1. How to treat a patient with stage III Colon Cancer in 2013
Aimery de Gramont
Barcelona July 6, 2013

2. Colo-rectal Cancer World Incidence: 1 234 000 (rank 3)
World Deaths: (rank 4)
Globocan 2007
Colon/Colorectum: 75%
Colon Cancer Stages
AJCC 2010

3. State of the Art
Standard Adjuvant Therapy Stage III
Biomarkers
Adjuvant Therapy - Elderly
Decision Algorithm
Ongoing Trials

4. State of the Art
Standard Adjuvant Therapy Stage III
Adjuvant Therapy Elderly
Biomarkers
Decision Algorithm
Ongoing Trials

5. There is an adjuvant therapy for colon cancer! The first step (1990)

6. Oxaliplatin plus 5FU is better than 5FU alone! The second step (2004)
MOSAIC
NSABP C07
Kuebler JCO 2007
XELOXA
NO16968
Haller JCO 2011

7. Oxaliplatin Trials - Efficacy
Stage III
MOSAIC
C07
XELOXA
Δ DFS
7.5%
7.8%
6.3%
HR DFS
0.78
0.80
Δ OS
4.2%
3.4%
HR OS
0.85
0.87
N1 DFS HR
0.84
0.73
N2 DFS HR
0.70

8. MOSAIC – 4+ Lymph Nodes 12.7% 11.8% 13.5% Disease-free Survival FOLFOX12 24 36 48 60 72 84
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
LV5FU2
FOLFOX
months
Disease-free Survival 8

9. Oxaliplatin Trials - Safety
Grade 3/4
FOLFOX4
N=1123
FLOX
N=1247
XELOX
N=944
mFOLFOX6
N=1321
Neutropenia
40% NR 9%
33%
Febrile N.
<2%
>2%
<1%
Platelets 2% 5% 3%
Diarrhea
11%
38%
19%
10%
Nausea
16%
Hand-Foot S.
Neuropathy
12% 8%
14%
60D Mortality
3 (0.3%)
15 (1.2%)
9 (1.0%)

10. The disillusion of targeted therapies in adjuvant colon cancer therapy
Bevacizumab
NSABP C08 Allegra JCO 2010
AVANT Lancet Oncol 2012
Cetuximab
N0 147 Alberts JAMA 2012
PETACC8 Taieb WGIC 2012

11. State of the Art
Standard Adjuvant Therapy Stage III
Biomarkers
Adjuvant Therapy Elderly
Decision Algorithm
Ongoing Trials

12. Different biology between stage II and III.
The need of Biomarkers
Different biology between stage II and III.
Markers
Stage II
Stage III
HR§
p value*
T Stage (T4 vs T3)
2.8
0.0001
1.6
0.0006
N Stage (N2 vs N1)
N/A
2.2
<0.0001
Histologic Grade (3-4 vs 1-2)
0.6
0.55
1.4
0.07
Age (>60 vs ≤60)
1.8
0.026
1.1
0.3
MSI (High vs Stable)
0.027
0.7
0.12
p53 (High)
0.27
1.3
0.015
SMAD4 (any loss)
1.0
0.9
0.0002
Treatment, Sex, Site, KRAS, BRAF,TS, 18qLOH (Stage II: HR 1.4, p=0.33), hTERT: not significant
* p values from the Wald test in a multiivariate Cox regression
§ HR = hazard ratio
Roth A et al. ASCO 2009

13. DFS in dMMR patients, pooled data
Stage II (N=102)
Stage III (N=63)
5 yr DFS
5 yr DFS
Untreated 87%
Treated %
HR: 2.80 ( )
p=0.05
Untreated 62%
Treated %
HR: 1.08 ( )
p=0.86
Sargent, JCO 2009

14. DFS in Stage III dMMR patients
Fluoropyrimidine
Stage III (N=63)
FOLFOX4
Stage III (N=47)
5 yr DFS
Untreated 62%
Treated %
HR: 1.08 ( )
p=0.86
Sargent, JCO 2009
Fléjou, ASCO 2013

