1. Adjuvant therapy in colon cancer
Christophe Louvet
Hôpital St-Antoine
Paris, France
Beyrouth, 14/11/08

2. Incidence of colorectal cancer in the U. S
Incidence of colorectal cancer in the U.S. and Western Europe (n~300,000)
Adjuvant
Chemotherapy =
Option
Stage I
24%
Stage II
26%
Stage IV
22%
Stage III
29%
Adjuvant
Chemotherapy =
Standard

3. When there was no 5FU….
3-year DFS~50%
Stage III

4. When there was only 5FU….
3-year DFS < 67%

5. X-ACT trial in adjuvant treatment of stage III colon cancer
1° endpoint: disease-free survival (DFS)
2° endpoints
overall survival (OS)
relapse-free survival (RFS)
tolerability (NCIC CTG)
pharmacoeconomics
QoL
Capecitabine
1250mg/m2 twice daily, d1–14, q21d
n=1004
Bolus 5-FU/LV
5-FU 425mg/m2 plus LV 20mg/m2, d1–5, q28d
n=983
Recruitment
1998–2001
24 weeks
Chemo-naïve
stage III,
resection £8 weeks
Twelves et al., ECCO 2007

6. Disease-free survival: 5-year update – median follow-up 6.8 years
Capecitabine (n=1 004) 60.8%
5-FU/LV (n=983) 56.7%
Estimated probability
1.0
0.8
0.6
0.4
0.2
0.0 6 42 48 78 96
Months
HR=0.88 (95% CI: 0.77–1.01)
NI margin 1.20 12 18 24 30 36 54 60 66 72 84 90
Test of non-inferiority p<0.0001
Test of superiority p=0.0682
Twelves et al., ECCO 2007
ITT population

7. Overall survival: 5-year update – median follow-up 6.8 years
Capecitabine (n=1 004) 71.4%
5-FU/LV (n=983) 68.4%
1.0
0.8
0.6
0.4
0.2
0.0 6 42 48 78 96 12 18 24 30 36 54 60 66 72 84 90
Estimated probability
Months
HR=0.86 (95% CI: 0.74–1.01)
NI margin 1.14
Test of non-inferiority p=
Test of superiority p=0.06
Twelves et al., ECCO 2007
ITT population

8. Fluoropyrimidine monotherapy
DFS in stage III CRC 80 67 70 65 64 62 61 60 52 50 44
DFS (%) 40 30 20 10
Moertel
IMPACT
IMPACT
Punt
Fields
Andre
X-ACT
Observation
Fluoropyrimidine monotherapy

9. Irinotecan Irinotecan Irinotecan hydrochloride SN-382 H 3
SN-38
N-H HO +
Carboxylesterases
Piperidinopiperidine

12. VanCutsem, ASCO 2005

13. Adjuvant Therapy DFS New standard 5FU bolus + LV LV5FU2 Capecitabine
5FU+lev
LV5FU/iri
IFL
better safety

14. trans-l-diaminocyclohexane oxalatoplatinum
Oxaliplatin
oxaliplatin
Diaminocyclohexane
(DACH) carrier
ligand
NH2 O C Pt O C
NH2 O
trans-l-diaminocyclohexane oxalatoplatinum
OXALIPLATIN

16. MOSAIC (FOLFOX4): Disease-Free Survival (all population)
3 years (April 20031)
5 years (June 20062)
FOLFOX4 (n=1123)
LV5FU2 (n=1123)
Median follow-up, months
37.9
37.8
73.5
73.4
Events (%)
21.1
26.1
27.1
32.1
DFS (%)
78.2
72.9
73.3
67.4 HR
0.77
0.80
[95% CI]
[0.65–0.91]
[0.68–0.93]
p-value
0.002
0.003
1. Andre, et al. N Engl J Med 2004;350:2343–2351
2. De Gramont et al. ASCO Abstract 4007.

17. 5 Yrs Disease-free Survival: Stage II and Stage III Patients
HR [95% CI] p-value
Stage II [0.62–1.14]
Stage III [0.65–0.93]
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
Months
Probability
1.0
0.8
0.6
0.4
0.2
0.9
0.7
0.5
0.3
0.1 6 12 18 24 60 30 36 42 48 54 66 72
p=0.258
3.8%
p=0.005
7.5%
Data cut-off: June 2006
De Gramont et al. ASCO Abstract 4007.

18. Disease-free Survival in Stage III Patients: N1 & N2
1.0
0.9
0.8
7.2%
0.7
0.6
11.5%
DFS probability
0.5
0.4
FOLFOX4 – 443 N1
LV5FU2 – 443 N1
FOLFOX4 – 229 N2
LV5FU2 – 232 N2
HR: 0.76
0.3
0.2
HR: 0.72
0.1
0.0 6 12 18 24 30 36 42 48 54 60 66
Data cut-off: January 16, 2005
Months

19. MOSAIC: OS with 6 years minimum follow-up (2008)
1.0
p=0.996
0.9
0.1%
0.8
p=0.023
0.7
4.4%
0.6
Probability
0.5
0.4
HR [95% CI]
Stage II [0.71–1.42]
Stage III [0.66–0.98]
FOLFOX4 stage II
LV5FU2 stage II
FOLFOX4 stage III
LV5FU2 stage III
0.3
0.2
0.1 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Data cut-off: January 2007
De Gramont et al. ASCO Abstract 4007.

