What are the benefits for the elderly in the adjuvant setting?
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Transcript What are the benefits for the elderly in the adjuvant setting?
Treatment of Elderly Patients with
GI Cancer
D Papamichael MB BS FRCP
14th World Congress on Gastrointestinal Cancer
“Meet the Expert concurrent presentations”
Barcelona, Spain
29th June 2012
Outline
•
Background
•
Adjuvant therapy
- Single agent 5FU-based therapy
- Combination chemotherapy
•
Management of metastatic disease
•
Conclusions
Background
Fastest growing section of population in
Western countries is that of over 65s
Approximately half the incidence of colorectal
cancer occurs in the over 70s
Evidence that elderly patients with colorectal
cancer are:
- under-staged
- under-treated
- under-represented in clinical trials
Percentage of total population aged 60 years or older
2002
The boundaries shown on this maps do not imply official endorsement by the United Nations
http://www.un.org/esa/population/publications/ageing/Graph.pdf
Percentage of total population aged 60 years or older
2050
The boundaries shown on this maps do not imply official endorsement by the United Nations
http://www.un.org/esa/population/publications/ageing/Graph.pdf
Background
Fastest growing section of population in
Western countries is that of over 65s
Approximately half the incidence of colorectal
cancer occurs in the over 70s
Evidence that elderly patients with colorectal
cancer are:
- under-staged
- under-treated
- under-represented in clinical trials
Probability (%) of Developing Colorectal
Cancer in the Next 10 Years by Age
NCIC, Canadian Cancer Statistics 2002
Life Expectancy
Women have a life expectancy of more than 20 years at
60, 15 years at 70 and 10 years at 80
Men of 20 years at 60, 12 years at 70 and 8 years at 80
China
30
France
China
30
France
India
25
Japan
India
25
Japan
United Kingdom
United Kingdom
United States of America
20
15
15
10
10
5
5
0
United States of America
20
F
0
60 years
80 years
M
60 years
80 years
Most recurrences of Stage III and high-risk Stage II colon cancer
occur in the 3 years after surgery…Adjuvant chemotherapy should
http://data.un.org/Data.aspx?d=GenderStat&f=inID%3A36
be considered
Background
Fastest growing section of population in
Western countries is that of over 65s
Approximately half the incidence of colorectal
cancer occurs in the over 70s
Evidence that elderly patients with colorectal
cancer are:
- under-staged
- under-treated
- under-represented in clinical trials
relative
frequency
< 50
50-60
60-70
FOCUS patients
FOCUS: Lancet 370:143-52, 2007
70-80
> 80
population
UK Cancer Registry data
How is cancer treatment studied?
• Primarily middle-aged patients; minimal inclusion of
older patients in clinical trials (approx. 20% of
patients included in large adjuvant colorectal trials
over 70 – median age at presentation is 71!)
• Minimal co-morbidities; patients with other medical
problems excluded
• Caucasian
• Cancer centre based
Geriatric conditions that impact on life
expectancy
Co-morbidity: presence of 2 or more usually chronic conditions
Disability: conditions that cause dependency in performing tasks
Geriatric conditions: e.g. dementia, delirium, falls
•
>3 clinically significant co-morbidities: life expectancy around 5
years
•
Functional limitation: doubles 5 year mortality risk
•
Geriatric syndromes: raise mortality risk by another 30%
•
Geriatric assessment: can focus on physiologic or functional age
rather than chronologic age
.
Koroukian S M et al. JCO 2006;24:2304-2310
.
