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D. Haller,1 J. Cassidy,2 J. Tabernero,3 J. Maroun,4 F. de Braud,5 T. Price,6 E. Van Cutsem,7 M. Hill,8 F. Gilberg,9 H-J. Schmoll10
1University of Pennsylvania, Philadelphia, USA; 2Glasgow University, Glasgow, Scotland; 3Vall d'Hebron University Hospital, Barcelona, Spain;
4Ottawa Regional Cancer Centre, Ottawa, Canada; 5Istituto Europeo di Oncologia, Milan, Italy; 6The Queen Elizabeth Hospital, Adelaide, Australia; 7University Hospital Gasthuisberg, Leuven, Belgium; 8Maidstone Hospital, Maidstone, UK; 9Hoffmann-La Roche, Basel, Switzerland; 10Martin Luther
University, Halle, Germany
Phase III Trial of Capecitabine + Oxaliplatin vs Bolus 5-FU/LV in
Stage III Colon Cancer (NO16968): Impact of Age on DFS and OS
2
Background
1. Sargent et al. NEJM 2001;345:1091–1097; 2. Twelves et al. NEJM 2005;352:2696–2704 3. André et al. J Clin Oncol 2009;27:3109–3116; 4. McCleary et al. ASCO 2009 (poster 4010)
• Adjuvant 5-FU/LV demonstrated benefit in older patients compared with surgery alone1
• Oral capecitabine is at least equivalent to bolus 5-FU/LV for disease-free survival (DFS) and overall survival (OS) as adjuvant therapy in patients with stage III colon cancer2
• Older patients (≥70 years) treated with capecitabine also showed improved outcomes vs. 5-FU/LV (X-ACT)2
• Recent data from the MOSAIC trial and ACCENT database demonstrated that newer adjuvant regimens (e.g. oxaliplatin combinations) were not associated with significant efficacy benefits vs. 5-FU/LV in patients ≥65 years compared with younger patients3,4
3
MOSAIC: DFS by age3
• MOSAIC trial demonstrated efficacy of FOLFOX4 vs. LV5FU2 is not maintained in patients ≥65 years
3. André et al. J Clin Oncol 2009;27:3109–3116
Prognostic factor (n) Hazard ratio (95% CI)
FOLFOX4 better LV5FU2 better
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6
Overall
Age
≥65 years (n=463)
<65 years (n=884)
4
ACCENT: efficacy not maintained in patients ≥70 years of age in overall population4
AgeEndpoint HR (95% CI)
Experimental vs. Control IV 5-FU/LV
Deaths within 6 mo Exp vs. Control %
(p-value)
DFS* OS* TTR*
<70 yearsn=10,499
0.85 (0.79, 0.91)
0.84 (0.79, 0.91)
0.85 (0.79, 0.91)
0.89 vs. 0.79 (p=0.58)
≥70 yearsn=2,170
1.11 (0.97, 1.28)
1.13 (0.96, 1.32)
1.13 (0.97, 1.32)
2.71 vs. 2.11 (p=0.37)
Interaction of age by treatment
p=0.005 p=0.005 p=0.004
*Values <1 favor experimental arm (oxaliplatin-based regimens)
4. McCleary et al. ASCO 2009 (poster 4010)
5
ACCENT: efficacy of oxaliplatin-based (MOSAIC/C-07) combinations by age4
AgeEndpoint HR (95% CI)
Experimental vs. Control IV 5-FU/LV
Deaths within 6 moExp vs. Control %
(p-value)
DFS* OS* TTR*
<70 yearsn=3,977
0.77 (0.68, 0.86)
0.81(0.71, 0.93)
0.76(0.67, 0.86)
0.81 vs. 0.81 (p=1.0)
≥70 yearsn=703
1.04 (0.80, 1.35)
1.19 (0.90, 1.57)
0.92(0.69, 1.23)
2.57 vs. 1.37 (p=0.25)
Interaction of age by treatment
p=0.016 p=0.037 p=0.21
*Values <1 favor experimental arm (oxaliplatin-based regimens)
4. McCleary et al. ASCO 2009 (poster 4010)
6
Chemo/radiotherapy-naïve stage III colon cancer ≤8 weeks since resection (n=1886)
n=944 n=942
RANDOMIZATION
NO16968 (XELOXA): trial design5
Bolus 5-FU/LV (6 months) Mayo Clinic (n=664)
orRoswell Park (n=278)
XELOX (6 months) capecitabine 1000 mg/m2 bid d1–14
oxaliplatin130 mg/m2 d1 q3w
8 cycles
5. Haller D, et al. Eur J Cancer Suppl 2009;7:4(Abst 5LBA)
7
NO16968 (XELOXA): patient demographics
Characteristic
XELOX (n=944)
5-FU/LV (n=942)
Male, % 54 53
Median age, years (range) <70 years, n (%) ≥70 years, n (%)
61 (22–83)752 (80)192 (20)
62 (24–82)725 (77)217 (23)
ECOG PS, % 0 1
7525
7822
CEA, % normal 92 93
Creatinine clearance, % 30–50 mL/min 50–80 mL/min >80 mL/min
340 57
34256
8
NO16968 (XELOXA) primary endpoint met: superior DFS with XELOX and benefit maintained and increased over time
Years
1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