20. Safety results: toxicity per patient
NCI Grade 3 FOLFOX4 LV5FU2 Patients (%) (n=1108) (n=1111)
Thrombocytopenia
Neutropenia (Grade 4: 12.2) 4.7
Febrile neutropenia/sepsis
Diarrhoea
Stomatitis
Vomiting
Allergy
Alopecia (Grade 2)
All-cause mortality
Andre T et al; N Engl J Med, 2004 Jun 3;350(23):

21. Long-term Safety Second cancer Peripheral Sensory Neuropathy 5.3 5.7
(% patients)
FOLFOX
5.3
LV5FU2
5.7
Second cancer
Peripheral Sensory Neuropathy
Evaluable patients n=811
Grade 0
84.3%
Grade 1
12.0%
Grade 2
2.8%
Grade 3
0.7%
Data cut-off: January 2007

23. Eloxatin combinations: NSABP C-07
Primary endpoint: 3-year DFS
5-FU/LV
5-FU: 500 mg/m2 iv bolus weekly x 6 LV: 500 mg/m2 iv weekly x 6 each 8-week cycle x 3, n=1207
2492 patients with stage II and III colon cancer R
FLOX
5-FU/LV + oxaliplatin 85 mg/m2 iv on Weeks 1, 3 and 5 of each 8-week cycle x 3, n=1200
P.Kuebler et al. JCO,2007,

24. Eloxatin combinations: NSABP C-07 3-year DFS
1.0
21% risk reduction for FLOX
0.9
0.8
0.7
4.9%
Probability
0.6
0.5
3-year DFS
0.4
76.5% %
FU/LV
FLOX
0.3
0.2
Hazard ratio: 0.79 (95% CI: 0.67–0.93)
p<0.004
0.1 1 2 3 4
Time (years)
P.Kuebler et al. JCO,June 2007,

25. LV/5FU bolus (Mayo or RPMI)
XELOX NO16968
LV/5FU bolus (Mayo or RPMI)
Closed april 2004 R
24 weeks
XELOX
stage III
24 weeks
n = 1864
Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting?
Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings
An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2].
Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis.
Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics.
Between November 1998 and November 2001, patients were enrolled from 164 centres worldwide.
1. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403).
1st endpoint: disease-free survival (DFS)
Results : end of 2008

26. XELOX vs bolus 5-FU/LV: main grade 3–4 treatment-related toxicities30
XELOX 25
5-FU/LV 20
Patients (%) 15 10 5
HFS
Diarrhoea
Nausea
Vomiting
Stomatitis
Neutropenia
Neurosensory
Febr. neutropenia
Schmoll et al, J Clin Oncol 2007

27. Adjuvant Therapy ? DFS New standard FLOX XELOX FOLFOX4 5FU bolus + LV
LV5FU2
Capecitabine
5FU+lev
LV5FU/iri
IFL
better safety

28. Fluoropyrimidine monotherapy
3y-DFS in stage III CRC 78 76 80 67 70 65 64 62 61 60 52 50 44
DFS (%) 40 30 20 10
C07
FLOX
Moertel
IMPACT
IMPACT
Punt
Fields
Andre
X-ACT
MOSAIC
FOLFOX4
Observation
Fluoropyrimidine monotherapy
Ox-based

31. Quick & Simple & Reliable
'Uncertain indication'
for chemotherapy
(3239 patients ’94 -’03)
Randomize
Observation
(n=1617)
5-FU/LV ± Lev
(n=1622)
Quasar Collaborative group-Lancet 2007;370:

32. QUASAR: Survival n deaths 5yS p Chemo 1622 311 80.3 0.008
None
Quasar Collaborative group-Lancet 2007;370:

33. MOSAIC: high-risk stage II patients
64% of stage II patients were defined as high-risk: T4
Bowel obstruction
Tumour perforation
Poorly differentiated tumour
Venous invasion
Number of examined lymph nodes <10

34. 5 Yrs Disease-free Survival: High-risk Stage II Patients
1.0
0.9
0.8
7.2%
0.7
FOLFOX4 n=286
LV5FU2 n=290
0.6
Probability
0.5
3-year 5-year
FOLFOX % %
LV5FU % %
HR [95% CI]: 0.74 [0.52–1.06]
0.4
0.3
0.2
0.1 6 12 18 24 30 36 42 48 54 60 66 72
Disease-free survival (months)
Exploratory analysis
De Gramont et al. ASCO Abstract 4007.