Physicians agreement on importance of patient age and
comorbidity
Keating N L et al. JCO 2008;26:2532-2537
Pooled analysis – NSABP Trials
•
5FU (+LV or LEV) vs observation –
stage II/III disease
•
Individual patient data
•
Total of 3351 patients / 7 studies
•
Endpoints
- OS / TTR
- Toxicity
- Deaths (with/without recurrence)
Sargent et al NEJM 2001;345: 10091-7
Pooled analysis - NSABP
•
Similar TTR and OS across all age groups
- Consistent benefit
- No significantly increased toxicity
•
Death without cancer:
13% > 70 yrs
7% in 61-70 yrs
4% in 51-60
1% < 50
Sargent et al NEJM 2001;345: 10091-7
Elderly vs younger patients
OS and DFS
Population based studies - 1
•
4768 stage III pts 65 or older 1992-1996
•
Half received adjuvant therapy
•
HR for death: 0.66 (95% CI 0.60-0.73) for 5FU based
tx; i.e. 5FU based adjuvant therapy significantly
associated with reduced mortality in older patients
Sundararajan et al Ann Int Med 2002;136: 349-57
(SEER)
Population based studies - 2
•
85934 pts, stage III, NCBD 1990-2002
•
Lower use of adjuvant tx in elderly
80% in <70
70% in 70-79
40% in >80
• Adjuvant chemotherapy increases survival in elderly as
it does in younger patients
Jessup et al JAMA 2005;294:2703-11
Population based studies – 3
Patients aged 75 or older with stage III colon carcinoma in
the Netherlands -regional variation in adjuvant
chemotherapy rates and improved survival
•
Nationwide population-based study (9 regional cancer registries)
•
4462 patients who underwent resection for stage III colon cancer
from 1997-2004
- 3104 (48%) aged 75-79
- 2102 (32%) aged 80-84
- 1263 (20%) aged 85 or older
van Steenbergen et al Ann Oncol 2012 ;16(5):767-72(Epub)
Population based studies – 3 (cont.)
•
Adjuvant therapy administered to 14% of patients
- aged 75-79
26%
- aged 80-84
6%
- aged 85 or older
0.2%
•
Males received adjuvant chemotherapy more often than females
•
Rates of adjuvant chemotherapy use increased over time: from 10% in
1997 to 18% in 2004
van Steenbergen et al Ann Oncol 2012;16(5):767-772 (Epub)
X-ACT
Dukes’ C colon
Capecitabine
1250 mg/m2 bid,
d1–14, q21d
n = 1004
R
24 weeks
Bolus 5-FU/LV
5-FU 425 mg/m2 plus
LV 20mg/m2, d1–5, q28d
n = 983
Scheithauer et al Ann Oncol 2003;14: 1735-43
Recruitment
1998–2001
X-ACT - safety
•
Effect of age on capecitabine toxicity
-
upper age limit 75 (but pts up to 82 yrs old
included!)
-
safety profile analyzed for pts under and
over 65 receiving capecitabine
-
result: no major differences
-
(consider renal impairement guidelines)
-
(capecitabine vs infusional 5FU?)
Scheithauer et al Ann Oncol 2003;14: 1735-43
Stage II Colon Cancer
“Edrecolomab study” – 1738 patients
Smoothing splines of (A) the log hazard for disease-specific disease-free survival by
number of nodes examined truncated at 32 nodes, representing 95% of the data,
and (B) the log hazard for disease-specific overall survival by age at trial entry with
95% confidence bands
Niedzwiecki D et al. JCO 2011;29:3146-3152
Adjuvant chemotherapy for stage II older colon cancer
patients with poor prognostic features
20,847 pts with stage II cancer (SEER
database)
Pts 66 and older, between 1992 and 2005
75% had at least one poor prognostic feature
HR (1.02 vs 1.03, non-poor vs poor) for the
benefit of chemotherapy
O’Connor E et al J Clin Oncol 2011;29:3381-3388
Quick, simple & reliable
'Uncertain indication'
for chemotherapy
(3239 patients ’94 -’03)
Randomize
Observation
(n=1617)
5-FU/LV ± Lev
(n=1622)
28
A pooled safety and efficacy analysis of
FOLFOX4 in elderly compared to younger
patients with colorectal cancer
-
Patients ≥70: n=614 <70: n=3,128
•
Study A: MOSAIC-FOLFOX vs LV5FU2 adjuvant Rx FOLFOX:
n=1,123
•
Study B: de Gramont et al-FOLFOX vs LV5FU2 1st line Rx for
mCRC FOLFOX: n=210
•
Study C: Goldberg et al-FOLFOX vs IFL vs IROX 1st line Rx for
mCRC FOLFOX: n=267
• Study D:Rothenberg et al – FOLFOX vs IFL vs oxaliplatin 2nd –
line treatment for mCRC FOLFOX: n=281
Goldberg R M et al J Clin Oncol 2006; 24:4085-4091
MOSAIC adverse events Grade > 3
•
< 70 vs > 70
- any
- non-heme
- Deaths in 60 days
No significant difference
Goldberg, R. M. et al. J Clin Oncol 2006; 24:4085-4091
Forest plot of progression or disease-free survival by study for oxaliplatin plus
fluorouracil/leucovorin administered bimonthly v control by age. de Gramont et al;
MOSAIC; Rothenberg et al; Goldberg et al
Goldberg, R. M. et al. J Clin Oncol 2006; 24: 4085-4091
Limitations
•
Selected patients fit for trial inclusion
•
MOSAIC eligibility – up to 75
•
Small numbers
Hazard ratios and 95% CIs for death in stage III patients administered
oxaliplatin plus fluorouracil and leucovorin compared with stage III
patients administered fluorouracil and leucovorin (FL) according to
baseline prognostic factors (intent-to-treat population).