15. State of the Art
Standard Adjuvant Therapy Stage III
Biomarkers
Adjuvant Therapy Elderly
Decision Algorithm
Ongoing Trials

16. Elderly - ACCENT Hazard ratio (95% CI) DFS OS ACCENT analysis4†
<70 years, n=3877
0.77 (0.68,0.86)
0.81 (0.71,0.93)
≥70 years, n=703
1.04 (0.80,1.35)
1.19 (0.90,1.57)
Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV.
McCleary et al. ASCO 2009 (poster 4010) 16

17. > 70 Years MOSAIC C0-7 OS OS DFS Interaction P=0.0391 Years LV5FU
FLOX OS OS
DFS
Interaction P=0.0391 2 4 6 8
Years

18. Elderly XELOXA Hazard ratio (95% CIs)* DFS OS NO16968
<70 years, n=1477
0.79 (0.66,0.94)
0.86 (0.69,1.08)
≥70 years, n=409
0.87 (0.63,1.18)
0.94 (0.66,1.34)
Haller ASCO GI 2011 18

19. DFS
RFS
MOSAIC OS
S post R
JCO 2012

20. Role of Gender in Elderly Patients
DFS

21. Stage IIIC (4+LN) in Elderly Patients
OS 18%
DFS 17%

22. State of the Art
Standard Adjuvant Therapy Stage III
Biomarkers
Adjuvant Therapy Elderly
Decision Algorithm
Ongoing Trials

23. When cure rate without oxaliplatin is 50%
Most patients want to be treated if they can have an absolute survival benfit of more then 3%
When cure rate without oxaliplatin is 50% %
When cure rate without oxaliplatin is 80% %
Benefit of oxaliplatin
Benefit of oxaliplatin
Love, ASCO 2007

24. AJCC7 (2010). Summary of changes
T4a (Tumor penetrates the surface of the visceral peritoneum)
T4b (Tumor directly invades or is histologically adherent to other organs or structures)
N1c T1-2 N0 with tumor deposit(s)(TD)
N1a (metastasis in 1 regional node)
N1b (metastasis in 2–3 nodes)
N2a (metastasis in 4–6 nodes)
N2b (metastasis in 7 or more nodes)
Stage II is subdivided into IIA (T3N0), IIB (T4aN0), IIC (T4bN0)
Stage III:
T4bN1 has been reclassified from IIIB to IIIC
T1N2a has been reclassified as IIIA
T1N2b,T2N2a-b and T3N2a have all been reclassified as IIIB
M1 has been subdivided into M1a for single metastatic site vs. M1b for multiple metastatic sites

26. DFS Stage III (AJCC not applicable)* *
* previous
AJCC

27. DFS AJCC Stage IIIA
N=56
N=46

28. DFS AJCC Stage IIIB

29. DFS AJCC Stage IIIC

30. Will Rogers’effect Recent trials vs. MOSAIC in Stage III
2004
XELOXA
2011
NCCTG N0147
2012
AVANT
Regimen
LV5FU2
FOLFOX4
XELOX
mFOLFOX6
3yr OS
81.3%
84.3%
86%*
87.9%
90%*
* from curves
FOLFOX4 MOSAIC vs. FOLFOX4 AVANT
3-yr DFS
5-yr OS
3-yr DFS <4LN
3-yr DFS ≥4LN
MOSAIC
73%
76%
71,8%
56,2%
AVANT
77%
85%*
85%
66%
* preliminary results
MOSAIC data
Haller, et al. JCO 2011
Alberts, et al. JAMA 2012
Lancet Oncol 2012

31. Decision Algorithm in Stage III Adjuvant Therapy
Risk <15%
Potential
Benefit<3%
Stage IIIA
5FU/cap RS
Risk 15-25%
Potential
Benefit>3%
FOLFOX
XELOX
Stage IIIB*
Stage IIIB T3N2a-b*
Stage IIIC
Elderly (M75, F80)
Risk >25%
Potential
Benefit>5%
FOLFOX
XELOX
Prexisting neuropathy
Frail patients
Elderly (M75, F80) Stage IIIA-B
5FU/cap

