Post on 13-Jan-2016
transcript
What is the reference cytotoxic regimen in
advanced gastric cancer?
Florian Lordick
Klinikum BraunschweigGermany
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 equallyTrumper et al. Eur J Cancer 2006; 42: 827-34
Established standard:Platinum-fluoropyrimidine-combination
Established standard:Platinum-fluoropyrimidine-combination
• Oxaliplatin can substitute for cisplatin
• Oral fluoropyrimidines can substitute for i.v. 5-FU
• A 3rd drug makes CTx more effective but more toxic
Al-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)
Oxaliplatin
Oxaliplatin in Gastric Cancer
Cunningham D et al. N Engl J Med 2008;358:36-46
R
A
N
D
O
M
R
A
N
D
O
M
E EpirubicinC CisplatinF Fluorouracil
E EpirubicinC CisplatinX Xeloda (Capecitabine)
E EpirubicinO OxaliplatinF Fluorouracil
E EpirubicinO OxaliplatinX Xeloda (Capecitabine)
N=964
Real-2-Study (UK)
Oxaliplatin in Gastric Cancer
Cunningham D et al. N Engl J Med 2008;358:36-46
Real-2-Study
Oxaliplatin in Gastric Cancer
R
A
N
D
O
M
R
A
N
D
O
M
P 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
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
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)
Oxaliplatin can substitute for cisplatin in gastric cancer!
Potential advantages inthe elderly and frail population
Oral fluoropyrimidines
Capecitabine in Gastric Cancer
Cunningham D et al. N Engl J Med 2008;358:36-46
R
A
N
D
O
M
R
A
N
D
O
M
E EpirubicinC CisplatinF Fluorouracil
E EpirubicinC CisplatinX Xeloda (Capecitabine)
E EpirubicinO OxaliplatinF Fluorouracil
E EpirubicinO OxaliplatinX Xeloda (Capecitabine)
N=964
Real-2-Study (UK)
Capecitabine in Gastric Cancer
Cunningham D et al. N Engl J Med 2008;358:36-46
Real-2-Study
Capecitabine in Gastric Cancer
R
A
N
D
O
M
R
A
N
D
O
M
F 5-FluorouracilP Cisplatin
N=316
ML17032-Study (Korea)
X Xeloda (Capecitabine)P Cisplatin
Kang YK et al. Ann Oncol 2009; 20: 666-673
Primary endpoint: overall survival(non-inferiority)
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)
Survival10.5 vs. 9.3 mon p=0.008
(non-inferior)
Response rate46% vs. 32% p=0.02
S-1/cisplatin versus 5-FU/cisplatin
S-1 25mg/m2 2x/d d1-21
Cisplatin 75mg/m2 d1q4w
S-1 25mg/m2 2x/d d1-21
Cisplatin 75mg/m2 d1q4w
R
A
N
D
O
M
R
A
N
D
O
M5-FU 1000mg/m2 d1-5
Cisplatin 100mg/m2 d1q4w
5-FU 1000mg/m2 d1-5
Cisplatin 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
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
Ajani J et al. J Clin Oncol 2010; 28: 1547-1553
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%
Toxicity in favor of S-1/cisplatin
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
Wagner et al. J Clin Oncol 2006; 24: 2903-9
HR = 0.83 (95% CI 0,76 – 0,91) in favor of cisplatinum
Anthracyclines
Wagner et al. J Clin Oncol 2006; 24: 2903-9
HR = 0.77 (95% CI 0,62 – 0,95) in favor of anthracyclines
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)
Docetaxel
Docetaxel 75mg/m2 d1
Cisplatin 75mg/m2 d1
5-FU 750mg/m2 d1-5q3w
Docetaxel 75mg/m2 d1
Cisplatin 75mg/m2 d1
5-FU 750mg/m2 d1-5q3w
R
A
N
D
O
M
R
A
N
D
O
MCisplatin 100mg/m2 d1
5-FU 1000mg/m2 d1-5q4w
Cisplatin 100mg/m2 d1
5-FU 1000mg/m2 d1-5q4w
Primary endpoint: time to progression (TTP)
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
Stage IV
n=445
Tax-325-Study (multinational)
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
Time to progression5.6 vs. 3.7 months p<0.01
Survival9.2 vs. 8.6 months p=0.02
Response rate37% vs. 25% p=0.01
Kaplan-Meier curve: time to progression
Docetaxel as 3rd Drug TAX-325
DCF Toxicity
Hematologic toxicity in DCF
Neutropenia grade 3/4 82%Febrile neutropenia 30%
Van Cutsem et al. J Clin Oncol 2006; 24: 4991-7
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-weekly5-FU 2000mg/m2 – folinic acid 200mg/m2 weekly
Response rate 46.6%Time to progression (metastatic) 8.1 monthsSurvival (metastatic) 15.1 months
Al-Batran et al. Ann Oncol 2008; 19:1882-87
FLOT regimen
Docetaxel 50mg/m2 + modified FOLFOX 2-weekly
Response rate 53%Time to progression 5.3 monthsSurvival 11.3 months
Alternative docetaxel-based regimen(MSKCC)
Shah et al. ASO 2010; abstract 4014
Fra
ctio
n S
urvi
ving
Months
15.1 mo12.6 mo
Modified DCF
Classic DCF
Median follow up 10.3 mo
Modified DCF vs. classic DCF + G-CSF (rand. Ph. II)
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, SD
FLOT Progression
De-escalationS-1
AIO – YMO – Maintain Study (proposal)
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
Arm A: EOX
Arm B: EOX-Panitumumab
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
• 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
REAL-3 study
3 + 1 = X…when the unpredictable comes true
Wardell et al. ASO 2012; abstract LBA 4000
349275EOC238278EOC-P
Number at risk
0
20
40
60
80
100
0 12 24 36
Months from Randomisation
Pro
bab
ility
of
Su
rviv
al (
%)
EOXEOX-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
Reference regimens for advanced gastric cancer in 2012
Triplets
Indication: Severe tumor symptomsPatient preference (most active tx)Intact organ functions
Regimens: EOX (epirubicine, oxaliplatin, cape.)mod. DCF (docetaxel, cisplatin, 5FU)FLOT (docetaxel + mod. FOLFOX)
Doublets
Indication: Patient preference for less toxicityImpaired organ functionsCombination with biologics
Regimens: Capecitebine-cisplatinS-1-cisplatinFOLFOX-like / CapOx (elderly)
Reference regimens for advanced gastric cancer in 2012
Doublet or Triplet?
2 : 0
or
3 : 0
Let‘s win the match!