35. Future directions: E5202 R Planned n=3125 mFOLFOX6
High-risk (MSS and 18q LOH)
Stage II colon cancer R
mFOLFOX6 + bevacizumab
SURGERY
Tumour block risk assessment based on biology (18q/MSI)
Low-risk (MSI or no loss of 18q LOH)
Observation
Planned n=3125

36. When there was only chemotherapy…
3-year DFS<74%

37. BEVACIZUMAB
VEGF
VEGFR

38. R NSABP C08 mFOLFOX6 12 cycles mFOLFOX6 + Bev Bev 12 cycles 6 months
stage II-III
(n=2700)
12 cycles
6 months
Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting?
Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings
An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2].
Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis.
Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics.
Between November 1998 and November 2001, patients were enrolled from 164 centres worldwide.
1. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403).
1st endpoint: disease-free survival (DFS)
Closed octobre 2006

39. R AVANT BO17920 study Primary endpoint: disease-free survival
FOLFOX4
Observation R
FOLFOX4 + Beva.
(5mg/kg q 2 weeks)
Beva. mono
(7.5mg/kg q 3 weeks)
Stage II/III colon cancer
(n=3450)
XELOX + Beva.
(7.5mg/kg q3 weeks)
Beva. mono
(7.5mg/kg q3 weeks)
Duration of treatment
24 weeks
24 weeks
Primary endpoint: disease-free survival
Secondary endpoints: safety, overall survival, pharmacoeconomics,
pharmacodynamics, convenience and satisfaction with chemotherapy

40. Capecitabine + Bevacizumab
Phase III adjuvant trial in high-risk stage II/III colon cancer (QUASAR-2)
Capecitabine R
Capecitabine + Bevacizumab
Stage II-III
N=3510
Ongoing trial phase III trial in patients with high-risk stage II/III colon cancer.
Over 30 patients with colon cancer have been enrolled to date.
Primary endpoint: disease-free survival.
Secondary endpoints include survival and tolerability analyses.
24 weeks
1st endpoint: disease-free survival (DFS)
Secondary endpoint: safety, overall survival

41. CETUXIMAB
EGFR1

42. R Modified Intergroup N0147 mFOLFOX6 24 weeks mFOLFOX6 + Cetuximab
Stage III
24 weeks
Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting?
Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings
An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2].
Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis.
Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics.
Between November 1998 and November 2001, patients were enrolled from 164 centres worldwide.
1. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403).
1st endpoint: disease-free survival (DFS)

43. R PETACC-8 - ACCORD - Merck FOLFOX4 24 weeks FOLFOX4 + Cetuximab
stage III
24 weeks
Xeloda is firmly established as first-line treatment for MCRC, leading to the question, ‘Can Xeloda replace 5-FU in the adjuvant setting?
Potential benefits: tumor-targeted action, improved tolerability, convenient oral therapy, cost savings
An open-label, multinational, randomised, phase III trial, the Xeloda Adjuvant Chemotherapy Trial (X-ACT), evaluated Xeloda versus bolus 5-FU/LV as adjuvant treatment for Dukes’ C colon cancer [1,2].
Primary objective: to demonstrate at least equivalent disease-free survival with Xeloda versus 5-FU/LV, in an event-driven analysis.
Secondary objectives: superiority and confirmatory analyses (subgroups, multivariate), relapse-free survival, overall survival, safety, QoL, and pharmacoeconomics.
Between November 1998 and November 2001, patients were enrolled from 164 centres worldwide.
1. Scheithauer W et al. Ann Oncol 2003;14:1735–43.
2. Cassidy J et al. Proc Am Soc Clin Oncol 2004 (Abst 1403).
1st endpoint: disease-free survival (DFS)
Now restricted to k-ras WT patients

44. Advances in the Adjuvant treatment of colon cancer
FU + levamisole better than BSC
months = 12 months
1998 levamisole of no additional benefit
1998 high-dose LV = low-dose LV
1998 Weekly = monthly schedule
1998 MOSAIC Adjuvant study starts
2001 Elderly benefit
2004 Capecitabine and UFT equivalence to IV 5FU
2004 QUASAR data for Dukes B
2004 MOSAIC (NSABP C-07) new standard of care Dukes C
2005 Irinotecan preliminary data / PETACC-3
2005 Targeted (Bevacizumab/ Cetuximab) agent studies start
MOSAIC Overall Survival data ACCENT DATABASE

45. New guidelines for adjuvant treatment of colon cancer: NCCN 2006
T1, N0, M0 and T2, N0, M0 (stage I)
No chemotherapy
T3, M0, N0 (stage II, no high-risk features)
Consider single-agent fluoropyrimidine or 5-FU/LV + oxaliplatin
N0 high risk and Stage III
FOLFOX (XELOX)
NCCN Clinical Practice Guidelines in Oncology v