1. Upper Gastrointestinal Cancers Overview : Review of the Latest Data and Practice Implications Esophageal and Gastric Cancers
Johanna Bendell, MD
Director, GI Oncology Research
Sarah Cannon Research Institute
Nashville, TN

2. Epidemiology Esophageal cancer Gastric cancer
In 2008, cases, deaths
87% fatality rate
Adenocarcinoma of esophagus and GE junction one of the fastest increasing cancers in the US
Barrett’s, obesity, tobacco, EtOH, genetics
Are adenocarcinomas of the distal esophagus, GE junction, and upper stomach the same?
SCC decreasing
Gastric cancer
In 2008, cases, deaths
53% fatality rate
Incidence decreasing
Incidence of adenocarcinoma due to Barrett’s, obesity, tobacco, EtOH, genetics
Is there a difference between esophageal, GE junctional, and gastric cancers?

3. Localized disease Esophageal cancer Gastric cancer
Preoperative chemoradiation therapy most commonly used in U.S.
Preoperative chemotherapy alone
Definitive chemoradiation therapy
Gastric cancer
Postoperative chemoradiation therapy most common in the U.S.
Perioperative chemotherapy alone

4. Preoperative Chemoradiation
Study
# Patients
Pathology
Chemotherapy
Radiation (Gy)
3-year
survival
Walsh et al, 1996
Trimodality: 58
Surgery: 55
Adeno
Cisplatin/5-FU 40
Tri: 32%
Surgery: 6%
P = 0.01
Bosset et al
(EORTC), 1997
Trimodality: 143
Surgery: 139
SCC
Cisplatin 37
Tri: 37%
Surgery: 35%
P = NS
Urba et al, 2001
Trimodality: 50
Surgery: 50
SCC,
Cisplatin/5-FU/vinblastine 45
Tri: 30%
Surgery: 16%
P = 0.15
Burmeister et al, 2005
Trimodality: 128
Surgery: 128 35
Tri: 33%
Surgery: 30%
P = 0.57
Tepper et al (CALGB), 2006
Trimodality: 30
Surgery: 26
50.4
Tri: 39%
5 year
P < 0.008

5. New chemotherapy agents with radiation
ASCO 2009, Abstr 4513
SWOG S0356, Leichman, et al.
Phase II esophageal adenocarcinoma, 98 pts
Preoperative chemoradiation therapy
5-FU CI 180 mg/m2/d d8-43, Oxaliplatin 85 mg/m2 d 1, 15, 29, XRT 45 Gy
pCR rate 33%
Very strong compared to historical pCR rates in the 20% range
Acceptable toxicity rates
18% of pts with G3/4 toxicity – GI, fatigue, pulmonary, hematologic, mucositis
This regimen will move forward into further studies

6. Preoperative chemotherapy
Study #
Patients
Pathology
Chemotherapy
Tumor
Location
5-year survival
MRC OEO-2, 2002
Chemo: 400
Surgery: 402
SCC,
Adeno
Cisplatin/5-FU
Stomach
10%
Distal eso
65%
Chemo: 23%
Surgery: 17%
P = 0.03
Cunningham et al, 2006
Chemo: 250
Surgery: 253
ECF
Stomach 74%
GE jn
12%
14%
Chemo: 36.3%
Surgery: 23.0%
P = 0.001
Kelsen et al, 2007
Chemo: 233
Surgery: 234
SCC, Adeno
Esophagus
Chemo: 26%
Surgery: 23%
3 year
P = 0.53
Boige, et al, 2007
Chemo: 113
Surgery: 111
Stomach 24%
GE jn 64%
Distal eso 11%
Chemo: 38%
Surgery: 24%
P = 0.021

7. CRT vs. Chemo - POET Trial
Arm A
Week
Arm B
PLF I
PLF II
PLF III (3 weeks)
Surgery 1
6 7
1314 17
20-21
15 x 2 Gy in 3 weeks
PLF I
PLF II
Surgery
Only high risk T3/4 treated
Accrual not met (33%) n=126
PE (1 week)
PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leucovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d 1,8,15,22,29,36
PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5
Stahl, ASCO 2007

8. Overall Survival Logrank p = 0.07 HR Arm B vs. A 0.67 (0.41-1.07)
47.4%
Arm A
27.7%
Follow-up 45.6 mo
Stahl, ASCO 2007

9. Definitive chemoradiation
Study #
Patients
Pathology
Treatment
Tumor
Location
5-year survival
RTOG 85-01, 1999
121
90% SCC
Cisplatin/5-FU + 50 Gy XRT
vs.
50 Gy XRT
Esophagus
CRT: 26%
RT: 0%
INT 0123, 2002
236
SCC, Adeno
Cis/5-FU Gy XRT
Cis/5-FU Gy XRT
RT low: 40%
RT high: 31%
2 year

