Transcript ASCO_2013_files/Ilson Poster Disc ASCO 2013

Gastric and Esophageal Cancers:
ASCO 2013 Poster Discussion Section
David H. Ilson, MD, PhD
Gastrointestinal Oncology Service
Memorial Sloan-Kettering Cancer Center
Disclosure
 Research
Funding
– Roche-Genentech
– Bayer
 Consulting
– Amgen
– Covidien
– Imclone
ASCO 2013 Gastric / Esophageal Cancer
Poster Discussion

Abst 4026: Does induction chemo added to
chemoradiotherapy improve response in
Esophageal and GEJ Cancer?

LB Abst 4024, Abstract 4025
– S-1 in metastatic gastric cancer
 Does increasing the frequency / dose of cisplatin + S-
1 improve outcome?
 How does S-1 + Cisplatin compare to 5-FU + Cisplatin
in China?

Abst 4027: Italian Trial of D1 vs D2 surgery
– Withdrawn, Dr. Degiuli could not attend
– Data not provided for review
Esophageal and GEJ Adenocarcinoma:
Consensus on Adjuvant Therapy

T2-3 or N+: Something more than surgery
alone should be done

Preop chemo ECF, CF improves overall
survival in some but not all trials
– MAGIC (ECF): 13% ↑ OS at 5 yr
– FFCD / FNLC (CF): 14% ↑ OS at 5 yr  same
as MAGIC, no epirubicin
Cunningham NEJM 355: 11; 2006, Ychou J Clin Oncol 29: 1715; 2011
CROSS Trial

5 weeks of chemo + RT  Surgery vs Surgery alone

Paclitaxel 50mg/m2 + Carboplatin AUC=2 weekly

RT 41.4 Gy in 23 fractions of 1.8 Gy

 Surgery within 6 weeks after completion of chemoRT
(THE/TTE)
Van Hagen et al NEJM 366: 2074; 2012
CROSS: Overall Survival
CRTx
Surgery
HR 0.67 95% CI (.49 - .91) P=0.012
HR 0.67 95% CI (0.49 - 0.91)
•5-year survival 47% versus 34%, HR 0.66
•Squamous path CR 49%, Adeno 23% (p = 0.008)
Preop Chemo
vs ChemoRT
Stahl J Clin Oncol: 27: 836; 2009
Preop Chemo vs Chemo RT: Stahl
•EUS, laparoscopy staged pts
•Siewert I-III, T3-4 adenocarcinoma
Arm
Pts
R0
pCR
N0
Median
Survival
3 yr OS Local
Control
Chemo 59
70%
2%
37%
21 mos
28%
59%
Chemo 60
RT
72%
16%
64%
33 mos
47%
P=
0.07
77%
P = 0.06
Stahl J Clin Oncol: 27: 836; 2009
Duration of Chemo on Positive Trials

MAGIC, FFCD chemo only: 4-6 months chemo
pre / post op
– 5 year OS: 13%, HR 0.69 – 0.75

Stahl, chemo vs chemoRT: 4 months chemo,
vs 3 mos chemo + 1 mo chemoRT preop
– 3 year OS: 19%, HR 0.67 (p = 0.07)

CROSS, chemoRT: 5 weeks chemo during RT
– 5 year OS: 13%, HR 0.66
Duration of Chemo on Positive Trials

MAGIC, FFCD chemo only: 4-6 months chemo
pre / post op
– 5 year OS: 13%, HR 0.69 – 0.75

Stahl, chemo vs chemoRT: 4 months chemo,
vs 3 mos chemo + 1 mo chemoRT preop
– 3 year OS: 19%, HR 0.67 (p = 0.07)

