1. Efficacy findings from a randomized phase III trial of capecitabine plus oxaliplatin versus bolus 5-FU/LV for stage III colon cancer (NO16968): No impact of age on disease-free survival (DFS).
Discussant: Aimery de Gramont

2. Treatment of Colorectal Cancer in Elderly Patients
Metastatic setting
Folprecht JCO N=2,692 (22%  70 yrs)
4 trials of irinotecan-based therapy
Improved PFS, trend to improved OS for elderly w/addition of irinotecan
Goldberg JCO N=3,742 (16%  70 yrs)
4 trials of oxaliplatin-based therapy
Similar survival benefit and toxicity in age subgroups
**Pooled analyses in metastatic setting showed improved or similar survival benefit for older pts receiving combination vs IV FU/LV
**Suggests older patients derive benefit from adjuvant therapy after surgery
**Formed basis of ACCENT data group

3. Treatment of Colorectal Cancer in Elderly Patients
Adjuvant setting
Sargent NEJM 2001 – N=3351 (15%  70 yrs)
7 trials of 5-FU + levamisole/leucovorin v surgery
No significant interaction observed between age and efficacy of treatment
**Pooled analyses in metastatic setting showed improved or similar survival benefit for older pts receiving combination vs IV FU/LV
**Suggests older patients derive benefit from adjuvant therapy after surgery
**Formed basis of ACCENT data group

4. Phase III Trial of Capecitabine + Oxaliplatin vs
Phase III Trial of Capecitabine + Oxaliplatin vs. Bolus 5-FU/LV in Stage III Colon Cancer (NO16968) Impact of Age on Disease-free Survival
D. Haller, J. Cassidy, J. Tabernero, J. Maroun F. de Braud, T. Price, E. Van Cutsem, M. Hill F. Gilberg, H-J. Schmoll 4

5. NO16968 Trial Design Primary endpoint: DFS
R A N D O M I Z
A T I O N
XELOX (6 months)
capecitabine 1000mg/m2 bid d1–14 oxaliplatin130mg/m2 d1
q3w 8 cycles
n=944
Chemo/ radiotherapy-naive
stage III colon
≤8 weeks since resection N=1886
Bolus 5-FU/LV (6 months) Mayo Clinic [n=664] or Roswell Park [n=278]
Centres pre-specified use of Mayo Clinic or Roswell Park regimens.
Mayo Clinic
Leucovorin 20 mg/m2 i.v. bolus injection + 5-fluorouracil 425 mg/m2 i.v. bolus injection daily on days 1-5 of a 4 week cycle, for a total of 6 cycles (24 weeks).
Roswell Park
Leucovorin 500 mg/m2 by 2 hour i.v. infusion + 5-fluorouracil 500 mg/m2 i.v. bolus injection daily on Day 1 of weeks 1-6 of an 8 week cycle, for a total of 4 cycles (32 weeks).
n=942
Primary endpoint: DFS
Secondary endpoints: RFS, OS, tolerability 5

6. DFS At 3, 4 and 5 Years: Benefit with XELOX Maintained and Increased Over Time
3-year DFS
4-year DFS
5-year DFS
70.9% %
66.1%
1.0
66.5% %
59.8%
0.8
Δ at 3 years: 4.5%
XELOX
0.6
5-FU/LV
Δ at 4 years: 6.1%
Δ at 5 years: 6.3%
0.4
0.2
0.0 1 2 3 4 5 6
Years
ITT population 6

7. Subgroup Analysis of DFS by Age
Unplanned analysis performed to:
Compare with data presented from ACCENT.
Assess benefits of XELOX vs. 5-FU/LV in patients aged >65 and >70 years.
Determine if ACCENT and MOSAIC findings are FOLFOX- or oxaliplatin-specific.

8. Subgroup Analysis of DFS by Age
3-year DFS
Hazard ratio
(95% CI)
XELOX
5-FU/LV
<70 years, n=1477
72%
69%
0.79 (0.66,0.94)
≥70 years, n=409
66%
60%
0.87 (0.63,1.18)
Subgroup Analysis of OS by Age
5-year OS
Hazard ratio
(95% CI)
XELOX
5-FU/LV
<70 years, n=1477
80%
76%
0.86 (0.69,1.08)
≥70 years, n=409
69%
67%
0.94 (0.66,1.34)
ITT population 8

