1. Treatment should start with Chemotherapy before Surgery:
Answer no 3
Bernard NORDLINGER M.D.
Hôpital Ambroise Paré – Boulogne
Assistance Publique Hôpitaux de Paris

2. Metastasis is resectable with adequat margin
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

3. Survival after surgery of CR liver metastases
22%
35%
25%
33%
39%
26%
32%
37%
38%
34%
58%
41% 5% 0% 3% - 4% 2%
2.8%
0.8% 1%
259 60 80
141
859
219
280
1818
204
1001
235
257
133
615
190
1981
1986
1987
1988
1991
1992
1994
1999
2000
2002
2003
2004
Foster
Iwatsuki
Nordlinger
Adson
Hughes
Scheele
Rosen
Nordlinger - Jaeck
Gayowski
Fong
Minigawa
Ercolani
Choti
Adam
Abdalla
5yr Survival
Op. Mort.
Patients
Year
Authors

4. This patient has a « good risk » metastasis
With surgery only
- Cancer relapses in 2/3 of patients Nordlinger et al Cancer 1994
- Life expectancy
Fong et al, Ann Surg 1999

5. Treatment options Surgery first +/- post-operative chemotherapy
Chemotherapy before surgery

6. Postoperative chemotherapy after resection of liver metastasis?

7. Post-operative chemotherapy
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

8. Meta-analysis of the two 5FU studies
DFS P=0,058
Mitry, JCO 2008
In multivariable analysis, adjuvant chemotherapy was independently associated with both progression-free survival and overall survival.

9. CPT-GMA 301 Phase III study
Adjuvant chemotherapy with more active regimen than 5FU only
CPT-GMA 301 Phase III study
5-FU / FA (6 months)
R0 resection of liver metastases R
FOLFIRI (6 months)
N=324,
Ychou et al.ASCO 2008

10. Disease-Free Survival
1-year DFS: 63% vs. 77%
2-year DFS: 46% vs. 51%

11. 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

12. Perioperative chemotherapy (before and after)

13. EORTC 40983: Peri-operative chemotherapy
Randomi Ze d
FOLFOX4
Surgery
FOLFOX4
6 cycles
(3 months)
6 cycles
(3 months)
Surgery
N=364 patients
With CR UK, ALM CAO, AGITG, FFCD

14. 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

15. Size of lesions after pre-operative chemotherapy *
Before mm (20-255)
After mm (0-230)
Relative reduction %
* SUM of the largest diameters
1. CT-scan measurements were consistent with the measurements performed at pathological examination
Pre-op CT with 6 cycles of FOLFOX4 decreased the diameter of lesions

16. Case no 1 - 4 cm metachronous solitary metastasis in left liver
- Easily resectable with adequat margin

17. Progression-free survival in resected patients Nordlinger et al
Progression-free survival in resected patients Nordlinger et al. Lancet 2008
HR= 0.73; CI: , p=0.025
100 90
+9.2% At 3 years 80
Periop CT 70 60 50
42.4% 40
Surgery only 30
33.2% 20 10
(years) 1 2 3 4 5 6 O N
Number of patients at risk :
104
152 85 59 39 24 10 93
151
118 76 45 23 6

18. Results Nordlinger et al. Lancet 2008
N pts CT
N pts Surgery
% absolute difference in 3-year PFS
Hazard Ratio
(Confidence Interval)
P-value
All patients
182
+7.2% (28.1% to 35.4%)
0.79 ( )
P=0.058
All eligible
Patients
171
+8.1% (28.1% to 36.2%)
0.77 ( )
P=0.041
All resected
151
152
+9.2% (33.2% to 42.4%)
0.73 ( )
P=0.025

19. Progression-free survival
EORTC 40983: progression free survival, all patients: update May25, 2009
Progression-free survival
Treatment
Patients (N)
Observed Events (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
126
0.79 (0.62, 1.01)
18.66 (15.41, 25.76)
36.37 (29.34, 43.42)

20. EORTC 40983: progression free survival, all patients: update May25, 2009

21. Progression free survival / irrespective of resection
EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009
Progression free survival / irrespective of resection
Treatment
Patients (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
123
0.76 (0.59, 0.97)
20.11 (16.46, 28.94)
38.50 (31.31, 45.63)

22. EORTC 40983: PFS irrespective of resection (usual definition), all patients, update May25, 2009

23. EORTC 40983
Peri-operative chemotherapy with FOLFOX reduces the risk of relapse of cancer after surgery by one quarter.

24. Potential negative impacts
Risk that metastases progress during chemotherapy
Liver damage induced by chemotherapy

25. Risk of progression during pre-operative chemotherapy: EORTC 40983
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%)…

26. Survival according to response to neoadjuvant CT (multiple metastases)
Outcome after resection when metastases progress during chemotherapy
Survival according to response to neoadjuvant CT (multiple metastases)
95%
100
Stabilization: 39
Progression: 34
Downstaging: 58
92% 80 60
55%
63%
44%
Survival (%) 40
37%
30%
Replace mine 20
12%
Log–rank: p<0.0001 8% 1 2 3 4 5
Years
Updated from: Adam R, et al. Ann Surg 2004;240:644–658

27. 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

28. 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)

29. Clinical significance: impact on surgery
Karoui Nordlinger et al, Ann.Surg. 2006
Mortality rate not increased
Morbidity rate related to the number of cycles of CT
Aloia Adam et al, Ann.Surg : Morbidity increased after 12 cycles
Nakano Jaeck et al, Ann.Surg : Morbidity increased after 6 cycles

30. EORTC 40983 : complications of surgery
Peri-op CT
Surgery
Reversible complications (pts) *
40 /159 (25%)
27 / 170 (16%)
Cardio-pulmonary failure 3 2
Bleeding
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
Need for reoperation
Other (lung, urinary, ascites, etc…) 20 10
Post-operative deaths
1 patient
2 patients
Other :…
*P=0.04
Nordlinger et al., Lancet 2008

31. 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

32. Complete pathological response after preoperative chemotherapy
Tumor is replaced by fibrosis

33. Impact of pathological response after chemotherapy on survival
75%
56%
33%
Complete response : 29/738 (4%)
Adam et al, JCO 2008
Complete response : 25/271 (9%)
Blazer et al, JCO 2008

34. 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.

35. 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

36. Future trials can go two ways
Perspectives
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 -

37. R EORTC 40091:BOS2 (Biologics,Oxaliplatin,Surgery) Resectable
FOLFOX
+ EGFR blocker R
Resectable
Liver
Metastases
from
CRC
n < 10
KRAS WT
+/-
Lung Mets < 2
+ VEGF inhibitor
+ EGFR blocker
follow up
SURGERY

38. Previously untreated patients with resectable mCRC
CRUK phase III study: CRC liver metastases:
Previously untreated patients with resectable mCRC
KRAS WT
Randomized
(expected n=340)
Oxaliplatin +
fluoropyrimidine
+ Cetuximab
Oxaliplatin +
fluoropyrimidine
2 weeks preoperative
12 weeks postoperative
PFS