André T et al. JCO 2009;27:3109-3116
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
J McCleary, Meyerhardt, Green, Yothers, de Gramont, Van
Cutsem, O’Connell, Twelves, Saltz, Sargent for the
ACCENT collaborative group
ASCO 2009
ACCENT: 6 trials
# pts
% pts ≥
70yrs
Experimental
treatment arm*
%
stage
III+
1998-01
2246
14
FOLFOX4
60
X-ACT
1998-01
1983
20
Capecitabine
100
NSABP C-06
1997-99
1557
23
Uracif/legafur
53
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
Trial
Accrual
Period
MOSAIC
*Compared to control arm of intravenous 5 fluorouracil ( IV 5 FU ) and leucovorin
(LV)
Efficacy – Overall population
Age
<70
n= 10,499
≥70
n=2,170
Interaction
of age by
treatment
p-value
Endpoint
FR (95% Cl)
Experimental v Control IV 5 FU/LV
Deaths within
6 mo
Exp v control
% (p-value)
DFS*
OS*
TTR*
0.85
(0.80,0.91)
0.86
(0.79,0.92)
0.84
(0.79,0.91)
0.89 v 0.79
(p=0.58)
1.11
1.14
1.13
(0.97, 1.27) (0.98, 1.32) (0.97, 1.32)
2.71 v 2.11
(p=0.37)
0.005
0.005
* Values < 1 favor experimental arm
0.004
Efficacy – Oxaliplatin-based therapy
Age
<70
n= 3,977
≥70
n= 703
Interaction
of age by
treatment
p-value
DFS*
OS*
TTR*
Deaths within
6 mo
Exp vs
control % (pvalue)
0.77
(0.68,0.86)
0.81
(0.71,0.93)
0.76
(0.67,0.86)
0.81 v 0.81
(p=1.0)
1.04
(0.080,1.35)
1.19
(0.90, 1.57)
0.92
(0.69, 1.32)
2.57 v 1.37
(p=0.25)
0.016
0.037
0.21
Endpoint
FR (95% Cl)
Experimental v Control IV 5 FU/LV
* Values < 1 favor experimental arm
Interpretation pitfalls
• No information for:
- Toxicity data
- Dose-intensity
- Comorbidity
This may confound interaction between age & newer
adjuvant chemotherapy regimens
(- Small population)
(- Different FP regimens)
Male < 70
60
80
Female < 70
Group Pts Events
FULV 587 222
FLOX 552 188
HR 0.87 (0.71-1.05),
P = 0.15
20
40
Group Pts Events
FULV 419 173
FLOX 455 137
HR 0.64 (0.51-0.80),
100 0
P = 0.0001
Male 70+
60
80
Female 70+
20
40
Group Pts Events
FULV
91 38
FLOX
81 34
HR 0.99 (0.62-1.57),
P = 0.97
Group Pts Events
FULV
112 50
FLOX
112 53
HR 1.11 (0.76-1.64),
P = 0.59
0
Percent Alive and Disease-Free
DFS
100
NSABP C-07
0
2
4
6
8 0
2
4
6
8
Multivariate Cox Models Show Treatment
Interaction with Age and Gender
Yothers
JCO 2011
NSABP C-07
Male < 70
Female < 70
100 0
20
40
Group Pts Deaths
FULV 419 119
FLOX 455 94
HR 0.67 (0.51-0.88),
P=0.0035
Group Pts Deaths
FULV 587 145
FLOX 552 133
HR 0.95 (0.75-1.21),
P=0.70
Male 70+
60
80
Female 70+
Group Pts Deaths
FULV
91 30
FLOX
81 28
HR 1.11 (0.661.85),P=0.70
Group Pts Deaths
FULV
112 38
FLOX
112 43
HR 1.22 (0.79-1.90),P=0.37
0
20
40
Percent Alive
60
80
100
OS
0
2
4
6
8 0
2
4
Multivariate Cox Models Show Treatment
Interaction with Age and Gender
6
8
Yothers
JCO 2011
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
The third oxaliplatin trial
NO16968 Trial design
Chemo/radiot
herapy-naïve
stage III colon
≤8 weeks
since
resection
N=1886
R
A
N
D
O
M
I
Z
A
T
I
O
N
n=944
n=942
• Primary endpoint: DFS
• secondary endpoints: RFS, OS, tolerability
XELOX (6 months)
capecitabine 1000mg/m2 bid
d1-14 oxaliplatin130mg/m2
d1
q3w
8 cycles
Bolus 5-FU/LV (6monts)
Mayo Clinic (n=664)
or
Roswell Park (n=278)
Comparison of NO16968 with ACCENT Analysis
Hazard ratio (95% Cls)*
DFS
OS
_____________________________________________________
ACCENT analysis 3+
<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)
(at 6 yrs)
(at 6 yrs)
____________________________________________________
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)
(at 3 yrs)
0.94 (0.66, 1.34)
(at 5 yrs)
•Values <1 favor Oxaliplatin-based therapy vs 5_FU/LV.
