induced by chemotherapy
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
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)
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
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)
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
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
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
Complete pathological response after preoperative chemotherapy
Tumor is replaced by fibrosis
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%
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.
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
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
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)
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
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