What is the reference cytotoxic

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What is the reference cytotoxic




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Slide1

What is the reference cytotoxic regimen in advanced gastric cancer?

Florian LordickKlinikum BraunschweigGermany

Slide2

Chemotherapy in Advanced Gastric

Cancer – What do we know? (I)

Wagner et al. J Clin

Oncol

2006; 24: 2903-9

Chemotherapy prolongs survival Chemotherapy improves symptom control Combinations are more active than monotherapy

Elderly (>70 years age) benefit equally

Trumper et al. Eur J Cancer 2006; 42: 827-34

Established

standard

:

Platinum-

fluoropyrimidine

-

combination

Slide3

Oxaliplatin can substitute for

cisplatin

Oral

fluoropyrimidines

can substitute for i.v. 5-FU A 3rd drug makes CTx more effective but more

toxicAl-Batran et al. J Clin Oncol 2008; 26: 1435-1442Cunningham et al. N Engl J Med 2008; 358: 36-46

Cunningham et al. N Engl J Med 2008; 358: 36-46

Kang et al.

Ann

Oncol

2009;

20: 666-673

Van

Cutsem et al. J Clin Oncol 2006; 24: 4991-7Wagner et al. J Clin Oncol 2006; 24: 2903-9

Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

Chemotherapy

in

Advanced

Gastric

Cancer

What

do

we

know

? (I)

Slide4

Oxaliplatin

Slide5

Oxaliplatin in Gastric Cancer

Cunningham D et al.

N Engl J Med 2008;358:36-46

R

A

N

DOME EpirubicinC CisplatinF Fluorouracil

E EpirubicinC CisplatinX Xeloda

(Capecitabine)

E Epirubicin

O

Oxaliplatin

F Fluorouracil

E

Epirubicin

O

OxaliplatinX Xeloda (Capecitabine)

N=964

Real-2-Study (UK)

Slide6

Oxaliplatin in Gastric Cancer

Cunningham D et al.

N Engl J Med 2008;358:36-46

Real-2-Study

Slide7

Oxaliplatin in Gastric Cancer

R

A

N

D

O

MP Cisplatin L LeucovorinF 5-Fluorouracil

O Oxaliplatin L

Leucovorin

F

5-Fluorouracil

N=220

AIO

-Study (Germany)

Al-Batran SE et al.

J Clin Oncol

2008;26:1435-1442

Slide8

AIO-study: FLO versus FLP

Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

PFS: p = 0.077

OS: p = 0.506

Overall

population

Slide9

AIO-study: FLO versus FLP

Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442

PFS: p = 0.029

OS: p = n. s.

Elderly

(

patients > 65 years)

Slide10

O

xaliplatin

can

substitute

for

cisplatin in gastric cancer!Potential advantages inthe elderly and frail population

Slide11

Oral fluoropyrimidines

Slide12

Capecitabine in Gastric Cancer

Cunningham D et al.

N Engl J Med 2008;358:36-46

R

A

N

DOME EpirubicinC CisplatinF Fluorouracil

E EpirubicinC Cisplatin

X Xeloda (

Capecitabine

)

E Epirubicin

O Oxaliplatin

F

Fluorouracil

E

EpirubicinO OxaliplatinX Xeloda (

Capecitabine

)

N=964

Real-2-Study (UK)

Slide13

Capecitabine in Gastric Cancer

Cunningham D et al.

N Engl J Med 2008;358:36-46

Real-2-Study

Slide14

Capecitabine in Gastric Cancer

R

A

N

D

O

MF 5-FluorouracilP Cisplatin

N=316ML17032-Study (Korea)X Xeloda

(Capecitabine)

P

Cisplatin

Kang YK et al.

Ann

Oncol

2009; 20: 666-673 Primary

endpoint: overall survival(non-inferiority)

Slide15

ML17032-Study: XP versus FP

Kang YK et al. Ann Oncol

2009; 20: 666-673

Progression-

free

survival5.6 vs. 5.0 mon

p<0.001 (non-inferior)

Survival

10.5

vs.

9.3

mon

p=0.008

(non-inferior)Response rate46

%

vs.

32%

p=0.02

Slide16

S-1/cisplatin versus 5-FU/cisplatin

S-1 25mg/m

2

2x/d d1-21

Cisplatin

75mg/m2 d1q4wRANDOM

5-FU 1000mg/m2 d1-5Cisplatin 100mg/m2 d1q4w

Primary endpoint: overall survival

(

superiority

)

N=1053

FLAGS-Study

(multinational Western World)

Ajani J et

al. J Clin Oncol 2010; 28: 1547-1553

Slide17

S-1/cisplatin versus 5-FU/c

isplatinIn a Non-Asian

patient population

S-1 was not

superior

to 5-FU

Ajani J et al. J Clin Oncol 2010; 28: 1547-1553

Slide18

S-1/cisplatin versus 5-FU/c

isplatin

Ajani J et

al.

J

Clin

Oncol 2010; 28: 1547-1553S-1/cisplatin5-FU/cisplatinNeutropenia G3/432.3%63.4%Complicated neuropenia5.0%14.4%Stomatitis1.3%13.6%Toxic Death2.5%

4.9%Toxicity in favor

of S-1/

cisplatin

Slide19

Oral

fluoropyrimidines

can

substitute

for i.v. 5-FU in

gastric cancer!Less severe toxicity for S-1/cisplatin

Slide20

Doublets or triplets?