10. Definitive chemoradiation
ASCO 2008, Abstr 4530
Updated data, Stahl, et al.
172 pts with SCC esophagus
CRT followed by surgery
CRT alone
5 year OS 28 vs. 17% (HR 1.15 [0.82,1.61]
Local failure 45% vs. 72%
Distant failure 52% vs. 25%

11. Chemoradiation vs. chemotherapy for gastric cancer
GI ASCO 2009, Abstr 5, ASCO 2009 Abstr 4537
ARTIST Trial safety/feasibility, Lee, et al.
Rand Ph III adjuvant CRT vs. chemo alone after D2 resection of gastric cancer
XPRT vs. XP
458 pts randomized
82% and 75% completed CRT and chemo
Toxicities relatively comparable
2% vs. 1% G3 neutropenia
We now await the results
Issue with int0116 – bad surgery

12. Neoadjuvant chemotherapy for gastric cancer
ASCO 2009, abstr 4510, Schuhmacher, et al.
Randomized Ph III trial
144 pts
5-FU/cisplatin x 2 48-day cycles preoperatively
Surgery alone
Stopped early due to low accrual
TTP HR 0.66 ( , p = 0.065)
Increased R0 resection rate with chemotherapy
Perioperative approach has better data
MAGIC
This trial only gave 3 months of chemotherapy
This trial was more purely gastric cancer patients

13. What have we learned about localized esophageal cancers?
Chemoradiation therapy remains standard
POET Trial shows improved local control and possibly survival
CRITICS Trial may shed more light
Definitive chemoradiation is possible, but inferior local control compared to CRT + S
New agents may improve outcomes
SWOG S0356 – oxaliplatin-based backbone with XRT
RTOG 0436 – cetuximab for unresectable disease
EORTC – neoadj chemo vs surgery alone loc adv gastric ca rand ph iii, 5-FU/cis regimen, chemo better (HR 0.66)
MAGIC 2 – periop ECF +/- bev
RTOG preop chemorads +/- cetux

14. What have we learned about localized gastric cancers?
Awaiting data on adjuvant CRT vs. chemotherapy
ARTIST trial - when surgery is controlled, is adjuvant radiation necessary?
Is a neoadjuvant approach feasible and better?
Neoadjuvant much more likely to receive therapy (SAKK)
EORTC – 3 months neoadjuvant chemo trends towards better
No randomized neoadjuvant CRT gastric studies reported yet
Attempts have been aborted secondary to low accrual
Data with targeted therapies, more aggressive chemotherapy
MAGIC 2 – ECF +/- bevacizumab
CALGB – ECF vs. 5-FU/LV with chemoradiation adjuvantly

15. Metastatic disease Is there a true standard regimen?
Multiple combinations are feasible in the first line setting
No data as to whether combinations are better than sequential therapy
Active agents
Fluoropyrimidines, platinums, taxanes, irinotecan, anthracyclines

16. Some combinations used
Regimen
RR (%)
TTP/PFS (mos)
OS (mos)
Ref CF
Cisplatin 100 mg/m2 D1
5-FU 1000 mg/m2 CIV D1-5 35
8.3
Bleiberg, Eur J Ca 1997
ECF
Epirubicin 50 mg/m2 D1
Cisplatin 60 mg/m2 D1
5-FU 200 mg/m2/d CIV D1-21 42
7.0
9.4
Ross, JCO 2002
TCF
Docetaxel 75 mg/m2 D1
Cisplatin 75 mg/m2 D1
5-FU 750 mg/m2 CIV D1-5 37
5.6
9.2
Van Cutsem, JCO 2006
EOX
Oxaliplatin 130 mg/m2 D1
Capecitabine 625 mg/m2 BID 48
11.2
Cunningham, NEJM 2008
Cis/Iri
Cisplatin 30 mg/m2 D1, 8
Irinotecan 65 mg/m2 D1, 8 57
4.2
14.6
Ilson, JCO 1999

17. S-1
Oral fluoropyrimidine consisting of tegafur, CDHP, and OXO in a 1:0.4:1 molar ratio
Tegafur is converted to 5-FU
CDHP (chloro-2.4-dihydroxypyridine) inhibits DPD, preventing 5-FU degradation
OXO (potassium oxonate) protects against drug induced diarrhea caused by phosphorylation of 5-FU by inhibiting the responsible enzyme – OPRT (oronate phosphoribosyl transferase)

18. S-1
Preliminary data suggested that S-1 could possibly be a superior fluoropyrimidine to 5-FU
Adjuvant S-1
Sakuramoto, NEJM 2007
Adjuvant S-1 vs. obs
HR 0.68 [0.52,0.87]
JCOG 9912
Boku, ASCO 2007 with update 2009
5-FU vs. S-1 vs. Irinotecan/cisplatin
S-1 equivalent to, with possible superiority to 5-FU

