Advanced Stomach CA

Question 1

Chemo > BSC for met gastric CA. True/False?

Answer 1

True.
Wagner et al Cochrane review 2010

BSC alone 4/12
Chemo+BSC +6months
QoL also improved

Chemo agents used the:
FAMTX
FEMTX
ELF

Question 2

In advanced gastric CA, is combination better or monotherapy better?

Answer 2

Combination.
Wagner Cochrane review 2010

Individual trials generally negative except those with TS-1

• START: TS1/Docetaxel > TS1
• SPIRITS: TS1/CDDP > TS1

Benefit of 6-8w

Question 3

What are the arms in START Trial ?

Answer 3

TS-1/Docetaxel vs TS-1

Question 4

What are the arms in SPIRITS Trial?

Answer 4

TS-1/CDDP vs TS-1

Question 5

Tell me about the SPIRITS trial

Answer 5

Koizumi Lancet Onc 2008
Aim was to show TS-1/CDDP > TS-1

Chemo-naive 
Advanced gastric CA
N=300
2 arms:
- S-1/CDDP
>> S-1 at 40-60 mg BD depending on BSA, PO, 3/52 on 2/52 off
>> IV CDDP (60) D8
>> 5week cycle 
- S-1 
>> 40-60mg BD depending on BSA 
>> 4w on 2w off, Q6w

RESULTS:
Med OS 13m vs 11m HR 0.8
1y OS 45% vs 55%
2y OS 15% vs 25%
PFS 6m vs 4m
1 patient with CR in combination arm, 46 with PR = ORR 50%
1 pt with CR in monotherapy arm, 32 PR = ORR 30%

Question 6

Tell me about the START trial

Answer 6

N=600

2 arms:

1) S-1
2) Doc/S-1

RESULTS:

• OS 11m vs 12.5m
• 1y OS 40% vs 50%
• 3y OS 9% vs 13%
• PFS 4m vs 5m
• ORR 30% vs 40%

Question 7

What is ELF and EAP

Answer 7

ELF = Etoposide, Leucovorin, 5FU

EAP = Etoposide, Doxorubicin, CDDP

Question 8

What is FAMTX

Answer 8

5FU, Doxorubicin, MTX

Question 9

How did ECF come to be one of the first line treatment options?

Answer 9

Webb JCO 1997

N=275
AdenoCarcinoma/undifferentiated
Advance esophagoastric CA, untreated

2 arms:

1) CF
2) FAMTX

Results:
ORR 45% (ECF) vs 20% 
Med Survival 8m (ECF) vs 6m 
1y OS 35% vs 20%
Med FFS 7m (ECF) vs 3m 
FAMTX caused more hematologic toxicity and serious invx
ECF caused more eyes is and alopecia

Question 10

Any value in adding a 3rd drug?

Answer 10

Supporting evidence of adding an anthracyclines is weak.
Benefit of ~2m

3 trials.
One of it is Ross et al JCO 2002
Epiruicin/Cisplatin/5FU vs Mitomycin/CDDP/5FU –> Comparable
- RR 40%, FFS 7m, OS 9m

Question 11

ECX vs CX (Capecitabine, CDDP). Which is better and what is the supporting evidence?

Answer 11

Yun et al

Chemo-naive
Advanced Gastric CA
N=90

2 arms:

1) CX
- CDDP (75) D1, Cape (1000) BD D1-14
2) ECX
- Epirubicin (50), CDDP (75), Cape (1000) BD D1-14

RESULTS:
G3/4 tox 80% ~
Discontinuation due to tox 0% (CX) vs 12% (ECX)
RR 40%~
PFS 6.5m~

Question 12

What is the risk of cardiotoxicity with anthracyclines?

Answer 12

> 5%

Question 13

Using modern day treatment, is triplet better than doublet? Specifically ref to Doctaxel

Answer 13

V325 trial Van Cutsem JCO 2006
Advanced gastric cancer

2 arms:
1) DCF Q3w 
Docetaxel (75) D1
CDDP (75) D1
5FU (750) CIV D1-5 
Q3w
2) CF
CDDP (100) D1
5U (1000) CIV D1-5
Q4w  

RESULTS:
TTP longer with DCF. 32% risk reduction
OS longer with DCF 23% Risk reduction
OS longer with DCF
2y OS 20% (DCF) vs 10% (CF)
ORR higher with DCF, 40% vs 25% 
G3/4 tox 70% (DCF) vs 60% 
G3/4 neutropenia 80% vs 60% 
FN rates 30% vs 10%

Question 14

What is the REAL2 trial?

