1. Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials
E Mitry, A Fields, H Bleiberg, R Labianca, G Portier, D Tu, V Torri, F Lazorthes, E Van Cutsem, C O'Callaghan, P Rougier

2. Introduction (1)
10 to 15% of colorectal cancer (CRC) liver metastases are considered resectable
Relapse after resection occurs in almost 75% of the cases
Adjuvant systemic chemotherapy administered after surgery may reduce the risk of recurrence but its benefit has never been demonstrated

3. A lack of power may explain these results
Introduction (2)
Two phase III trials (FFCD 9002/ACHBTH/AURC and EORTC/NCIC/GIVIO ENG trials), with a very similar design, compared an adjuvant chemotherapy to surgery alone after potentially curative resection of liver or lung CRC metastases
Both trials showed a non significant trend for improvement in progresion-free survival (PFS) and overall survival (OS) for patients treated with chemotherapy.
A lack of power may explain these results
the ENG trial was prematurely closed after the randomization of 129 patients in 4 years because of slow accrual of patients
only 173/200 patients were included in the FFCD trial between 1991 and 2001.

4. Methods
A pooled analysis based on individual data from both trials was performed
Statistical analysis
Progression free survival (PFS) was defined as time from metastases resection to first confirmed recurrence or death.
Overall survival (OS) was defined as time from metastases resection to death
Prognostic factors associated with PFS and OS in multivariate analysis were estimated

5. Main inclusion criteria
Histologically proven CRC
R0 surgical resection of the primary tumor and ≤ 4 metastases located in a single location (liver (FFCD trial); liver or lung (ENG trial)).
ECOG performance status ≤ 2
No previous chemotherapy (except adjuvant treatment of the primary tumor)
Age ≤ 75 years (FFCD trial) (ENG trial: no age limit)

6. Stratification criteria
Randomization
Stratification criteria
Treatment
Chemotherapy should start between 10 and 35 days after surgery in the FFCD trial
Randomization must occur within 49 days from surgery and treatment must begin within 7 days from randomization in the ENG trial
FFCD
Number of metastases (1 vs. ≥ 2)
Maximum size of metastases (≤ 5 vs. > 5 cm)
Disease free interval (≤ 1 vs. > 1 year)
Prior adjuvant chemotherapy
ENG
Number of metastases (1 vs. ≥ 2)
Treatment center
Disease free interval (≤ 6 vs. > 6 months)
Liver vs. lung metastases
Prior adjuvant chemotherapy

7. Adjuvant chemotherapy
Treatment schedule was almost similar in both trials
5-FU 400 mg/m² (ENG trial: 370) IV q.d. x 5 days plus leucovorin 200 mg/m² IV q.d. x 5 days
6 cycles at 28 days intervals
Population
FFCD trial : 173 patients recruited from 47 centers in France, Belgium and Switzerland between December 1991 and December 2001.
ENG trial : 129 patients recruited from XX centers (EORTC 20, NCIC CTG 54, GIVIO 55) between February 1994 and January 1998

8. 302 eligible patients recruited (FFCD 173, ENG 129)
Randomization
148 adjuvant chemotherapy (FFCD 86, ENG 62)
154 surgery alone (FFCD 87, ENG 67)
ENG trial : 22 patients excluded from analysis because no post baseline data available
FFCD trial : 2 pts with incomplete data excluded
138 adjuvant chemotherapy (FFCD 86, ENG 52)
140 surgery alone (FFCD 85, ENG 55)
66 died
22 alive with disease recurrence
50 alive and disease free
83 died
16 alive with disease recurrence
41 alive and disease free

9. Baseline characteristics (1)
FFCD trial
ENG trial
Pooled analysis *
n (%)
Chemotherapy
n = 86
Surgery alone
n = 85
n = 52
n = 55
n = 138
n = 140
Period of inclusion
DEC 1991 – DEC 2001
FEB 1994 – JAN 1998
Median age years [range]
63 [35-77]
63 [36-76]
63.5 [35-76]
60 [20-82]
62 [20-82]
Age group
<70 years
68 (79.1)
67 (78.8)
42 (80.8)
44 (80.0)
110 (79.7)
111 (79.3)
≥ 70 years
18 (20.9)
18 (21.2)
10 (19.2)
11 (20.0)
28 (20.3)
29 (20.7)
Male
46 (53.5)
53 (62.4)
34 (65.4)
36 (65.4)
80 (58.0)
89 (63.6)
Primary tumor
Rectum
35 (40.7)
34 (40.0)
14 (26.9)
17 (30.9)
49 (35.5)
51 (36.4)
Colon
31 (58.1)
51 (60.0)
32 (61.5)
35 (60.0)
82 (59.4)
84 (60.0)
Unknown
1 (1.2) -
6 (11.5)
5 (9.1)
7 (5.1)
5 (3.6)
Stage of primary tumor
T1-T3
73 (84.9)
79 (92.9)
44 (84.6)
43 (78.2)
117 (84.8)
122 (87.1) T4
8 (9.3)
2 (2.4)
8 (14.5)
14 (10.1)
10 (7.1) Tx
5 (5.8)
4 (4.7)
2 (3.8)
4 (7.3)
8 (5.7) N0
39 (45.8)
24 (46.1)
26 (47.3)
70 (50.7)
65 (46.4) N1
39 (44.3)
43 (50.6)
26 (50.0)
25 (45.4)
65 (47.1)
68 (46.6) Nx
3 (3.5)
2 (3.9)
3 (2.2)
7 (5.0)

