development of conventional chemotherapy · 0 2 4 6 8 10 12 14 16 18 chemotherapy vs. "best...
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Claus-Henning Köhne Klinik für Onkologie und Hämatologie
Development of conventional chemotherapy
ESMO Preceptorship Program 26. October Vienna
0 2 4 6 8 10 12 14 16 18
Chemotherapy vs. "Best supportive care"
# Pat Response TTP Survival
BSC 12 0% 2.3 mo 5 mo
BSC + CTx 24 33% 6.0 mo 11 mo
p<0.001 p=0.006
Monate
LQ -FLIC
BSC
CTx
Scheithauer et al. BMJ 306, 1993
Immediate vs. delayed CTx in metastatic CRC
Treatment NPat Time without Survival Symptoms Progression (median)
Immediate 92 10 mo 8 mo 14 mo
Delayed 90 2 mo 3 mo 9 mo
p-value <.001 <.001 <.002
Glimelius et al. JCO 1992
Steps
Biochemical modulation, infusional 5-FU
Oral fluoropyrimidines
Combination treatment (irinotecan, oxaliplatin)
Biochemical Modulation of 5-FU
dThDDP
dUMP
FdUMP
dTMP dTMP DNATS
TKFolinsäure
IFN
Ura
F- Ura
UMP
FUMP
UDP
FUDP
UTP
FUTP (FU)RNA
RNA
MTXPRPP
PALAde novo Pyrimidinsynthese
F-Ura
Ura
5-FU dose intensity and response
0
10
20
30
40
0 600 1200 1800 2400
Bolus Infusional
5-FU dose intensity mg / m2 / week
modified according to Hyrniuk and Wils
Results from Meta-Analyses
Treatment N studies N Pat Response
(CR/PR) p-valueMediane
OS (Months)
p-value
FU FU/FA
9
1381
11% 23%
<0.001
11,0 11,5
0,57
FU FU/MTX
8
1178
10% 19%
<0.001
9,110,7
0.024
FU Bolus FU CI
6
1219
14% 22%
<0.001
11,3 12,1
0.04
FU+/-FA FU+/-FA+IFN
12
1866
25% 24%
n.s.
11,4 11,5
n.s.
FU/FA FU/IFN
7
1488
23% 18%
0.04
11,7 11,3
n.s.
5-FU Prodrugs
FUra
Capecitabine 5’deoxy-5-fluorocytidin-
pentoxycarbomyl
5’deoxy-5-fluorocytidine
5’deoxy-5-fluorouridine
S1: Tegafur [1] CDHP [0.4] Oxo [1]
UFT: Tegafur [1] Uracil [4]
FUH2
FUMP
FdUMP
Carboxylesterase
Cytidindeaminase
Pyrimidin Phosphorylase
EU CDHP
OXO
DPDCDHP: 5-chloro-2,4-dihydoxypyridineEU: EthynyluracilOxo: Oxonic acid
C-5‘ OxidationC-2‘ Hydrolysis Cytochrom P450
Oral Fluorpyrimidines vs. Mayo-Clinic regimen
N Pat CR/PR PFS (mo) Survival (mo)
Cape 301 19% 5.2 13.2
Mayo 301 15% 4.7 12.1
Cape 302 25% 4.3 12.5 Mayo 303 16% 4.7 13.3
UFT/LV 190 11% 3.4 12.2 Mayo 190 9% 3.3 11.9
UFT/LV 409 12% 3.5 12.4 Mayo 407 15% 3.8 13.4
Van Cutsem JCO 2001, Hoff JCO 2001; Douillard JCO 2002 2001, Carmichael JCO 2002
Randomised trilas have shown:
a. FOLFOX improves survival over FU/FA
b. FOLFIRI improves survival over FU/FA
c. FOLFOX and FOLFIRI both improve
survival over FU/FA
Metastatic CRC Oxaliplatin
Regimen N RR PFS OS Author
LV5FU2 210 22% 6.6 14.7 DeGramont
+ Oxaliplatin 210 57% 9.0 16.2 JCO 2000
FUCM/LV 100 16% 6.1 19.9 Giacchetti
+ Oxaliplatin 100 53% 8.7 19.4 JCO 2000
Mayo 124 23% 5.3 16.1 Grothey
AIO+Oxaliplatin 125 49% 7.8 21.4 ASCO 01/ 02
FU/FA 710 29% 6.3 13.7 Seymour
FOLFOX 357 57% 8.8 15.0 Lancet 2007
No significant effect on survival
Regimen N RR PFS OS Author
Douillard/AIO 338 23% 4.4 14.1 Douillard
+ Irinotecan 35% 6.7 17.4 Lancet 2000
FL (Saltz) 440 21% 4.3 12.6 Saltz
+ Irinotecan 39% 7.0 14.8 NEJM 2000
AIO 430 34% 6.4 16.9 Köhne
AIO+Irinotecan 62% 8.5 20.1 JCO 2005
FU/FA 710 29% 6.3 13.7 Seymour
FOLFIRI 356 51% 8.6 16.2 Lancet 2007
Metastatic CRC Irinotecan
3 of 4 trials positiv
e for survival
Survival (Study V303)
* Medians † Log-rank test
p<0.032†
CPT-11/5-FU/LV (N=198)5-FU/LV (N=187)
17.4 mo*
14.1 mo*