Answer 14

Cunningham NEJM 2008
Question: CDDP vs Ox and 5FU vs Cape

N=1000
2x2 factorial design

4 arms:

1) ECF
- Epirubicin (50) + CDDP (60) + 5FU (200mg/m2/day)
2) ECX
- Epirubicin
- Capecitabine 1250mg/2/day
3) EOX
4) EOF
- Oxaliplatin (130)

RESULTS:
Med survival times: 10m (ECF), ECX (10m), 9m(EOF) and 11m (EOX)
1y OS: 38% (ECF), 41%(ECX), 40% (EOF) and 47% (EOX)
OS longer with OX than with ECF HR 0.8
PFS (7m)
ORR 41% (ECF) vs 46% (ECX) vs 42% (EOF) vs 48% (EOX)

CONCLUSION:

1) Cape is non-inferior to infused 5FU
2) Ox is non-inferior to CDDP

Question 15

Any other studies besides REAL-2 study that you know about comparing Oxaliplatin and CDDP?

Answer 15

Yes Al-Batran JCO 2008

N=220
German Phase III study

2arms:

• 5FU/LV+Ox (FLO)
• 5FU/LV+CDDP (FLP)

Results:
PFS: 6m vs 4m (FLP) p not sig
OS: 11m vs 9m (FLP) p not sig
Less toxicity with FLO
Older patients >65yo had better efficacy with FLO

Question 16

Tell me about the ML1703 trial that compared Cape and 5FU.

Answer 16

Kang et al Ann Oncol 2009

N=300
Advanced Gastric CA, with Karnofsky PS of 70 or less
No prior palliative chemo. Prior neoadjuvant/adjuvant allowed
No RT to target lesions

2 arms:

1) CDDP (80) D1 + Cape (1000) BD D1-14 Q21 days
2) CDDP (80) D1 + 5FU (800) D1-5 Q3w

RESULTS (significant p)
PFS 5.5 m (Cape) vs 5m (5FU) HR 0.8
OS 10.5m (Cape) vs 9m (5FU) HR 0.85

Question 17

What is S-1

Answer 17

Tegafur : Gimeracil : Oteracil Potassium
1:0.4:1

It is a 4th generation Oral Fluoropyrimidine

Question 18

What is the evidence to use S-1 over 5FU?

Answer 18

1) JCOG 9912, Boku et al

N=700

3 arms:

1) CI 5FU
- 800 mg/m2/d D1-5 Q4w
2) CPT-11 + CDDP
- CPT-11 70mg/m2 D1,15 + CDDP (80) D1 Q4w
3) S-1
- 40mg/m2/BD d1-28 Q6w

RESULTS:
S-1 non-inferior to 5FU
CPT-11+CDDP is not superior to 5FU
=============
2) FLAGS Trial Ajani JCO 2010
Aim: To test efficacy of S-1 in advanced Gastric/oesophageal AdenoCA 

N=1000

2 arms:

1) S-1 (50) BD 21days + CDDP (75) D1 Q28days
2) CI 5FU 1000 mg/m2/24 hours for 120 hourss + CDD (100) D1 Q28days

RESULTS:
- med OS 8.5m (CDDP/S1) vs 8m (CDDP/5FU) p not sig, HR 0.9 
- Significant safety advantages observed in CDDP/S-1 arm vs CDDP/CI5FU am in terms of:
>> G3/4 neutropenia 30% vs 60%
>> Complicated neutropenia 5% vs 15%
>> stomatitis 1% vs 13.5%
>> Hypokalemia 3.5% vs 11%
>> Tx-related deaths 2.5% vs 5%

Question 19

What is the SPIRITS trial?

Answer 19

Kazumi et al Lancet Onco 2008

N=300
2 arms:
- S-1
- S-1+CDDP

RESULTS:
Med OS 11m (S-1) vs 13m (S-1+CDDP)
2y Survival 15% vs 23.5%