And which is the relevant third drug?

Slide21

Cisplatinum

Wagner et al. J Clin Oncol 2006; 24: 2903-9

HR = 0.83 (95% CI 0,76 – 0,91) in

favor

of

cisplatinum

Slide22

Anthracyclines

Wagner et al. J Clin Oncol 2006; 24: 2903-9

HR = 0.77 (95% CI 0,62 – 0,95) in

favor

of anthracyclines

Slide23

AnthracyclinesECF versus EOX

Cunningham D et al. N Engl J Med

2008;358:36-46

HR = 0.80

(95% CI, 0.66

to

0.97; P=0.02) Real-2-Study (UK)

Slide24

Docetaxel

Docetaxel 75mg/m

2

d1

Cisplatin 75mg/m

2

d15-FU 750mg/m2 d1-5q3wRANDOM

Cisplatin 100mg/m2 d15-FU 1000mg/m2 d1-5q4w

Primary endpoint: time

to

progression

(TTP

)

Van Cutsem et al.

J Clin Oncol 2006; 24: 4991-7Stage IVn=445

Tax-325-Study (multinational)

Slide25

Van Cutsem et al. J Clin Oncol

2006; 24: 4991-7

Time

to

progression

5.6 vs. 3.7 months p<0.01Survival9.2 vs. 8.6 months p=0.02Response rate37% vs. 25% p=0.01Kaplan-Meier curve

: time to progressionDocetaxel as 3rd Drug TAX-325

Slide26

DCF Toxicity

Hematologic toxicity in DCFNeutropenia grade 3/4

82%Febrile neutropenia

30%

Van Cutsem et al.

J Clin Oncol

2006; 24: 4991-7

Slide27

Alternative docetaxel-based regimen

(AIO studies)Lorenzen et al. Ann

Oncol 2007; 18: 1673-9

GastroTax-1

regimen

Docetaxel 40mg/m2 + cisplatin 40mg/m2 2-weekly 5-FU 2000mg/m2 – folinic acid 200mg/m2 weekly Response rate 46.6% Time to progression (metastatic) 8.1 months Survival (metastatic) 15.1 months

Al-Batran et al. Ann Oncol 2008; 19:1882-87FLOT regimen Docetaxel

50mg/m2 + modified FOLFOX 2-weekly Response rate 53%

Time

to

progression

5.3 months Survival

11.3 months

Slide28

Alternative docetaxel-based regimen

(MSKCC)Shah et al. ASO 2010; abstract 4014

Fraction Surviving

Months

15.1 mo

12.6 mo

Modified DCFClassic DCFMedian follow up 10.3 moModified

DCF vs. classic DCF + G-CSF (rand. Ph. II)

Slide29

The future of triplets

in gastric cancer:Sequential treatment?

Arm A

(120 pat.)

R

2:1

Arm B(80 pat.)Induction6 cycles FLOT

(3 months) CR, PR, SDFLOT

Progression

De-

escalation

S-1

AIO – YMO –

Maintain

Study (

proposal)

Slide30

Triplets

are

more

effective

than

doublets!But…Side effects are an issue!Patients‘ preferences matter!Watch out for overlapping side effects and interactions

, when combining with biologics

Slide31

3 + 1 = X…when the

unpredictable comes true

Arm A

:

EOX

Arm B:

EOX-PanitumumabR

EOX (Arm A):

Epirubicin 50mg/m2

IV D1

Oxaliplatin

130mg/m

2

IV D1

Capecitabine

1250mg/m2

/day PO in two divided doses D1-21mEOX-P (Arm B)1:

Epirubicin

50mg/m

2

IV D1

Oxaliplatin

100mg/m

2

IV D1

Capecitabine

1000mg/m

2

/day PO

in two divided doses D1-21

Panitumumab

9mg/kg IV D1

Wardell

et

al.

ASO

2012;

abstract

LBA 4000

REAL-3

study

Slide32

3 + 1 = X…when the

unpredictable comes true

Wardell

et

al.

ASO 2012; abstract

LBA 4000

3

49

275

EOC

2

38

278

EOC-P

Number at risk

0

20

40

60

80

100

0

12

24

36

Months from Randomisation

Probability of Survival (%)

EOX

EOX-P

Median OS

(95% CI)

% alive at 1 year

(95% CI)

11.3m (9.6 – 13.0)

46% (38% - 54%)

8.8m (7.7 – 9.8)

33% (26% - 41%)

HR 1.37, p = 0.013

HR 1.37 (95% CI: 1.07 – 1.76)

6

18

30

Slide33

Reference

regimens

for advanced gastric

cancer

in 2012

TripletsIndication: Severe tumor symptoms Patient preference (most active tx) Intact organ functions Regimens: EOX (epirubicine, oxaliplatin, cape.) mod. DCF (docetaxel, cisplatin, 5FU) FLOT (docetaxel + mod. FOLFOX)

Slide34

Doublets

Indication

: Patient

preference

for less toxicity

Impaired organ functions Combination with biologicsRegimens: Capecitebine-cisplatin S-1-cisplatin FOLFOX-like / CapOx (elderly)Reference regimens for advanced gastric cancer in 2012

Slide35

Doublet or Triplet?

2 : 0or3 : 0

Let‘s

win

the match!

Slide36


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