+ Data for Oxaliplatin-based regimens
3. McClearly et al, J Clin Oncol 2009;27 (suppl. 15s):Abstr 4010
Population and hazard-ratios
N>70
%
DFS HR
OS HR
Reference
755
21.3
1.13
1.17
ASCO 2009
0.93 b
Twelves NEJM
2005, ASCO
GI 2008
ACCENT
Oral FP
X-ACT
a
20.0
C-06
358
22.3
ACCENT
Oxaliplatin
703
15.0
1.04
1.19
ASCO 2009
315 c
14.0
0.91
1.10
unpublished
C-07
388
16.9
NO16968 a
409
21.7
MOSAIC
a
0.93 b
397
stage III
b estimated
from forest plot
NA>1.13 NA>1.17
NA>1.04 NA>1.19
0.87
c stage
0.94
III 190 patients
Lembersky
JCO 2006
Kuebler JCO
2007
ASCO GI 2010
MOSAIC data in patients > 70 years
OS
Management of relapse and causes of death
FOLFOX
LV5FU2
155
160
Living with relapse
7
13
Relapse
51
53
Chemotherapy
23
34
0.070
16:10/6
30:14/17/(1)
0.011
Surgery Metastases
9
22
0.010
Death colon cancer
29
34
Death other
22
11
0.043
Second cancer
9
1
0.020
Cardiovascular
7
4
N
Irinotecan/oxali/(both)
P
#3522: Impact of age and medical comorbidity (MC) for
oxaliplatin on adjuvant treatment outcomes for stage III
colon cancer (CC): a pooled analysis of individual
patient data from four randomized controlled trials
Haller DG, O’Connell M, Cartwright TH, Twelves C,
McKenna EF, Sun W, Saif MW, Lee S, Yothers G,
Schmoll H-J
Summary description of stage III cohorts
8,734 Total Stage III aCC
Patients for Analysis
X-ACT
(n = 1,982)
LV/5-FU
(n = 982)
Capecitabine
(n = 1,000)
XELOXA
(n = 1,881)
LV/5-FU
(n = 939)
NSABP C-08
(n = 2,004)
XELOX
(n = 942)
mFOLFOX-6
(n = 1,001)
mFOLFOX-6
+ BV
(n = 1,003)
FOLFOX-4
(n = 955)
Total LV/5-FU
(n = 1,921)
Total
XELOX/FOLFOX
(n = 2,898)
5-FU, 5-fluorouracil; aCC, adjuvant colon cancer; BV, bevacizumab; FOLFOX, leucovorin,
5-fluorouracil plus oxaliplatin; ITT, intention-to-treat; LV, leucovorin; XELOX, capecitabine plus
oxaliplatin
AVANT
(n = 2,867)
FOLFOX-4 +
BV
(n = 960)
XELOX + BV
(n = 952)
Multivariate efficacy analyses
Disease-free survival
Effect/covariate
Overall survival
Hazard ratio
95% CI
P
Hazard ratio
95% CI
P
Randomized treatment:
XELOX/FOLFOX versus
LV/5-FU
0.66
0.59 to 0.73
<.0001
0.62
0.55 to 0.71
<.0001
Gender (female versus male)
0.84
0.76 to 0.94
.0020
0.85
0.75 to 0.96
.0102
Age (<70 years versus ≥70
years)
0.90
0.79 to 1.02
.0983
0.77
0.66 to 0.89
.0004
T-stage (T1–2 versus T3–4)
0.57
0.46 to 0.71
<.0001
0.56
0.43 to 0.73
<.0001
N-stage (N1 versus N2)
0.57
0.51 to 0.63
<.0001
0.51
0.45 to 0.57
<.0001
CCI (≤1 versus >1)
0.79
0.69 to 0.90
.0004
0.76
0.65 to 0.89
.0005
Randomized treatment:
XELOX/FOLFOX versus LV/5FU
0.66
0.59 to 0.73
<.0001
0.62
0.55 to 0.71
<.0001
Gender (female versus male)