Months
Prob
abili
ty
0.00.10.20.30.40.50.60.70.80.91.0
0 6 12 18 24 30
40986: Overall Survival 5-FU24h/LV (AIO) +/- Irinotecan (Secondary Endpoint) 40986
(months)0 6 12 18 24 30 36 42
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :146 216 186 136 88 43 16 4142 214 196 153 104 52 18 4
HDFU/FAHDFU/FA/CPT11
Median 95% CI
AIO + IRI 20.1 [18.0 – 21.9]
AIO 16.9 [15.3 – 19.0]
p=0.2779 log-rank
p=0.0509 Wilcoxon
40986: Overall Survival 5-FU24h/LV (AIO) +/- Irinotecan (Secondary Endpoint) 40986
(months)0 6 12 18 24 30 36 42
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk :146 216 186 136 88 43 16 4142 214 196 153 104 52 18 4
HDFU/FAHDFU/FA/CPT11
Median 95% CI
AIO + IRI 20.1 [18.0 – 21.9]
AIO 16.9 [15.3 – 19.0]
p=0.2779 log-rank
p=0.0509 Wilcoxon20% of pts
FOCUS- trial Seymour, Lancet 2007
Irinotecan vs. Oxaliplatin
Regimen N RR PFS ÜLZ Author
IFL (Saltz) 264 29% 6.9 14.1 Goldberg
FOLFOX 267 38% 8.8 18.6 JCO 2004
FOLFIRI 226 56% 8.5 21.5 Tournigand
FOLFOX 54% 8.0 20.6 JCO 2004
0 6 12 18 24 30 36 42 48
Overall Survival (months)
0,0
0,2
0,4
0,6
0,8
1,0
Kum
. Übe
rlebe
n
Treatment groups5-FU bolus5-FU bolus + irinotecan5-FU infus5-FU infus + irinotecan5-FU bolus + irinotecan-zensiert5-FU bolus -zensiert5-FU infus + irinotecan-zensiert5-FU infus-zensiert
pAge = < 70
Überlebensfunktionen
0 6 12 18 24 30 36 42 48
Overall Survival (months)
0,0
0,2
0,4
0,6
0,8
1,0
Kum
. Übe
rlebe
n
Treatment groups5-FU bolus5-FU bolus + irinotecan5-FU infus5-FU infus + irinotecan5-FU bolus + irinotecan-zensiert5-FU bolus -zensiert5-FU infus + irinotecan-zensiert5-FU infus-zensiert
pAge = >= 70
Überlebensfunktionen
< 70 years n=2092 ≥ 70 years n=599
── 5-FU infus. / Iri - - - 5-FU bolus / Iri ── 5-FU infus. - - - 5-FU bolus
FOLFIRI 1st line Overall survival depending on age and 5-FU schedule
in 2,691 patients, 4 studies including source data treated with 5-FU +/- irinotecan
Folprecht….Köhne et al, JCO 2008
Percenatge of 2nd line Treatment in randomised Trials
Author Regime 2nd line treatment Oxaliplatin Irinotecan Survival
Goldberg IFL 17% - 14.1 JCO 2004 FOLFOX - 52% 18.6
Tournigand FOLFIRI 74% - 21.5
JCO 2004 FOLFOX - 62% 20.6
Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials
Ark
enau
et a
l. JC
O 2
009
Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials
Ark
enau
et a
l. JC
O 2
009
% Patienten mit FU, Oxaliplation und Irinotecan
Med
iane
Übe
rlebe
nsze
it (M
onat
e)
80706050403020100
22
21
20
19
18
17
16
15
14
IROX
FOLFOX type
FOLFIRI type
IFL
P= .0008
Grothey et al. J Clin Oncol 2004; 22;1209-1214
Survival according to availability of lines of treatment
FOLFIRI vs. FOFOXIRI
Regimen N RR PFS OS Author FOLFIRI 122 41% 6.9 16.7 Falcone
FOLFOXIRI 122 66% 9.9 23.6 JCO 2007
FOLFIRI+Bev 256 53% 9.7 25.8 Falcone
FOLFOXIRI+Bev 252 65% 12.2 31.0 NEJM 2015
• FOLFOXIRI more effective than FOLFIRI • Unroven role of bevacizumab
Oxaliplatin in adjuvant pretreated patients
Falcone et al. ASCO 2013, Yamazaki et al. ASCO 2014
Colon Cancer Collaborative Group, BMJ 2000 / Tournigand, JCO 2004 / Adam, Ann Surg 2004
Long term survival with chemotherapy and resection
--- BSC--- 5-FU--- FOLFIRI/FOLFOX6--- FOLFOX6/FOLFIRI--- resectabel--- primary non-resectabel
91%
66%
48%
30%
23%
33%
52%
20
40
60
80
100
0 1 3 42 5 6 8 97 10
Survival with multidiciplinary approach