1. Meta-analysis of three trials investigating 5-FU and irinotecan.
Folprecht, Rougier, Saltz, van Cutsem, Douillard, Sastre, Mitry, Hecker, Schubert, Köhne: Irinotecan in first line therapy of elderly and non-elderly patients...
Irinotecan in first line therapy of elderly and non-elderly patients with metastatic colorectal cancer:
Meta-analysis of three trials investigating 5-FU and irinotecan.
Gunnar Folprecht1, Philippe Rougier2, Leonard Saltz3,
Eric van Cutsem4, Jean-Yves Douillard5, Javier Sastre6,
Emmanuel Mitry2, Hartmut Hecker7, Ute Schubert8,
Claus-Henning Köhne8
1University hospital Dresden, Germany; 2Hopital Ambroise Paré, Boulogne, France; 3Memorial Sloan Kettering Cancer Center, New York;
4University Hospital Gasthuisberg, Leuven, Belgium;
5Centre R Gauducheau, St. Herblain, France;
6Hospital Clinico San Carlos, Madrid, Spain; 7Medical School Hannover, Germany;
8Klinikum Oldenburg, Germany
ASCO 2006, abstract 3578

2. 5-FU/FA ± irinotecan in elderly patients
< 70 years
≥ 70 years
1259 pts from
3 randomized trials
Progression free survival
5-FU
5-FU + Irinotecan
HR 0.72
( ) p<0.0001
Overall survival
5-FU
5-FU + Irinotecan
HR 0.82
( )
p=0.004

3. Elderly vs. younger pts. with 5-FU/irinotecan
1259 pts from
3 randomized trials
Progression free survival
< 70 y.
≥ 70 y.
HR 1.11 ( ) p=0.24
Overall survival
< 70 y.
≥ 70 y.
HR 0.99
( )
p=0.87

4. Administration of 5-FU/ irinotecan in elderly patients
< 70 years
≥ 70 years
Overall survival
1259 pts from
3 randomized trials
5-FU Bolus
+ Irinotecan
5-FU Infus.
Folprecht et al, ASCO 2006

5. Background
Irinotecan has been shown to improve response rates and progression free survival in three randomized studies. Data regarding efficacy and toxicity with irinotecan in elderly patients are lacking.
With 5-FU- therapy, pooled analyses describe a similar treatment benefit in elderly as in younger patients in palliative (Folprecht. Ann Oncol 2004) and in adjuvant treatment (Sargent. NEJM 2001).
Although no increased toxicity was described in a analysis from the Royal Marsden hospital with palliative treatment of elderly patients, slightly higher rates of stomatitis (Popescu. JCO 1999) or leucocytopenia (Sargent. NEJM 2001) are reported in adjuvant 5-FU containing therapy.
Folprecht et al, ASCO 2006

6. Methods
We performed a metaanalysis using source data of three randomized trials investigating 5-FU/FA/irinotecan vs. 5-FU/FA (Saltz 2000, Douillard 2000, Köhne 2005 [EORTC 40986]) to explore the efficacy and toxicity in elderly (≥70 years) and non-elderly (< 70 years) patients. The data from the 5-FU/FA and Irinotecan/5-FU/FA arms were included, only. All patients who did not receive therapy were excluded.
Differences in proportional values were investigated using the chi square test or Fisher’s exact test, where appropriated. For progression free survival or overall survival, Kaplan-Meier plots and log rank tests were used. A multivariate analysis including treatment (5-FU/FA vs. 5-FU/FA/irinotecan) and age (< 70 y. vs. ≥ 70y.) was performed.
Folprecht et al, ASCO 2006

7. Patients’ characteristics (I)
Patients: age groups
Study group
treatment
<70 years
≥70 years y. y.
≥80 y.
Saltz et al *
IFL
170 55 35 15 5
NEJM 2000
Mayo 49 29 16 4
Douillard et al
Iri/AIO 40 14 12 2
Lancet 2000
AIO 8 7 1
FOLFIRI
124 21
LV5FU2
121 22 19 3
EORTC (Köhne et al)
173 41
JCO 2005
177 39 9
Pts. with 5-FU/Irinotecan
507
131 97
Pts. with 5-FU monotherapy
503
118 84
total
1010
249
181 58 10
* pts receiving irinotecan monotherapy or no treatment were excluded
Folprecht et al, ASCO 2006