0.85
0.76 to 0.94
.0021
0.85
0.75 to 0.96
.0108
Age (<70 years versus ≥70
years)
0.90
0.79 to 1.02
.1024
0.77
0.66 to 0.89
.0004
T-stage (T1–2 versus T3–4)
0.57
0.46 to 0.71
<.0001
0.56
0.43 to 0.73
<.0001
N-stage (N1 versus N2)
0.57
0.51 to 0.63
<.0001
0.50
0.44 to 0.57
<.0001
NCI (≤1 versus >1)
0.80
0.70 to 0.91
.0006
0.77
0.66 to 0.90
.0007
Model including CCI
Model including NCI
CCI, Charlson Combined Index; CI, confidence interval; FOLFOX, leucovorin, fluorouracil plus
oxaliplatin; LV/5-FU, leucovorin/5-fluorouracil; NCI, National Cancer Institute Combined Index;
XELOX, capecitabine plus oxaliplatin
Oxaliplatin interaction analyses
Effect/covariate
Model including CCI
Randomized treatment:
XELOX/FOLFOX versus LV/5-FU
Gender (female versus male)
Age (<70 years versus ≥70 years)
T-stage (T1–2 versus T3–4)
N-stage (N1 versus N2)
ECOG at baseline (0 versus 1)
CCI (≤1 versus >1)
Ox*age interaction (Ox/<70 versus
rest)
Ox*CCI interaction (Ox/≤1 versus rest)
Model including NCI
Randomized treatment:
XELOX/FOLFOX versus LV/5-FU
Gender (female versus male)
Age (<70 years versus ≥70 years)
T-stage (T1–2 versus T3–4)
N-stage (N1 versus N2)
ECOG at baseline (0 versus 1)
NCI (≤1 versus >1)
Ox*age interaction (Ox/<70 versus
rest)
Ox*CCI interaction (Ox/≤1 versus rest)
Disease-free survival
Hazard ratio
95% CI
P
Overall survival
Hazard ratio
95% CI
P
0.59
0.86
0.86
0.63
0.54
0.89
0.72
0.42 to 0.81
0.77 to 0.97
0.71 to 1.04
0.50 to 0.79
0.48 to 0.61
0.77 to 1.02
0.60 to 0.88
.0014
.0143
.1104
<.0001
<.0001
.0942
.0011
0.65
0.87
0.73
0.60
0.48
0.85
0.79
0.45 to 0.95
0.76 to 1.00
0.60 to 0.90
0.45 to 0.80
0.42 to 0.55
0.72 to 1.00
0.63 to 1.00
.0263
.0517
.0031
.0005
<.0001
.0508
.0478
0.93
1.26
0.70 to 1.23
0.94 to 1.69
.6080
.1197
0.92
1.09
0.67 to 1.28
0.77 to 1.54
.6299
.6441
0.58
0.86
0.86
0.63
0.54
0.89
0.73
0.42 to 0.80
0.77 to 0.97
0.71 to 1.04
0.50 to 0.79
0.48 to 0.61
0.77 to 1.02
0.60 to 0.88
.0009
.0148
.1128
<.0001
<.0001
.0951
.0011
0.62
0.87
0.73
0.60
0.48
0.85
0.77
0.43 to 0.90
0.76 to 1.00
0.60 to 0.90
0.45 to 0.80
0.42 to 0.55
0.72 to 1.00
0.62 to 0.97
.0110
.0526
.0033
.0005
<.0001
.0516
.0234
0.92
1.29
0.70 to 1.23
0.97 to 1.72
.5893
.0816
0.92
1.17
0.66 to 1.27
0.83 to 1.65
.5956
.3618
CCI, Charlson Combined Index; CI, confidence interval; ECOG, Eastern Cooperative Oncology
Group; FOLFOX, leucovorin, fluorouracil plus oxaliplatin; LV/5-FU, leucovorin/5-fluorouracil; NCI,
National Cancer Institute Combined Index; Ox, oxaliplatin; XELOX, capecitabine plus oxaliplatin
Which adjuvant treatment in ederly pts?