CROSS, chemoRT: 5 weeks chemo during RT
– 5 year OS: 13%, HR 0.66

Survival benefits = for short course vs
protracted chemo

Does extended chemo improve outcome?
Rationale for Induction Chemo 
ChemoRT

Establish safety / tolerance of chemo prior to
adding RT

Improve dysphagia in 70-80% of patients
– Reduce need for feeding tube placement

Increase in pathologic response to therapy
– Increase in R0 resection

Assess response to chemo on early PET scan
– MUNICON trial: PET non responders can stop
ineffective chemo and go to early surgery
– U.S. CALGB 80803: PET non responders have chemo
changed during chemoRT to increase pathologic CR
Randomized Phase II Trial of Extended
versus Standard Neoadjuvant Therapy
for Esophageal Cancer
NCCTG (Alliance) Trial N0849
SR Alberts1, GS Soori2, Q Shi1,3, DA Wigle1, RP Sticca4, RC Miller1, JL
Leenstra5, PJ Peller1, T-T Wu1, HH Yoon1, TF Drevyanko6, SJ Ko7, BI
Mattar8, DA Nikcevich9, RJ Behrens10, MF Khalil11, GP Kim7
1Mayo
Clinic, Rochester, MN; 2Missouri Valley Cancer Consortium, Omaha, NE; 3Alliance
Statistics and Data Center, Rochester, MN; 4Meritcare Hospital CCOP, Fargo, ND; 5St. Vincent
Regional Cancer Center CCOP, Green Bay, WI; 6Iowa Oncology Research Association CCOP, Des
Moines, IA; 7Mayo Clinic, Jacksonville, FL; 8Wichita Community Clinical Oncology Program,
Wichita, KS; 9Essentia Health Duluth Clinic CCOP, Duluth, MN; 10Iowa Oncology Research
Association, Des Moines, IA; 11Geisinger Medical Center, Danville, PA
Abstract 4026
Goals
Primary
• To compare the pathologic complete response (PCR) rate
between patients receiving standard neoadjuvant +/- DOC
Secondary
• To assess and compare the adverse event (AE) profile
• To assess and compare the overall survival (OS) and
disease-free survival (DFS)
• To assess and compare the clinical tumor response rate
measured before surgery
• To evaluate the profiles of pharmacogenetic and proteomic
biomarkers and FDG PET/CT measures
Schema
Randomization portion
DOC  5FU/Oxaliplatin/RT
Early toxicity assessment portion
R
DOC  5FU/Oxaliplatin/RT
5FU/Oxaliplatin/RT
Docetaxel 60 mg/m2 day 1, Oxaliplatin 85 mg/m2 day 1, and Capecitabine 1250
mg/m2/day days 1-14 x 2 cycles [DOC]; 5-FU 180 mg/m2/day continuous IV through
radiation + Oxal 85 mg/m2 days 1,15,29 + 50.4 Gy radiation (chemo-RT)
Table 1
Table 2
Induction Chemo prior to ChemoRT

Small, underpowered study looking for a large
difference in path CR (25%  45%)

No improvement in RO resection 94-100%

No improvement in pCR: higher rate, 48%,
without induction chemo
– Comparison to SWOG S0356: 93 pts, CIV 5-
FU, oxaliplatin, RT  surgery
– Path CR 28%

Survival data pending
– 42 patient trial
Induction Chemo prior to ChemoRT

Was only 2 cycles of DOC enough?
– Data argue similar benefit for 5 weeks of chemo + RT
vs 4-6 months of chemo

Is induction chemo harmful due to delay of RT?
– Anal cancer (RTOG): induction 5-FU / cisplatin
prior to chemoRT worsened local control and
OS
– Protracted preop chemo 3-4 months does not
worsen outcome

This trial reinforces chemoRT, without added
chemotherapy, as the standard or care
Advanced EsophagoGastric Cancer
Chemotherapy: What regimen to use?
Oxali:
Cape:
XP
FLO
FUFIRI
S-1
Cis
DCF
ECF
EOX or
EOF
ECX or
EOX
Pts
489
513
160
109
170
305
221
126
%RR
44%
45%
41%
34%
32%
54%
36%
45%
TTP, mos
6.7
6.5
5.6
5.5
5.0
6.0
5.6
7.4
OS, mos
10.9
10.4
10.5
10.7
9.0
13.0
9.2
8.9
S-1

S-1: oral fluorouracil formulation

Tegafur, 5-FU prodrug +

CDHP: DPD inhibitor +

Oxo (potassium oxonate): reduces bowel
toxicity, inhibiting orotate PRT

Developed as orally absorbed 5-FU preparation
with potentially less bowel toxicity

Japan: toxicity hematologic, dose 80 mg/m2/d
x 3 weeks + cisplatin, 2 week rest

U.S. / Europe: toxicity diarrheal, dose 50
mg/m2/d x 3 weeks + cisplatin, 2 week rest
S-1: Mechanism of Action
Gastric Cancer: S-1 vs S-1 + Cisplatin,
Spirits