ITT population
Δ at 4 years: 6.1%Δ at 5 years: 6.3%
Δ at 3 years: 4.5%
70.9%
3-yearDFS
66.5%
5-yearDFS
59.8%66.1%
XELOX
5-FU/LV
4-yearDFS
62.3%68.4%
HR=0.80 (95% CI: 0.69–0.93)p=0.0045
9
NO16968 (XELOXA): trend toward improved OS with XELOX
ITT population
1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6
XELOX 5-FU/LV
Δ at 5 years: 3.4%
HR=0.87 (95% CI: 0.72–1.05)p=0.1486
Years
77.6%
5-yearOS
74.2%
10
NO16968 (XELOXA): subgroup analysis
Survival outcomes by age – analysis performed to:
• Compare with data presented from ACCENT and MOSAIC
• Assess treatment effects of XELOX vs. 5-FU/LV in patients by age:
– ≥65 (planned) and ≥70 years (unplanned)
• Determine if findings from ACCENT meta-analysis also apply to XELOX regimen
• Determine relapse-free survival (RFS) overall and according to age
11
NO16968 (XELOXA): subgroup analysis of DFS by age
Age group3-year DFS
Hazard ratio(95% CI)XELOX 5-FU/LV
<65 vs. ≥65 years
<65 years (n=1142) 72% 69% 0.80 (0.65–0.98)
≥65 years (n=744) 68% 62% 0.81 (0.64–1.03)
<70 vs. ≥70 years
<70 years (n=1477) 72% 69% 0.79 (0.66–0.94)
≥70 years (n=409) 66% 60% 0.87 (0.63–1.18)
Interaction of age by treatment*
p=0.6222
ITT population
*Multiple Cox regression This non-significant p-value indicates that XELOX efficacy is positive, irrespective of age
12
NO16968 (XELOXA): subgroup analysis of OS by age
ITT population
Age group5-year OS
Hazard ratio(95% CI)
XELOX 5-FU/LV
<65 vs. ≥65 years
<65 years (n=1142) 80% 77% 0.87 (0.67–1.13)
≥65 years (n=744) 73% 70% 0.90 (0.68–1.19)
<70 vs. ≥70 years
<70 years (n=1477) 80% 76% 0.86 (0.69–1.08)
≥70 years (n=409) 69% 67% 0.94 (0.66–1.34)
Interaction of ageby treatment*
p=0.7065
*Multiple Cox regression This non-significant p value indicates that XELOX efficacy is positive, irrespective of age
13
NO16968 (XELOXA): subgroup analysis of RFS by age
Age group
3-year RFSHazard ratio
(95% CI)XELOX 5-FU/LV
Overall (n=1886) 72% 67% 0.78 (0.67–0.92)
<70 vs. ≥70 years
<70 years (n=1477) 73% 69% 0.78 (0.65–0.93)
≥70 years (n=409) 69% 61% 0.83 (0.60–1.15)
ITT population
14
Comparison with ACCENT analysis
*Values <1 favor oxaliplatin-based therapy vs. 5-FU/LV; †Data for oxaliplatin-based regimens
4. McCleary et al. ASCO 2009 (poster 4010)
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) 1.18 (0.90–1.57)
Interaction of age by treatment p=0.016 p=0.037
NO16968 (XELOXA)
<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)
Interaction of age by treatment p=0.6222 p=0.7065
15
NO16968 (XELOXA): safety by age
*Includes granulocytopeniaSafety population
Grade 3/4 AEs, %
XELOX 5-FU/LV
<70 years(n=748)
≥70 years(n=190)
<70 years(n=711)
≥70 years(n=215)
All grade 3/4 AEs 57 70 51 60
Diarrhea 18 26 19 25
Nausea/vomiting 8 11 6 5
Stomatitis <1 1 9 8
Neutropenia* 9 10 16 17
Febrile neutropenia <1 <1 4 4Hand-foot syndrome 6 4 <1 <1Neurosensory 11 11 <1 0
16
NO16968 (XELOXA): conclusions
• XELOX results in superior DFS compared with bolus 5-FU/LV as adjuvant treatment for patients with stage III colon cancer
• These findings confirm the benefits previously demonstrated with the addition of oxaliplatin to 5-FU in stage III patients
• Efficacy benefits are maintained in patients ≥65 and ≥70 years in contrast to results from ACCENT and MOSAIC in which no significant benefit is shown with FOLFOX in this age group:
– reasons for this apparent difference are unknown
• OS data thus far indicate a trend toward superior survival with XELOX
• XELOX is an effective adjuvant therapy and should be considered for all eligible patients, without an arbitrary upper age limit
17
Acknowledgments
• Thank you to the:
– 1886 patients and their families
– 226 participating centers and investigators
– nurses and study coordinators
– NO16968 (XELOXA) Steering Committee
– others who made this contribution to the advancement of patient care possible