Capecitabine alone, in stage III patients, may be a reasonable
option
XELOX or FOLFOX can still be considered for the DFS
advantage… waiting for a new ACCENT analysis, and
biomarkers to better identify the population that could benefit
of oxaliplatin.
(Can OS might be improved with a more intensive
management at relapse ?.)
(IDEA (International Duration Evaluation of Adjuvant
Chemotherapy) A Prospective Pooled Analysis might give us
some clues )
Conclusions – adjuvant therapy
•
Toxicity probably not a major issue for “fit” elderly. Comorbidities, functional status, PS, physiologic changes
with age more relevant
•
Gain may be inversely proportional to age due to
increased deaths from other causes
•
Oxaliplatin-based combination chemotherapy may be
associated with decreased efficacy in the over 70s
•
Multiple regimens to consider: 5FU/LV, capecitabine,
FOLFOX or XELOX can all be considered as options,
but (try to) discuss in light of recent data
Age dependent efficacy of 5-FU
age
< 70 y
> 70 y
70-74
75-79
>=80
n
3,196
629
484
125
20
OS
11.3
10.8
10.9
9.4
13.4
(5.1-5.5)
(5.2-5.8)
5.5
5.5
6.4
24%
26%
(11%)
p = 0.31
PFS
5.3
5.5
(5.1-5.5)
(5.2-5.8)
p = 0.1
CR/PR
21.1%
23.9%
p = 0.14
Folprecht et al. Ann Oncol 2004;15:1330-8
Efficacy and 5-FU administration
age
< 70 y.
> 70 y.
5-FU
Bolus
infus.
Bolus
infus.
n
2072
1124
456
173
OS
10.7
12.3
11.3
11.9
p < 0.0001
PFS
4.8
p = 0.014
5.9
p < 0.0001
CR/PR
18.5%
26.2%
p < 0.0001
Folprecht et al. Ann Oncol 2004;15:1330-8
5.2
5.8
p = 0.0002
21.3%
p = 0.014
31.2%
Studies Included
Study
Comparator Setting
regimen
N
MOSAIC1
5-FU/LV
Adjuvant
2246
N97412
IFL
1st Line
546
de Gramont3
5-FU/LV
1st Line
420
Rothenberg4
5-FU/LV
2nd Line
531
Total
1Andre
et al, NEJM 2004; 2Goldberg et al, JCO 2004;
3de Gramont et al, JCO 2000; 4Rothenberg et al, JCO 2003
3743
Efficacy, toxicity, dose intensity
No difference in:
- DFS, OS in 1st line
- OS 2nd line
- Adverse events
- Dose intensity
for <70 vs >70
Irinotecan for mCRC in the elderly
Combined analysis on source data of 4 first-line, phase III trials
- n=2691 patients (age ≥ 70 years, n=599; age < 70 years, n=2092)
< 70 years
≥ 70 years
≥ 75 years
I-FU
FU/FA
I-FU
FU/FA
I-FU
FU/FA
• Overall Survival, months
17.1
14.7
17.6
14.2
14.5
14.2
• PFS, months
8.2
6.3
9.2
7.0
9.2
7.7
• Overall Response, %
46.6
29.0
50.5
30.3
48.3
26.4
EFFICACY
I-FU
FU/FA
: irinotecan/fluorouracil/folinic acid
: fluorouracil/folinic acid
Folprecht G et al. J Clin Oncol 2008;26:1443-1451
Folprecht G et al. J Clin Oncol 2008;26:1443-1451
Incorporation of targeted therapies in the elderly
with MCRC
Three monoclonal antibodies have recently
been registered for advanced colorectal
cancer patients: cetuximab, panitumumab and
bevacizumab
Is there enough information about activity and
toxicity of these drugs in the elderly population
to recommend its use routinely?
