Transcript Gastrointestinal Cancer Committee

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
Treatment of Colorectal Cancer
in Elderly Patients
• Metastatic setting
• Folprecht JCO 2008 - 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 2006 - N=3,742 (16%  70 yrs)
• 4 trials of oxaliplatin-based therapy
• Similar survival benefit and toxicity in age
subgroups
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
The Adjuvant Colon Cancer End
Points (ACCENT) Group
• Established in 2003
• A collection of individual patient
data from trials in the US, Canada,
Australia and Europe
• Original objective - to validate DFS
as a surrogate endpoint in adjuvant
colon cancer trials
O'Connell MJ, et al. JCO 2008; Sargent DJ, et al. JCO 2007; Sargent DJ, et al. JCO 2005
ACCENT update: 6 trials added
Trial
Accrual
Period
# pts
% pts
≥70 yrs
Experimental
treatment arm†
% stage
III‡
MOSAIC
1998-01
2246
14
FOLFOX4
60
NSABP C-07
2000-02
2434
16
FLOX
71
CALGB 89803 1999-01
1263
24
IFL
98
PETACC-3
2000-02
3186
13
FOLFIRI
71
NSABP C-06
1997-99
1557
23
Uracil/tegafur
53
X-ACT
1998-01
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
Pooled data: 6 adjuvant trials
• 12,669 pts, Accrual from 1997-2002
• 17% ≥70 years
• Available data
• Age
• Gender
• Disease stage
• Treatment arm
• Survival and recurrence status at last follow-up
• ACCENT does not collect toxicity data
Objective
• Determine impact of age (prospectively specified
age 70 threshold), on benefit of chemotherapy in
the adjuvant setting for colon cancer
• Disease-free survival (DFS)
• Time from randomization to the first event of
either recurrent disease or death
• Overall survival (OS)
• Time from randomization to death from any
cause
• Time-to-recurrence (TTR)
• Time to colon cancer recurrence, where
deaths without recurrence are censored at
the time of death
Statistical considerations
• Pooled individual patient data from 6 trials
• Pre-specified age grouping:
• Age < 70 or > 70
• Secondary analysis with STEPP model
• Hazard ratios calculated using Cox
proportional hazards regression model
• Stratified by original trial
• Adjust for gender, treatment arm, stage
• Test age-by-treatment interaction
Baseline characteristics – pooled data
Characteristic
Gender
Female
Male
Stage
II
III
Treatment arm
Control
Experimental
<70 years (%)
N=10,499
≥70 years (%)
N=2,170
45
55
44
56
26
74
23
77
50
50
52
48
Efficacy – overall population
<70
n = 10,499
Endpoint
Deaths within
HR (95% CI)
6 mo
Experimental v Control IV 5 FU/LV
Exp v Control
% (p-value)
DFS*
OS*
TTR*
0.85
0.86
0.84
0.89 v 0.79
(0.80,0.91) (0.79,0.92) (0.79,0.91)
(p=0.58)
≥ 70
n = 2,170
1.11
(0.97,1.27)
1.14
(0.98,1.32)
1.13
(0.97,1.32)
Interaction
of age by
treatment
p-value
0.005
0.005
0.004
Age
* Values < 1 favor experimental arm
2.71 v 2.11
(p=0.37)
Efficacy – oxaliplatin-based therapy
<70
n = 3,977
Endpoint
Deaths within
HR (95% CI)
6 mo
Experimental v Control IV 5-FU/LV
Exp v Control
% (p-value)
DFS*
OS*
TTR*
0.77
0.81
0.76
0.81 v 0.81
(0.68,0.86) (0.71,0.93) (0.67,0.86)
(p=1.0)
≥ 70
n = 703
1.04
(0.80,1.35)
1.19
(0.90,1.57)
0.92
(0.69,1.23)
0.016
0.037
0.21
Age
Interaction
of age by
treatment
p-value
* Values < 1 favor experimental arm
2.57 v 1.37
(p=0.25)
Efficacy – oral fluoropyrimidines
<70
n = 2,785
Endpoint
HR (95% CI)
Exp v Control IV 5-FU/LV
DFS*
OS*
TTR*
0.89
0.87
0.90
(0.79,1.0)
(0.76,1.0) (0.79,1.0)
≥ 70
n = 755
1.13
(0.90,1.42)
Age
Interaction
of age by
treatment
p-value
0.10
1.17
1.16
(0.92,1.48) (0.90,1.50)
0.06
* Values < 1 favor experimental arm
0.13
Deaths within
6 mo
Exp v Control
% (p-value)
1.0 vs 1.3
(p=0.50)
1.7 vs 2.5
(p=0.43)
Forest Plots of Hazard Ratios
Disease-Free Survival
Oral
Oxaliplatin
Irinotecan
Age < 70
Overall
0.2
Age >= 70
0.4
0.6
0.8
1
1.2
1.4
Hazard Ratio
1.6
1.8
2
2.2
Forest Plots of Hazard Ratios
Overall Survival
Oral
Oxaliplatin
Irinotecan
Age < 70
Overall
0.2
Age >= 70
0.4
0.6
0.8
1
1.2
1.4
Hazard Ratio
1.6
1.8
2
2.2
Forest Plots of Hazard Ratios
Time to Recurrence
Oral
Oxaliplatin
Irinotecan
Age < 70
Overall
0.2
Age >= 70
0.4
0.6
0.8
1
1.2
1.4
Hazard Ratio
1.6
1.8
2
2.2
What if restricted to stage III disease?