8. Patients’ characteristics (II)
<70 years
≥70 years p
5-FU/Irinotecan
5-FU mono
N=507
N=503
N=131
N=118
Gender
male
328
(64,7%)
277
(55,1%) 87
(66,4%) 75
(63,6%)
0,007
female
179
(35,3%)
226
(44,9%) 44
(33,6%) 43
(36,4%) PS
245
(48,3%)
259
(51,5%) 65
(49,6%) 50
(42,4%)
0,30 1
222
(43,8%)
201
(40,0%)
(38,2%) 59
(50,0%) 2 40
(7,9%)
(8,5%) 16
(12,2%) 9
(7,6%)
No tumor sites
280
(55,2%)
273
(54,3%) 79
(60,3%) 76
(64,4%)
0,17
>1
225
(44,4%)
230
(45,7%) 52
(39,7%) 42
(35,6%)
unknown
(0,4%)
(0,0%)
adjuvant
yes
102
(20,1%) 90
(17,9%) 27
(20,6%) 23
(19,5%)
0,84
treatment no
286
(56,4%)
293
(58,3%) 72
(61,0%)
119
(23,5%)
120
(23,9%) 25
(19,1%)
primary tumor site
rectum
183
(36,1%)
178
(35,4%)
(30,5%) 32
(27,1%)
0,19
colon
321
(63,3%)
325
(64,6%) 91
(69,5%) 85
(72,0%)
unknown or both 3
(0,6%)
(0,8%)
Folprecht et al, ASCO 2006

9. Results: Toxicity (I) <70 years ≥70 years 5-FU/Irinotecan 5-FU mono
<70 years
≥70 years
5-FU/Irinotecan
5-FU mono
Comp. ≥70 y. vs. < 70 y.
Leucopenia
Grade ≥3
100
(22,6%) 49
(11,5%) 35
(29,2%) 13
(12,9%)
all patients
p=0.12
Grade <3
342
(77,4%)
377
(88,5%) 85
(70,8%) 88
(87,1%)
p=0.14
p<0.001
p=0.003
p=0.70
Neutro-
161
(35,0%)
125
(27,2%) 48
(39,3%) 41
(37,3%)
p=0.03
penia
299
(65,0%)
335
(72,8%) 74
(60,7%) 69
(62,7%)
p=0.37
p=0.01
p=0.81
Thrombo- 5
(1,4%) 2
(2,4%) 1
(1,3%)
p=0.72
343
(98,6%) 81
(97,6%) 75
(98,7%)
p=0.62
p=1.00
Infection
(1,2%)
(1,1%)
(2,8%)
p=0.60
171
(98,8%)
175
(98,9%) 40
(97,2%)
Stomatitis 6
(3,1%)
(5,7%) 4
(8,7%)
(8,3%)
p=0.10
185
(96,9%)
217
(94,3%) 42
(91,3%) 55
(91,7%)
p=0.11
p=0.25
p=0.55
For each age group and treatment group, significance was calculated with the Chi-square test or Fisher's exact test
Folprecht et al, ASCO 2006

10. Results: toxicity (II)
Folprecht, Rougier, Saltz, van Cutsem, Douillard, Sastre, Mitry, Hecker, Schubert, Köhne: Irinotecan in first line therapy of elderly and non-elderly patients...
Results: toxicity (II)
<70 years
≥70 years
5-FU/Irinotecan
5-FU mono
Comp. ≥70 y. vs. < 70 y.
Diarrhea
Grade ≥3 91
(27,8%) 59
(19,8%) 31
(34,1%) 18
(22,8%)
all patients
p=0.20
Grade <3
236
(72,2%)
239
(80,2%) 60
(65,9%) 61
(77,2%)
p=0.25
p=0.02
p=0.11
p=0.56
Nausea 37
(12,1%) 26
(8,9%) 15
(17,4%) 6
(8,2%)
p=0.34
269
(87,9%)
265
(91,1%) 71
(82,6%) 67
(91,8%)
p=0.21
p=0.09
p=0.85
Vomiting 27
(9,8%)
(6,9%) 10
(13,5%) 2
(3,5%)
p=0.78
249
(90,2%)
242
(93,1%) 64
(86,5%) 55
(96,5%)
p=0.39
p=0.23
p=0.05
p=0.40
Hand-foot-
(1,2%) 3
(1,7%)
(0,0%) 1
(2,6%)
p=1.00
syndrome
171
(98,8%)
174
(98,3%) 41
(100,0%) 38
(97,4%)
p=0.48
Cerebro- 4
(2,3%) 5
(2,8%)
(7,7%)
p=0.72
vascular
169
(97,7%)
172
(97,2%) 36
(92,3%)
p=0.59
p=0.75
p=0.37
Thrombosis 9
(4,9%) 8
(4,2%)
(4,3%)
(4,5%)
176
(95,1%)
182
(95,8%) 44
(95,7%) 42
(95,5%)
p=0.80
For each age group and treatment group, significance was calculated with the Chi-square test or Fisher's exact test.
Folprecht et al, ASCO 2006, abstract 3578
Folprecht et al, ASCO 2006
ASCO 2006, abstract 3578

