Development of conventional chemotherapy -...

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


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

(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

(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

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

1,0Treatment 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

% 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


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

FOLFOXIRI in different molecular subgroups

Cremolini et al. Lancet Oncol 2015

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

Development of conventional chemotherapy -...

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