S-1 40-60 mg/body BID x
4 weeks every 6 weeks

Vs

S-1 x 3 weeks + Cisplatin
60 mg/m2 day 8, every 5
weeks

S-1 + Cisplatin a new
standard in Japan
Koizumi Lancet Oncol 9: 215; 2008
S-1
S-1 + Cis
Number
150
148
RR
31%
54%
0.002
PFS
4mos
6mos
0.001
OS
11mos
13 mos
0.04,
HR 0.77
1 year
47%
54%
2 year
15%
24%
Grade 3/4 11%
Neut
Grade 3/4 3%
Diarrhea
Grade 3/4 1%
Nausea
40%
4%
11%
p
Gastric Cancer: S-1 + Cisplatin vs 5-FU +
Cisplatin, FLAGS




S-1 50 mg/m2 x 21 days +
Cisplatin 75mg/m2 every
4 weeks
vs
5-FU 1000 mg/m2 days 15 + Cisplatin 100 mg/m2
every 4 weeks
S-1 + Cisplatin less toxic,
no difference in RR, PFS,
OS
Ajani JCO 28: 1547; 2010
S-1
5-FU
p
Number
521
508
RR
29%
32%
0.40
OS
8.6 mos
7.9 mos
0.20
PFS
4.8 mos
5.5 mos
0.92
Second
Line
Chemo
Grade 3/4
Neut
Grade 3/4
Stomatitis
Toxic
Deaths
29.6%
33.3%
32.3%
63.6%
1.3%
13.6%
2.5%
4.9%
LB Abstract 2024, Ryu et al

Non inferiority trial of escalated S-1 + cisplatin
– PFS primary endpoint

Increase cisplatin exposure by 60%

Increase S-1 exposure by 10%

Standard S-1 + Cisplatin
– Cisplatin 60 mg/m2 D-1 + S-1 80-120 mg/body/day
D1-21
 Cycled every 5 weeks vs
– Cisplatin 60 mg/m2 D-1 + S-1 80-120 mg/body/day
D 1-14
 Cycled every 3 weeks
3 week vs 5 week Schedule of S-1 +
Cisplatin (Abstract LBA 4024)

Large, adequately powered and well
conducted study

Non inferiority for the 3 week schedule
was demonstrated

No meaningful difference in PFS (2
weeks), no improvement in OS, non
significant 10% increase in RR
3 week vs 5 week Schedule of S-1 +
Cisplatin (Abstract LBA 4024)

Greater hematologic toxicity, need for
more frequent administration of
cisplatin offer no advantage

No quality of life component
– Likely worsened QOL with a 60%
increase in cisplatin exposure