10. Baseline characteristics (2)
FFCD trial
ENG trial
Pooled analysis *
n (%)
Chemotherapy
n = 86
Surgery alone
n = 85
n = 52
n = 55
n = 138
n = 140
Prior chemotherapy No
64 (74.4)
63 (74.1)
34 (65.4)
36 (65.5)
98 (71.0)
99 (70.7)
Yes
22 (25.6)
22 (25.9)
17 (32.7)
16(29.1)
39 (28.3)
38 (27.7)
Unknown -
1 (1.9)
3 (5.4)
1 (0.7)
3 (2.1)
Disease Free Interval
≤1 year
42 (48.8)
39 (45.9)
18 (34.6)
21 (38.2)
60 (43.5)
60 (42.9)
>1 year
44 (51.2)
46 (54.1)
34 (65.3)
34 (61.8)
78 (56.5)
80 (57.1)
Site of metastase
Liver
86 (100)
85 (100)
44 (84.6)
46 (83.6)
130 (94.2)
131 (93.6)
Lung
7 (13.5)
6 (10.9)
7 (5.1)
6 (4.3)
1 (.7)
Number of metastases
Median [range]
1 [1-7]
1 [1-4] 1
59 (68.6)
59 (69.4)
33 (63.5)
37 (67.3)
92 (66.7)
96 (68.6) ≥2
27 (31.4)
26 (30.1)
19 (36.5)
18 (32.7)
46 (33.3)
44 (31.4)
* No statistically significant difference between treatment groups
ECOG performance status available was not available for FFCD trial, all patients have an ECOG PS ≤ 2 (inclusion criteria)
Size of metastases was not available for ENG trial

11. Progression Free Survival
Survival by treatment group
Progression Free Survival
Overall survival
Chemotherapy
Surgery alone
Surgery alone
n *
137
Median (months)
27.9
[21.0 – 41.9]
18.8
[14.7 – 23.8]
62.2 [ ]
47.3 [40.6 – 57.2] HR
1.32 [1.00 – 1.76]
1.32 [0.95 – 1.82]
p (log rank test)
0.058
0.095
* 4 patients from ENG trial excluded from survival analysis because the date of metastases resection is missing

12. Progression Free Survival by treatment group

13. Overall survival by treatment group

14. Chemotherapy Surgery alone
Factors associated with survival in univariate analysis
Progression Free Survival
Median PFS (months)
p (log rank test)
Treatment group
Chemotherapy Surgery alone
0.058
Number of metastases
1 2+
0.036
Previous adjuvant CT
No Yes
0.081
Maximum size of metastases *
≤ 5 cm > 5 cm
0.052
* FFCD trial, 171 patients
Only factors associated with PFS with a p value < 0.1 are presented

15. Chemotherapy Surgery alone
Factors associated with PFS in multivariate analysis HR
95% CI p
Treatment group
Chemotherapy Surgery alone
1 1.39
[ ]
0.026
Number of metastases
1 2+
1 1.43
[ ]
0.022
Prior chemotherapy
No Yes
1 0.74
[ ]
0.082
Factors associated with PFS with a p value < 0.1 in univariate analysis were introduced into the Cox regression model (excepted for the size of metastases which was not available for ENG trial), model was stratified by trial

16. Chemotherapy Surgery alone
Factors associated with overall survival in univariate analysis
Median PFS (months)
p (log rank test)
Treatment group
Chemotherapy Surgery alone
0.09
Number of metastases
1 2+
0.02
Disease free interval
≤ 1 year > 1 year
0.07
Maximum size of metastases *
≤ 5 cm > 5 cm
0.003
Performance status **
0 1 2
0.002
* FFCD trial, 171 patients, ** ENG trial, 103 patients
Only factors associated with PFS with a p value < 0.1 are presented

17. Chemotherapy Surgery alone
Factors associated with overall survival in multivariate analysis HR
95% CI p
Treatment group
Chemotherapy Surgery alone
1 1.39
[ ]
0.046
Number of metastases
1 2+
1 1.49
[ ]
0.023
Disease Free Interval
≤ 1 year > 1 year
1 0.74
[ ]
0.075
Factors associated with OS with a p value < 0.1 in univariate analysis were introduced into the Cox regression model (excepted for the size of metastases and performance status which were not available for all the patients), model was stratified by trial

18. Conclusion
Adjuvant CT with a 5FU bolus based regimen tends to improve PFS and overall survival after complete resection of CRC metastases.
This pooled analysis supports the use of adjuvant CT, with a more effective regimen, after potentially curative resection of CRC metastases.