Bevacizumab in combination with 5 FU/LV improves
survival in patients with metastatic CRC: a combined
analysis
Probability of survival
1.0
Median survival (months): 14.6 vs 17.9
HR=0.74, p=0.0081
0.8
0.6
5-FU/LV/Avastin 5mg (n=249)
5-FU/LV or IFL (n=241)
0.4
0.2
14.6
17.9
0
0
Median age 67y
Range 23 – 90y
10
20
30
40
Months since treatment initiation
Kabbinavar et al. J Clin Oncol 2005;23:3706-3712
Safety and Effectiveness Outcomes, by
age Subgroup in BRiTE
All
(N=1953)
<65y
(n=1057)
65-74 y
(n=533)
≥75y
(n=363)
≥80y
(n=161)
Safety,%
GI perforation
2.0
2.6
1.5
1.1
0.6
Post-op bleeding or WHCs
5.1
5.5
4.5
4.5
3.8
ATE
1.9
1.6
1.3
3.9
3.7
Grade ¾ bleeding
2.6
2.2
3.4
2.5
1.2
New/worsening HTN
20.7
20.5
20.6
21.2
21.1
Median PFS, months
9.9
10.2
9.7
9.8
9.2
1-yr survival rate, %
74.4
77.1
72.5
69.4
65.8
Median OS, months
23.5
27.3
21.3
19.5
16.2
Survival
Clinical Trials and the Elderly ?
“Your pulse may be too
weak to be eligible for my
study”
MRC FOCUS2
Chemotherapy choices and doses
in frail and elderly patients
with advanced colorectal cancer
Matt Seymour, Tim Maughan, Harpreet Wasan, Alison Brewster, Steve Shepherd,
Sinead O’Mahoney, Beth May, Lindsay Thompson, Angela Meade and Ruth Langley,
on behalf of
The UK NCRI Colorectal Clinical Studies Group and FOCUS2 Investigators
Trial Design: 2x2 Factorial
FU
OxFU
X
Cap
OxCap
Progression free
survival
1.00
Progression Free Survival
eventsEvents
total
MdG->OxMdG
FU
111
OxMdG
OxFU
110
Cap
106
MdG->OxCap
OxCap
106
OxCap
0.75
Factorial PFS
111
115
110
115
115
106
114
106
Total
med
PFS
115
3.5
115
5.8
5.2
115
5.8
114
HR (95% CI)
p-value
0.84 (0.69, 1.01)
0.07
0.99 (0.82, 1.20)
0.93
0.50
no oxaliplatin vs oxaliplatin
0.25
[FU + Cap] vs [OxFU + OxCap]
FU vs capecitabine
0.00
[FU =
+ OxCap]
0 OxFU] vs [Cap
3
6
At risk:
FU
OxFU
Cap
OxCap
115
115
115
114
76
90
76
90
36
48
37
46
9
Time (Months)
12
15
18
15
17
14
16
8
10
8
7
5
3
7
2
3
1
5
1
Quality of Life
improvement
• Percentage of patients with improvement in EORTC QLQ-C30
global scale between baseline and week 12:
Factorial QoL improvement
no oxaliplatin vs oxaliplatin
[FU + Cap] vs [OxFU + OxCap]
FU vs capecitabine
[FU = OxFU] vs [Cap + OxCap]
% patients
p-value
62% vs 49%
0.04
56% vs 56%
0.94
Response seen by 12
weeks
n=450 (98%) patients with assessable disease at baseline
Factorial Response
Regimen
FU% patients
OxFU
Cap p-value
OxCap
randomised
115
115
no oxaliplatin
vs oxaliplatin
eligible,
with measurable
disease
112
111
13% vs 35%
0
0.9
11.6
36.9
33.9
30.6
52.7
24% vs27.9
23%
1.8
3.6
[FU + Cap] vs [OxFU + OxCap]
%CR
%PR
%SD
FU vs capecitabine
%PD, clinical deterioration or death
% missing
[FU = data
OxFU] vs [Cap + OxCap]
%CR+PR*
* at 12 weeks. Responses seen only
after 12 weeks not included
115
114
114
113
<0.0001
1.8
1.8
10.5
30.1
35.1
31.9
51.8
34.5
0.83
0.9
1.8
11.6
37.8
12.3
31.9
(reference)
p<0.0001
p=0.88
p<0.0001
Toxicity by
regimen
Regimen
Factorial Toxicity
n
FU
OxFU
Cap
OxCap
109
109
112
109
Any Gr ≥3 toxicity
24%
29%
37%
worse with oxaliplatin:
60d all-cause mortality
11%
3%
6%
diarrhoea (6% vs 12%)
no
oxaliplatin vs oxaliplatin 2.8%
sens. neuro
(0% vs 2%)
2.8%
0.9%
Haemoglobin
[FU + Cap] vs [OxFU + OxCap]
Neutropenia
p-value
41%
7%
1.8%
0.042
0.024
1.8%
Nausea
2.8%
4.6%
1.8%
worse with no oxaliplatin:
hand/foot1.8%
derm (5% v5.4%
0.5%)
0.9%
Vomiting
0.9%
2.8%
Anorexia
2.8%
5.4%
3.7%
worse with1.8%
capecitabine:
any grade
>3 tox (27%
v 39%) 1.8% 0.006
0.9%
1.8%
0.9%
nausea (1% v 5%)
0.032
3.7%
8.9%
17.4% 0.003
diarrhoea6.4%
(5% v 13%)
lethargy (8% v 14%)
0.037
8.3%
4.6%
9.8%
5.5%
hand/foot derm. (0% v 5%)
<0.001
7.3%
8.3%
13.4%
14.7%
Stomatitis
FU vs capecitabine
Diarrhoea
[FU = OxFU] vs [Cap + OxCap]
Pain
Lethargy
1.8%
2.7%
4.6%
Peripheral Neuropathy
0%
0.9%
0%
3.7%
Hand foot syndrome
0%
0%
9.8%
0.9%
0.004
Overall
Survival
1.00
Overall Survival
Factorial Overall Survival
0.75
0.50
no oxaliplatin vs oxaliplatin
[FU + Cap] vs [OxFU + OxCap]
events
MdG->OxMdG
FU
87
OxMdG
OxFU
84
FU vs capecitabine
Cap
83
MdG->OxCap
OxCap
88
[FU = OxFU] OxCap
vs [Cap + OxCap]
0.00
0.25
0
3
6
At risk:
115
94
81
115
115
102
94
114
100
Events
total
87
115
84
115
115
83
114
88
HR (95% CI)
p-value
0.99 (0.81, 1.18)
p=0.91
Total
med OS
115
9.7
115
10.7
11.3
115 (0.79, 1.17)
0.96
12.4
114
9
Time (Months)
p=0.71
12
15
18
60
38
29
15
82
78
62
62
43
44
30
29
20
23
81
67
49
28
16
Comprehensive Geriatric Assessment
Group 1: fit patients
Group 2: ‘in-between’
Group 3: frail patients
• functionally independent
• dependence in one activity
• dependence for daily activities
• no comorbidities
• 1-2 comorbidities
• ≥ 3 comorbidities
Cancer < Life Expectancy < Cancer
Life-prolonging Treatment
Adapted Treatment Only
Balducci L and Extermann M. The Oncologist 2000;5:224-237
Palliation
Conclusions – metastatic disease
It is important to establish an overall treatment plan
for the management of elderly metastatic CRC
patients
Age shouldn’t be the single decision parameter
Assessment tools – collaboration in an MDT setting
There is, as in younger patients, a need to identify
the right patient for the right treatment
(pharmacogenetics, pharmacogenomics ,
biomarkers etc.)
THANK YOU
Elderly colon cancer
case
78 yr old man, retired diplomat
PR bleeding
colonoscopy → lesion at 50cm → sigmoid
colectomy (7/2009):
– adenocarcinoma
– T3N0(0/9)Mx
– GII, vascular/lymphatic invasion
Past Medical History
Pacemaker in situ for cardiac arrythmia
Hypertension
Renal stones
Appendectomy as young adult
Medications
Amlodipine 5 mg, od
Metoprolol 200 mg, od
Aspirin 75 mg, od
Family history
brother with colon ca at age 69, alive and well
Social history
Married with two sons, aged 41 and 45 years
Smoking 1-2 cigars/day
Occasional alcohol use
Regular holidays around the year
1. Would you administer adjuvant
chemotherapy?
2. FU/LV or Oxaliplatin-based?
After discussion, he did not receive
adjuvant treatment and was put on
regular follow-up
9/2011: elevated CEA (11.6 ng/ml)
CT scan: single 4cm lesion on left liver
lobe
Treatment options:
1. chemotherapy +/- surgery
2. up-front metastasectomy +/- chemo
3. chemotherapy
4. BSC
Left liver lobectomy – November 2011
On 7th post-op day: upper GI bleeding
– Blood products support
– Endoscopy: duodenal ulcer
– PPIs
Recovered uneventfully
Histology report
Adenocarcinoma
Consistent with colon primary
Clear resection margins
Further management
1.“adjuvant” chemotherapy?
2. Simple follow-up?
He decided to receive no further treatment
4 months later, CEA:1.2 ng/ml
Last seen in clinic 6/2012: In radiological and
marker CR