What is the reference
cytotoxic regimen in
advanced gastric cancer?
Florian Lordick
Klinikum Braunschweig
Germany
Chemotherapy in Advanced Gastric Cancer
– What do we know? (I)
• Chemotherapy prolongs survival
• Chemotherapy improves symptom control
• Combinations are more active than monotherapy
Wagner et al. J Clin Oncol 2006; 24: 2903-9
• Elderly (>70 years age) benefit equally
Trumper et al. Eur J Cancer 2006; 42: 827-34
Established standard:
Platinum-fluoropyrimidine-combination
Chemotherapy in Advanced Gastric Cancer
– What do we know? (I)
• Oxaliplatin can substitute for cisplatin
Al-Batran et al. J Clin Oncol 2008; 26: 1435-1442
Cunningham et al. N Engl J Med 2008; 358: 36-46
• Oral fluoropyrimidines can substitute for i.v. 5-FU
Kang et al. Ann Oncol 2009; 20: 666-673
Cunningham et al. N Engl J Med 2008; 358: 36-46
Ajani J et al. J Clin Oncol 2010; 28: 1547-1553
• A 3rd drug makes CTx more effective but more toxic
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
Wagner et al. J Clin Oncol 2006; 24: 2903-9
Oxaliplatin
Oxaliplatin in Gastric Cancer
Real-2-Study (UK)
N=964
R
A
N
D
O
M
E Epirubicin
C Cisplatin
F Fluorouracil
E Epirubicin
C Cisplatin
X Xeloda (Capecitabine)
E Epirubicin
O Oxaliplatin
F Fluorouracil
E Epirubicin
O Oxaliplatin
X Xeloda (Capecitabine)
Cunningham D et al. N Engl J Med 2008;358:36-46
Oxaliplatin in Gastric Cancer
Real-2-Study
Cunningham D et al. N Engl J Med 2008;358:36-46
Oxaliplatin in Gastric Cancer
AIO-Study (Germany)
N=220
R
A
N
D
O
M
P Cisplatin
L Leucovorin
F 5-Fluorouracil
O Oxaliplatin
L Leucovorin
F 5-Fluorouracil
Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442
AIO-study: FLO versus FLP
Overall population
PFS: p = 0.077
OS: p = 0.506
Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442
AIO-study: FLO versus FLP
Elderly (patients > 65 years)
PFS: p = 0.029
OS: p = n. s.
Al-Batran SE et al. J Clin Oncol 2008;26:1435-1442
Oxaliplatin can substitute for cisplatin
in gastric cancer!
Potential advantages in
the elderly and frail population
Oral fluoropyrimidines
Capecitabine in Gastric Cancer
Real-2-Study (UK)
N=964
R
A
N
D
O
M
E Epirubicin
C Cisplatin
F Fluorouracil
E Epirubicin
C Cisplatin
X Xeloda (Capecitabine)
E Epirubicin
O Oxaliplatin
F Fluorouracil
E Epirubicin
O Oxaliplatin
X Xeloda (Capecitabine)
Cunningham D et al. N Engl J Med 2008;358:36-46
Capecitabine in Gastric Cancer
Real-2-Study
Cunningham D et al. N Engl J Med 2008;358:36-46
Capecitabine in Gastric Cancer
ML17032-Study (Korea)
N=316
R
A
N
D
O
M
F 5-Fluorouracil
P Cisplatin
Primary endpoint: overall survival
(non-inferiority)
X Xeloda (Capecitabine)
P Cisplatin
Kang YK et al. Ann Oncol 2009; 20: 666-673
ML17032-Study: XP versus FP
Response rate
46% vs. 32%
p=0.02
Progression-free survival
5.6 vs. 5.0 mon
p<0.001
(non-inferior)
Survival
10.5 vs. 9.3 mon
p=0.008
(non-inferior)
Kang YK et al. Ann Oncol 2009; 20: 666-673
S-1/cisplatin versus 5-FU/cisplatin
FLAGS-Study (multinational Western World)
N=1053
R
A
N
D
O
M
S-1
Cisplatin
25mg/m2 2x/d d1-21
75mg/m2 d1
q4w
Primary endpoint: overall survival
(superiority)
5-FU
1000mg/m2 d1-5
Cisplatin 100mg/m2 d1
q4w
Ajani J et al. J Clin Oncol 2010; 28: 1547-1553
S-1/cisplatin versus 5-FU/cisplatin
In a Non-Asian patient population S-1 was not superior to 5-FU
Ajani J et al. J Clin Oncol 2010; 28: 1547-1553
S-1/cisplatin versus 5-FU/cisplatin
Toxicity in favor of S-1/cisplatin
S-1/cisplatin
5-FU/cisplatin
Neutropenia G3/4
32.3%
63.4%
Complicated
neuropenia
5.0%
14.4%
Stomatitis
1.3%
13.6%
Toxic Death
2.5%
4.9%
Ajani J et al. J Clin Oncol 2010; 28: 1547-1553
Oral fluoropyrimidines can substitute
for i.v. 5-FU in gastric cancer!