32. State of the Art
Standard Adjuvant Therapy Stage III
Biomarkers
Adjuvant Therapy Elderly
Decision Algorithm
Ongoing Trials

33. Incidence of Neurosensory Symptoms
during Treatment and Follow-up after FOLFOX
Evaluable patients n=811 at 4 years
Grade 0
84.3%
Grade 1
12.0%
Grade 2
2.8%
Grade 3
0.7%
Andre et al J Clin Oncol Jul 1;27(19):

34. Relapse-free Survival by Adjuvant Treatment Arms
6 Months of bolus 5FU/LV vs. 3 months of Continuous Infusion 5FU
Relapse-free survival by treatment arms in all patients. 5-FU, 5-fluorouracil; PVI, protracted venous infusion; LV, leucovorin.
Chau I et al. Ann Onco 2005

35. R IDEA – Meta-Analysis TOSCA SCOT GERCOR CALGB HORG JAPAN
mFOLFOX6/XELOX
TOSCA
N= 3249 R
12/8 cycles
mFOLFOX6/XELOX
SCOT
stage II-III
6/4 cycles
N= 3656
Non inferiority trial (HR<1.1 – N 10500)
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).
N= 9101 (Nov 2012)
GERCOR
CALGB
HORG
JAPAN
N= 1136
N= 590
N= 470
Started 35

36. Ongoing Trials (June 2013)
CALGB 80702: Phase III Trial of 6 vs. 12 Treatments of Adjuvant Folfox Plus Celecoxib or Placebo for Patients with Resected Stage III Colon Cancer N=2500
ASCOLT: Aspirin vs Placebo
Stage II-III Colon & Rectum N=2660 Asia
CHALLENGE: Colon Health + Life-Long Exercise Change trial
NSABP: Rosuvastatin vs Placebo
Stage I-II polyps and recurrence N=1740
Japan: UFT +/- PSK stage IIIAB n=300
UK: CAPOX vs no therapy locally advanced rectal cancer N=800
France: follow-up vs laparotomy+HIPEC High-risk peritoneal N=130

37. 5 year Recurrence Risk based on Recurrence Score Category
New Biomarkers
Detection of guanylyl cyclase C mRNA in lymph nodes of resected stage II colorectal cancer is highly correlated with the risk of tumor recurrence
Hyslop CCR 2011
Molecular signatures: Oncotype Dx Colon 12
5 year Recurrence Risk based on Recurrence Score Category
Low
Intermediate
High
Stage IIIA/B
21%
29%
38%
Stage IIIC
40%
51%
64%
NSABP C07 – O’Connell et al ASCO 2012 Abstract 3512

38. Molecular Classification of Colon Cancer
Stage II-III
Salazar, et al. ASCO 2013

39. What is the signal to launch an adjuvant trial?
Drug
Preclinical model
Metastatic
trial
Adjuvant
study
Results
Levamisole No
Yes
Positive
LV5FU
Phase III
Irinotecan
Negative
Oxaliplatin
Phase III (PFS)
Interferon α
Phase II
Edrecolomab
Cetuximab
Bevacizumab

40. R COLADJ 2012 Antiangiogenic Agent X mFOLFOX6 6-12 cycles Control
ASCO 2018 40

41. Conclusions: Decision Algorithm
Prexisting neuropathy
Frail patients
Elderly (M75, F80) Stage IIIA-B
Stage IIIA
Stage IIIB*
Stage IIIB T3N2a-b*
Stage IIIC
Elderly (M75, F80)
Risk <15%
Potential
Benefit<3%
Risk 15-25%
Benefit>3%
Risk >25%
Benefit>5%
5FU/cap
FOLFOX
XELOX RS