9. Comparison with ACCENT Analysis
Hazard ratio (95% CIs)*
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)
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)
*Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV.
†Data for oxaliplatin-based regimens. 4. McCleary et al. ASCO 2009 (poster 4010) 9

10. Treatment Exposure by Age: NO16968
Mean value
XELOX
5-FU/LV
<70 years
(n=748)
≥70 years
(n=190)
(n=711)
(n=215)
Duration of therapy, days
5-FU –
175
164
Capecitabine
158
130
Oxaliplatin
154
124
Dose intensity
0.82
0.76
0.78
0.59
0.79
0.63
Safety population 10

11. Safety by Age Grade 3/4 AEs, % XELOX 5-FU/LV <70 years (n=748)
All grade 3/4 57 70 51 60
Diarrhea 18 26 19 25
Nausea/vomiting 8 11 6 5
Stomatitis
<1 1 9
Neutropenia* 10 16 17
Febrile neutropenia 4
Hand-foot syndrome
Neurosensory
*Includes granulocytopenia.
Safety population 11

12. NO16968 (XELOXA): Conclusions
In the total patient population, XELOX significantly improves DFS compared with bolus 5-FU/LV in adjuvant therapy for stage III colon cancer.
DFS and OS improvements with XELOX are maintained in patients >65 and >70 years, in spite of shorter treatment duration and lower dose intensity in the elderly.
These findings differ from those of the MOSAIC study and the ACCENT analysis.
Reasons for this apparent difference between other 5- FU/LV-oxaliplatin regimens (FOLFOX, FLOX) and XELOX are unknown. 12

13. Impact of NO16968 Findings on Practice
Current analysis supports consideration of XELOX for patients with stage III colon cancer, regardless of age.
These other statements are vague: what analyses???? 13

14. MOSAIC data in patients > 70 years
DFS

15. MOSAIC data in patients > 70 years
DFS

16. MOSAIC data in patients > 70 years

17. MOSAIC data in patients > 70 years

18. Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients with stage II / III colon cancer: Findings from the ACCENT Database N. Jackson McCleary, J.A. Meyerhardt, E. Green, G. Yothers, A. de Gramont, E. Van Cutsem, M. O’Connell, C.J. Twelves, L.B. Saltz, D.J. Sargent for the ACCENT collaborative group

19. ACCENT update: 6 trials added
Accrual
Period
# pts
% pts
≥70 yrs
Experimental
treatment arm†
% stage III‡
MOSAIC
2246 14
FOLFOX4 60
NSABP C-07
2434 16
FLOX 71
CALGB 89803
1263 24
IFL 98
PETACC-3
3186 13
FOLFIRI
NSABP C-06
1557 23
Uracil/tegafur 53
X-ACT
1983 20
Capecitabine
100
† Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and leucovorin (LV)
‡ Remaining patients were stage II or unknown
Recently added data from 6 newer studies evaluating the survival benefit of either intravenous (IV) FU combination chemotherapy or oral FU chemotherapy compared to standard IV FU/LV monotherapy in stage II and III CRC
Abbreviations: MOSAIC, Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer; XACT, Xeloda in Adjuvant Colon Cancer Therapy; NSABP, National Surgical Adjuvant Breast and Bowel Project; CALGB, Cancer and Leukemia Group B; PETACC, Pan-European Trials in Adjuvant Colon Cancer; FOLFOX, infusional 5-FU/LV + oxaliplatin; FLOX, bolus IV 5-fluorouracil (FU)/ leucovorin (LV) + oxaliplatin; IFL, bolus IV 5-FU/LV + irinotecan; FOLFIRI, infusional 5-FU/LV + irinotecan
† Compared to control arm of intravenous 5-flourouracil (IV 5-FU) and
leucovorin (LV)
‡ Remaining patients were stage II or unknown

20. Forest Plots of Hazard Ratios Disease-Free Survival
To reiterate graphically, these forest plots depict no alteration of treatment effect by age.
**These associations are further illustrated by forest plots organized by drug class (Figure 1).

