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Claus-Henning Köhne
University Clinic for Oncology and Haematology
Northwest German Cancer Center
Development of conventional
chemotherapy
ESMO Preceptorship Colorectal Cancer Prague 2016, Czech Republic
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 SurvivalSymptoms 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
StepsSteps
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 intensitymg / m2 / week
modified according to Hyrniuk and Wils
Results from Meta-Analyses
TreatmentN
studiesN Pat
Response(CR/PR) p-value
Mediane OS
(Months)p-value
FUFU/FA 9 1381
11%23% <0.001
11,011,5 0,57
FUFU/MTX 8 1178
10%19% <0.001
9,110,7 0.024
FU BolusFU CI 6 1219
14%22% <0.001
11,312,1 0.04
FU+/-FAFU+/-FA+IFN 12 1866
25%24% n.s.
11,411,5 n.s.
FU/FAFU/IFN 7 1488
23%18% 0.04
11,711,3 n.s.
5-FU Prodrugs
FUra
Capecitabine5’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
EUCDHP
OXO
DPDCDHP: 5-chloro-2,4-dihydoxypyridineEU: EthynyluracilOxo: Oxonic acid
C-5‘ OxidationC-2‘ HydrolysisCytochrom P450
Oral Fluorpyrimidines vs. Mayo-Clinic regimenOral 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 12.5Mayo 303 16% 4.7 13.3
UFT/LV 190 11% 3.4 12.2Mayo 190 9% 3.3 11.9
UFT/LV 409 12% 3.5 12.4Mayo 407 15% 3.8 13.4
Van Cutsem JCO 2001, Hoff JCO 2001; Douillard JCO 2002 2001, Carmichael JCO 2002
Find the correct answer:
Randomized trials 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
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
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
Pro
bab
ility
0.00.1
0.20.3
0.40.5
0.60.7
0.80.9
1.0
0 6 12 18 24 30
40986: Overall Survival 5-FU24h/LV (AIO) +/- Irinotecan (Secondary Endpoint)
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 4
142 214 196 153 104 52 18 4
HDFU/FA
HDFU/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: 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 4
142 214 196 153 104 52 18 4
HDFU/FA
HDFU/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
1. line 2. line 3. line
A 5-FU/FA Irinotecan OxCape
B1 5-FU/FA FOLFIRI OxCape
B2 5-FU/FA FOLFOX IriCape
C1 FOLFIRI OxCape
C2 FOLFOX IriCape
2100 Pts.not suitable
for neoadjuv.
therapy
16%
19%
33%
Pts receiving all 3 drugs
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
1,0Treatment groups
pAge = < 70
0 6 12 18 24 30 36 42 48
Overall Survival (months)
0,0
0,2
0,4
0,6
0,8
1,0Tr
< 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
al. J
CO
2009
Efficacy of Oxaliplatin Plus Capecitabine or Infusional Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer: A Pooled Analysis of Randomized Trials
Ark
enau
et
al. J
CO
2009
% 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 29.8 NEJM 2015
Lancet Oncol 2015
• FOLFOXIRI more effective than FOLFIRI• Unroven role of bevacizumab
N MST (m)
Category Subgroup mFOLFOX6
+Bev FOLFIRI+Bev mFOLFOX6
+Bev FOLFIRI+Bev HR p value
Overall 198 197 10.7 12.0 0.874 0.234
SWJOG4407GS Subgroup analysis for PFS FOLFIRI / Bev vs. FOLFOX / Bev
ECOG PS 0 154 159 11.1 12.9 0.913 0.478 1 44 38 9.3 9.4 0.775 0.297
Adjuvant Chemotherapy
yes 31 33 11.5 19.4 0.551 0.042 no 167 164 10.7 11.0 0.979 0.860
Favors FOLFIRI+Bev Favors mFOLFOX6+Bev0,100 1,000 10,000 *Except for 3 patients of multiple sites
Factor N HR p
0.5 1 1.5 2
FOLFOXIRI + Bev FOLFIRI + Bev
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