Current 5 week schedule should remain
standard
A Phase Ⅲ study of S-1 Plus Cisplatin Versus
Fluorouracil Plus Cisplatin in Patients With
Advanced Gastric or Gastro-oesophageal Junction
Adenocarcinoma
(Abstract 4025)
Rui-hua Xu*, Guo-ping Sun, Hui-shan Lu, Yun-peng Liu, Jian-ming Xu,
Mei-zuo Zhong, He-long Zhang, Shi-ying Yu, Wei Li, Xiao-hua Hu, Jiejun Wang, Ying Cheng, Jun-tian Zhou, Zeng-qing Guo, Zhong-zhen Guan
* Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou GD,
CHINA
33
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Objectives
Primary Endpoint:
To access Progression Free Survival (PFS) in the patients with advanced
Gastric or Gastro-oesophageal Junction Adenocarcinoma treated with S1 plus
Cisplatin to Fluorouracil plus Cisplatin in the first line treatment.
Second Endpoint:
To compare the two treatment arms with respect to overall survival (OS),
time to failure (TTF), overall response rate ( ORR) and safety profile.
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Methods: Study Design
Unresectable or
recurrent Gastric or
Gastro-oesophageal
Junction
Adenocarcinoma
1st line
Three stratification factors:
 PS
 Number of metastatic
lesions
 Gastrectomy
R
A
N
D
O
M
I
Z
A
T
I
O
N
S-1(oral drug)：40mg/m2 bid for 21 d
Cisplatin ：20 mg/m2 IV for 4 d
A cycle of chemotherapy was 35 days，
a total of 6 cycles
5- fluorouracil ：800 mg/m2/day CIV for 5d
Cisplatin ：20 mg/m2 IV for 4 d
A cycle of chemotherapy was 28 days，
a total of 6 cycles
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Demography in two groups
S-1 ＋Cisplatin
N=120
5- Fu＋Cisplatin
N=116
P value
Mean
(Min, Max)
53
(25, 76)
55
(21, 76)
0.177
Female
36 (30%)
31(27%)
0.577
Male
84(70%)
85 (73%)
History of
disease
New diagnosis
77(64%)
73(63%)
recurrence
43(36%)
43(37%)
Tissue typing
Low
differentiation
57(48%)
65(57%)
Moderate
differentiation
28(24%)
17(15%)
High
differentiation
1( 1%)
4( 3%)
Yes
13 (11%)
3 (2.6%)
No
106(89%)
113 (97%)
Age
Gender
History of drug
allergy
中山大学肿瘤防治中心
0.8437
0.1574
0.0112
SUN YAT-SEN UNIVERSITY CANCER CENTER
Demography in two groups
ECOG PS
S-1 ＋Cisplatin
N=120
5- Fu＋Cisplatin
N=116
P value
0
28 (23%)
29 (25%)
0.5692
1
85(71%)
83 (72%)
2
7(6 %)
4 (3 %)
The number of
metastatic
lesions
1
18 (15%)
18 (16%)
≥1
102(85%)
98 (84%)
Gastrectomy
Yes
55(45.83%)
52(44.83%)
No
65(54.17%)
64(55.17%)
0.9120
0.8767
 The three stratification factors (general status, number of metastatic
lesions, gastrectomy) between the two groups had no significant difference.
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Progression-Free Survival （PFS）
Primary endpoint:

S-1：5.5 months

5-Fu：4.6 months
 The
two groups had no
significant difference
（P=0.859）.
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Overall Response （ ORR）
Primary endpoint：
S-1：32.5%
 5-Fu：30.2%
 The two groups had no
significant difference
（P=0.7）.
The efficacy confirmed
After 4 weeks
 S-1：22.5%
 5-Fu：21.6%
 The two groups had no
significant difference
（P=0.8605）.
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Overall Survival（OS）
Secondary endpoint ：
 S-1：10.0 months
 5-Fu：10.5 months
 The two groups had no
significant difference
（P =0.820）。
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
Safety Assessment
The two groups of AE and SAE had no significant difference （P= 0.377，0.948）.
The two groups of drug related AE/SAE had no significant difference （P=0.292，0.141）.
The two groups of leading the drop due to AE had no significant difference （P=0.587）.
中山大学肿瘤防治中心
SUN YAT-SEN UNIVERSITY CANCER CENTER
S-1 + Cisplatin vs 5-FU + Cisplatin
(Abstract 4025)

Stat Design: Equivalence for PFS
– One sided alpha 0.025, 80% power: 252 pts
– Underpowered: Requires a much large sample
– Very large confidence intervals

No difference between conventional infusional
5-FU + Cisplatin vs S-1 + Cisplatin

S-1 + Cisplatin acceptable but not necessarily
better than other alternatives

Less toxicity for FU/Cis than the 5-FU/Cis arm
of the FLAGS trial
– Lower doses of both 5-FU and cisplatin
The Future

We do not need any more 600 pt trials with S-1!

Characterize the biologic differences and
potential biomarkers in the 3 subtypes of upper
GI adenocarcinoma
– Esophageal / GEJ
– Distal Gastric, Intestinal
– Distal Gastric, Diffuse

Evaluation of novel targeted agents in
populations enriched for a biomarker or target
Colorectal Cancer 5-FU Dosing, Gastric
Cancer: Oxaliplatin vs Cisplatin

FLO vs FLP
FLO
FLP
P
TTP
5.8
mo
3.9
mo
.077
OS
10.7
mo
8.8
mo
NS
% RR
35 %
25%
NS
– Oxaliplatin 85/m2 vs
Cisplatin 50/m2 q 2 weeks

24 hr CIV 5-FU 2000-2600/m2
+ LV 200/m2 bi-weekly

210 pts randomized

TTP primary endpoint

Non inferiority for
Oxaliplatin

Oxaliplatin superiority for
patients > 65
Al-Batran JCO 26: 1435; 2008