21. Forest Plots of Hazard Ratios Overall Survival

22. Limitations Lack of … Toxicity data Dose-intensity Comorbidity data
…may confound interaction between age & newer adjuvant chemotherapy regimens
- Small population,
- Only two trials in each subgroup
- Different FP regimens
**Lack of consistent toxicity data
May be more critical if the point estimates for the older patients was at least less than 1 so that clinicians can weigh the risk – benefit ratio
**Lack data on dose-intensity or proportion of dose delivered compared to the total dose planned
unable to comment on the extent to which the amount of actual dose received may account for lack of benefit among older patients receiving adjuvant therapy
**Lack mechanistic explanation
?impact of comorbidity
?impact of functional decline
Dewys WD, et al. Am J Med 1980; Eagles JM, et al. BMJ 1990; Landi F ZG, et al. J Am Geriatr Soc 1999;
Lee Y et al. J Epidemiol Community Health 2000; Satariano WA, et al. Ann Intern Med 1994;
Wedding U, et al. J Cancer Res Clin Oncol 2007.

23. Impact of ACCENT Analysis on Practice
ACCENT conclusions have resulted in changes to:
German treatment guidelines
PETACC-8 trial design
UK and US clinical practice (some investigators) 23

24. Population and Hazard-Ratios%
DFS HR
OS HR
reference
ACCENT
Oral FP
755
21.3
1.13
1.17
ASCO 2009
X-ACTa
397
20.0
0.93b
Twelves NEJM 2005, ASCO GI 2008
C-06
358
22.3
NA >1.13
NA >1.17
Lembersky JCO 2006
Oxaliplatin
703
15.0
1.04
1.19
MOSAIC
315c
14.0
0.91
1.10
unpublished
C-07
388
16.9
NA >1.04
NA >1.19
Kuebler JCO 2007
NO16968a
409
21.7
0.87
0.94
ASCO GI 2010
a stage III
b estimated from forest plot
c stage III 190 patients

25. Population In trials ~ 20% of the patients are > 70 years of age
In the US, from , the median age at diagnosis for cancer of the colon and rectum was 71 years of age (M69, F73)* *

26. Disease-free Survival
There is a benefit in DFS in all trials except NSABP C06 and C07
Role of the FP regimen?
The benefit might be lower in the ederly population than in the younger population
HR~0.9 vs ~0.8
- dose-intensity
toxicity

27. Overall Survival
There is no benefit in OS (HR>1) in all trials except a small benefit in the two capecitabine-based trials (HR 0.93 and 0.94)
Results are better in stage III than in stage II.
C-06, C-07 and MOSAIC include both stage II and stage III patients
X-ACT and NO16968a include stage III only

28. MOSAIC data in patients > 70 years
Comorbidities and Serious Adverse Events
FOLFOX
LV5FU2 P N
155
160
Comorbidities* 85 93
cardiovascular 74 75
malignancy 1
endocrine 12 13
multiple 19 18
SAE 30 15
0,018
*Adult Comorbidity Evaluation-27 Washington University School of Medicine
*including death of any cause

29. MOSAIC data in patients > 70 years
Management of Relapse and Causes of Death
FOLFOX
LV5FU2 P N
155
160
living with relapse 7 13
Relapse 51 53
Chemotherapy 23 34
0.070
Irinotecan/oxali/(both)
16: 10/6
30: 14/17/(1)
0.011
Surgery Metastases 9 22
0.010
Death colon cancer 29
Death other 11
0,043
Second K 1
0,020
Cardiovascular 4

30. MOSAIC data in patients > 70 years
Survival after DFS
Death other than colon cancer
Management of relapse

31. Capecitabine alone or with Oxaliplatin in patients > 70 years?
Both trials have comparable:
Population: stage III, ~20% >70 years
Control arm: 5FU bolus
N>70 %
DFS HR
OS HR
reference
X-ACTa
397
20.0
0.93*
Twelves NEJM 2005, ASCO GI 2008
NO16968a
409
21.7
0.87
0.94
ASCO GI 2010
* estimated from forest plot

32. CONCLUSIONS
The benefit of oxaliplatin in DFS might be reduced in the ederly population
Decreased dose intensity NO16968
increased toxicity NO16968, MOSAIC
The lack of survival benefit in OS
is not due to imbalance in comorbidities (MOSAIC)
might be due to deaths of concomitant disease (cancer) and less intensive management of relapse (MOSAIC)
Worst outcome of second cancer and less intensive management of relapse might be patient- related or physician-related

33. Which adjuvant treatment in ederly pts?
Capecitabine alone, in stage III patients, might be a reasonable option
XELOX or FOLFOX can still be considered for the DFS advantage.
OS might be improved with a more intensive management of relapse or second-cancer.
The results of the AVANT trial will provide a comparison between the two regimens
A reduced duration of chemotherapy should be tested and could help ederly patients to accept to resume therapy: IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Colon Cancer Prospective Pooled Analysis