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