• Stage II
disease
comprised
25% of
overall
cohort
Disease-Free survival
p interaction = 0.062
Oxaliplatin
• X-ACT and
CALGB
89803
limited to
stage III pts
p interaction = 0.005
Overall
Age < 70
Age >= 70
0.2
0.4
0.6
0.8
1
1.2
1.4
Hazard Ratio
1.6
1.8
2
2.2
What if age modeled differently?
Exploratory Analysis
• Subpopulation Treatment Effect Pattern
Plot (STEPP) analysis
• Method for estimating treatment benefit
for a sequence of patient subgroups
defined by a characteristic of interest,
such as age, without set cut points
• Can enhance interpretation of for
individual patient decision-making.
Gelber. Breast, 2003; Bonetti. Stat Med 2009.
STEPP analysis – Overall population
age cutoff validation for observed lack of added treatment effect
100.0
3 Year DFS
80.0
60.0
Control
Experimental
40.0
P=value = 0.038
20.0
0.0
37
42
47
52
57
Age
62
67
72
STEPP analysis – Oxaliplatin-based therapy
age cutoff validation for observed lack of added treatment effect
100.0
3 Year DFS
80.0
60.0
Control
Experimental
40.0
P=value = 0.33
20.0
0.0
37
42
47
52
57
Age
62
67
72
Limitations
• Lack of …
• Toxicity data
• Dose-intensity
• Comorbidity data
…may confound interaction between age &
newer adjuvant chemotherapy regimens
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.
Toxicity and Dose-Intensity Issue
• In recent C-08 (FOLFOX +/- Bevacizumab), advanced age
was associated with significantly greater grade 3+
toxicities in both treatment arms
Toxicity
Gr 3+ ANC
Gr 3+ fatigue
Age < 70
35%
7%
Age > 70
57%
15%
Gr 3+ dehydration
Gr 3+ diarrhea
3%
10%
11%
16%
Febrile neutropenia
All grade 3+
1%
73%
3.5%
81%
• Dose intensity for patients age > 60 was significantly less
for 5-FU and oxaliplatin than < 60 (p < 0.001)
Allegra CJ et al JCO online ahead of print May 4, 2009
Implications of individual study design
• The 6 included adjuvant trials tested regimens
beyond variations in IV 5-FU/LV dosing schedule
• 4 trials (MOSAIC, NSABP C07, CALGB 89803 and
PETACC-3) designed to demonstrate superiority of
experimental regimen in improving DFS or OS
compared to standard IV FU/LV
• Do not demonstrate superiority of experimental
regimen in subset of older patients
• 2 trials (X-ACT and NSABP C06) designed to
demonstrate non-inferiority of oral fluoropyrimidine
therapy compared to standard IV FU/LV
• Data support that oral fluoropyrimidines are noninferior both older and younger patients
Conclusions
• Newer adjuvant regimens were not associated with
a significant benefit in DFS, OS, or TTR compared
to standard IV 5-FU/LV in pts > 70 years
• A key question that must be addressed is whether
subgroups of > 70 would benefit from combination
therapy
• Lack of significant interaction for TTR for age and
treatment in oxaliplatin-based trials suggests
competing risks
• Oxaliplatin may reduce risk of early recurrence
but does not translate into DFS or OS benefit
due to deaths from other causes
Conclusions
• These data do not contradict early studies
of benefit of adjuvant therapy with 5flurouracil and leucovorin vs surgery
alone in elderly patients
With gratitude…
• ASCO Young • ACCENT Collaborators:
Investigator’s
Award 200809 to Dr.
JacksonMcCleary
• Hartford
Foundation
• S Wieand, G Yothers, M O’Connell, N Wolmark – NSABP
• J Benedetti, C Blanke – SWOG; C O’Callaghan – NCIC
• R Labianca – Ospedali Riuniti (Italy)
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•
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D Haller, P Catalano, A Benson – ECOG
•
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R Goldberg, J Meyerhardt, N Jackson, L Saltz – CALGB
JF Seitz – University of the Mediterranean (France)
G Francini – University of Siena (Italy)
A de Gramont, T Andre – GERCOR
M Buyse – IDDI (Belgium); R Gray, D Kerr – QUASAR
D Sargent, A Grothey, S Alberts, E Green, Q Shi –Mayo Clinic
C Twelves -University of Bradford (UK)
• J Cassidy – University of Glasgow (UK)
• F Sirzen – Roche ; L Cisar - Pfizer
• E Van Cutsem –University Hospital Gasthuisberg (Belgium);
• A Sobrero - Ospedale San Martino (Italy)