Less severe toxicity for S-1/cisplatin
Doublets or triplets?
And which is the relevant third drug?
Cisplatinum
HR = 0.83 (95% CI 0,76 – 0,91) in favor of cisplatinum
Wagner et al. J Clin Oncol 2006; 24: 2903-9
Anthracyclines
HR = 0.77 (95% CI 0,62 – 0,95) in favor of anthracyclines
Wagner et al. J Clin Oncol 2006; 24: 2903-9
Anthracyclines
ECF versus EOX
Real-2-Study (UK)
HR = 0.80 (95% CI, 0.66 to 0.97; P=0.02)
Cunningham D et al. N Engl J Med 2008;358:36-46
Docetaxel
Tax-325-Study (multinational)
Stage IV
n=445
R
A
N
D
O
M
Docetaxel 75mg/m2 d1
Cisplatin
75mg/m2 d1
5-FU
750mg/m2 d1-5
q3w
Primary endpoint: time to progression (TTP)
Cisplatin 100mg/m2 d1
5-FU
1000mg/m2 d1-5
q4w
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
Docetaxel as 3rd Drug
TAX-325
Response rate
37% vs. 25%
p=0.01
Time to progression
5.6 vs. 3.7 months
p<0.01
Survival
9.2 vs. 8.6 months
p=0.02
Kaplan-Meier curve: time to progression
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
DCF Toxicity
Hematologic toxicity in DCF
Neutropenia grade 3/4
Febrile neutropenia
82%
30%
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
Alternative docetaxel-based regimen
(AIO studies)
GastroTax-1 regimen
Docetaxel 40mg/m2 + cisplatin 40mg/m2 2-weekly
5-FU 2000mg/m2 – folinic acid 200mg/m2 weekly
Response rate
Time to progression (metastatic)
Survival (metastatic)
46.6%
8.1 months
15.1 months
Lorenzen et al. Ann Oncol 2007; 18: 1673-9
FLOT regimen
Docetaxel 50mg/m2 + modified FOLFOX 2-weekly
Response rate
Time to progression
Survival
53%
5.3 months
11.3 months
Al-Batran et al. Ann Oncol 2008; 19:1882-87
Alternative docetaxel-based regimen
(MSKCC)
Modified DCF vs. classic DCF + G-CSF (rand. Ph. II)
Fraction Surviving
Median follow up 10.3 mo
Modified DCF
Classic DCF
12.6 mo
15.1 mo
Months
Shah et al. ASO 2010; abstract 4014
The future of triplets in gastric cancer:
Sequential treatment?
AIO – YMO – Maintain Study (proposal)
(120 pat.)
Induction
6 cycles FLOT
(3 months)
Arm B
FLOT
Arm A
CR, PR, SD
De-escalation
S-1
R
2:1
(80 pat.)
Progression
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
3+1=X
…when the unpredictable comes true
REAL-3 study
R
• EOX (Arm A):
– Epirubicin 50mg/m2 IV D1
– Oxaliplatin 130mg/m2 IV D1
– Capecitabine 1250mg/m2/day PO
in two divided doses D1-21
Arm A:
EOX
Arm B:
EOX-Panitumumab
• mEOX-P (Arm B)1:
– Epirubicin 50mg/m2 IV D1
– Oxaliplatin 100mg/m2 IV D1
– Capecitabine 1000mg/m2/day PO
in two divided doses D1-21
– Panitumumab 9mg/kg IV D1
Wardell et al. ASO 2012; abstract LBA 4000
3+1=X
…when the unpredictable comes true
Probability of Survival (%)
100
80
60
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
40
EOX
EOX-P
20
HR 1.37 (95% CI: 1.07 – 1.76)
0
0
6
12
18
24
30
36
Months from Randomisation
Number at risk
EOC
EOC-P
275
278
49
38
3
2
Wardell et al. ASO 2012; abstract LBA 4000
Reference regimens for advanced
gastric cancer in 2012
Triplets
Indication: 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)
Reference regimens for advanced
gastric cancer in 2012
Doublets
Indication:
Patient preference for less toxicity
Impaired organ functions
Combination with biologics
Regimens:
Capecitebine-cisplatin
S-1-cisplatin
FOLFOX-like / CapOx (elderly)
Doublet or Triplet?
2:0
or
3:0
Let‘s win the match!