11. Efficacy <70 years ≥70 years 5-FU/Irinotecan 5-FU mono
<70 years
≥70 years
5-FU/Irinotecan
5-FU mono
Comp. ≥70 y. vs. < 70 y.
Response
N=507
N=503
N=131
N=117 CR 16
(3,2%) 10
(2,0%) 4
(3,1%) 2
(1,7%) PR
199
(39,3%)
109
(21,7%) 57
(43,5%) 35
(29,9%) OR
215
(42,4%)
119
(23,7%) 61
(46,6%) 37
(31,6%)
p=0.39
95% CI
(38,2-46,7%)
(20,2-27,6%)
(38,2-55,1%)
(23,9-40,5%)
p=0.07 SD
153
(30,2%)
225
(44,7%) 34
(26,0%) 59
(50,4%)
PD/other
139
(27,4%)
159 36
(27,5%) 21
(17,9%)
Comp. OR
p<0.0001
p=0.016
Time to progression
N=373
N=365
N=107
N=91
median
7,53
4,83
8,05
6,31
p=0.58
( )
( )
( )
( )
p=0.18
p=0.063
Overall survival
N=497
N=499
N=130
N=115
17,33
14,4
18,02
15,45
p=0.59
( )
( )
( )
( )
p=0.78
p=0.0042
p=0.45
Folprecht et al, ASCO 2006

12. Progression free survival
5-FU/FA
5-FU/FA
5-FU/FA
5-FU/FA + Irinotecan
5-FU/FA + Irinotecan
5-FU/FA + Irinotecan
< 70 y.
≥ 70 y.
HR 1.11 ( ) p=0.24
< 70 years
< 70 years
< 70 years
≥ 70 years
≥ 70 years
≥ 70 years
5-FU
5-FU + Irinotecan
HR 0.72
( ) p<0.0001

13. Overall survival 5-FU/FA 5-FU/FA + Irinotecan < 70 y. ≥ 70 y.
HR 0.99
( )
p=0.87
< 70 years
≥ 70 years
5-FU
5-FU + Irinotecan
HR 0.82
( )
p=0.004

14. Conclusions
Elderly patients have similar response rates, progression free and overall survival with irinotecan/5-FU/FA as younger patients do.
No significant differences were found between the efficacy in younger and elderly patients
The response rates are significantly improved with irinotecan in elderly patients.
Although progression free and overall survival significantly differ in younger patients between the irinotecan- and non-irinotecan arms, no formal significant differences were observed in elderly patients.
At least with progression free survival, this is probably due to the lower number of events.
A trend to an unfavourable overall survival during the first treatment weeks was observed with elderly versus younger patients in the irinotecan- arm. Regarding the subgroups, this trend could only be observed in the bolus 5-FU groups, but not with infusional 5-FU (Fig 3).
This trend might be explained by the early mortality with the IFL- regimen (Rothenberg. JCO 2001).
However, comparing toxicity in elderly and non-elderly patients, there was found a slightly higher rate of neutropenia in elderly patients, only - receiving 5-FU/FA but not receiving irinotecan/5-FU/FA. All other toxicities did not differ significantly.
Folprecht et al, ASCO 2006, abstract 3578