19. Phase III Study (JCOG9912) 5-FU CI CPT-11 + CDDP S-1 Randomization
800 mg/m2/day, ci, days 1-5
q 4 weeks
CPT-11 + CDDP
Randomization
CPT mg/m2, div, days 1&15
CDDP 80 mg/m2, div, day 1
q 4 weeks
N=704, S-1 vs. 5-FU noniferiority, 5-fu vs. cis/iri full comparison, os primary endpoint
S-1
S-1 40 mg/m2, po, bid, days 1-28
q 6 weeks
Continued until disease progression, unacceptable toxicities, patient’s refusal
BSA < mg/body/day
1.25 < BSA < mg/body/day
1.5 < BSA mg/body/day
Boku, ASCO 2007

20. JCOG9912 n Med OS (mos) HR (95% CI) p 5-FU 234 10.8 - Iri/cis 236 12.3
0.82 ( )
0.019
S-1
11.5
0.83 ( )
0.023
Fuse ASCO 2009

21. JCOG9912 S-1 at least equivalent to 5-FU
Adjusting survival for poorer prognostic factors
# metastatic sites
PS >/= 1
Present target lesion
HR 0.80 ( ), p = 0.017

22. FLAGS Trial GI ASCO 2009, Abstr 8 Ajani, et al.
Rand Ph III Trial for first line treatment of advanced gastric cancer
1053 patients randomized
S-1 25 mg/m2 BID D Cisplatin 75 mg/m2 D1, q 4 weeks
5-FU 1000 mg/m2 CIV D1-4 + Cisplatin 100 mg/m2 D1, q 4 weeks

23. FLAGS n RR (%) PFS (mos) OS (mos) S-1/cis 521 29.1 4.8 8.6 5-FU/cis
508
31.9
5.5
7.9 p
0.9
0.92
0.20
Ajani, GI ASCO 2009

24. FLAGS Toxicity S-1/cis 5-FU/cis G3/4 neutropenia 18.6% 40%
G3/4 fever and neutropenia
1.7%
6.9%
G3/4 stomatitis
1.3%
13.8%
Renal AE
18.8%
33.5%
Treatment-related deaths
2.5%
4.9%

25. FLAGS No difference in efficacy between arms
S-1 arm significantly less toxic
Cisplatin dose different between the two arms
S-1 dose much lower than Japanese dose
Polymorphisms of CYP2A6 different in Caucasians and Asians
Controls rate of conversion of tegafur to 5-FU
Phase II U.S. trial found the S-1/cis dosing
If the trial were designed differently would this have made a difference?

26. Improving tolerance of chemotherapy
DCF toxicity includes 82% G3/4 neutropenia, CF 40%
ASCO 2008, Abstr 4512, Ridwelski, et al.
DC vs. FLC
FLC = 5-FU 2000 mg/m2 CIV x 24h + LV 500 mg/m2 D1, 8, 15, 22, 29, 36, cisplatin 50 mg/m2 D1, 15, 29
RR 24.1%, TTP 6.6 mo, OS 9.6 mo
Neutropenia 12.2%, no fever and neutropenia
GI ASCO 2009, Abstr 10, Jhawer, et al.
mDCF plus bevacizumab
5-FU 400mg/m2 D1, 5-FU 1000 mg/m2 CIV D1-2, LV 500 mg/m2 D1, Cisplatin 40 mg/m2 D3, Docetaxel 40 mg/m2 D1, Bev 10 mg/Kg D1
G3/4 neutropenia 51%

27. New biologic agents
VEGF Inhibitors
EGFR inhibitors
HER2 inhibitors

28. Bevacizumab Shah, et al. JCO 2007
Phase II met gastric or GEJ adenoca
First line therapy – cisplatin/irinotecan/bev
N = 47, 34 with measurable disease
RR 65%, OS 12.3 mo
Enzinger, et al. ASCO 2008, Abstr 4552
Phase II met esophagogastric cancer
First line therapy – docetaxel/cisplatin/irinotecan
N = 32
RR 63%
Jhawer, et al. GI ASCO 2009, Abstr 10
mDCF plus bevacizumab
N = 45
RR 67%, PFS 12 mo, OS 16.2 mo
AVAGAST study accrual completed
XP +/- bevacizumab
Following toxicities carefully – thrombosis, perforation

29. Sorafenib ASCO 2008, Abstr 4535, Sun, et al. ECOG 5203
Phase II study of sorafenib, docetaxel, cisplatin
44 pts with advanced gastric or GE junctional cancers
RR 38.6%, PFS 5.8 mo, OS 14.9 mo

30. Cetuximab Lordick, et al. Pinto, et al.
Phase II FUFOX+cetuximab
N = 28, RR 64%
Pinto, et al.
Phase II FOLFIRI+cetuximab
N = 33, RR 44%, TTP 8 mo, OS 16 mo
Gold, et al. ASCO 2008, Abstr 4536
SWOG Ph II cetuximab as 2nd line therapy for esophageal adenocarcinomas
N = 55, RR 36%, PFS 1.8 mo, OS 4 mo
Lordick, et al. ASCO 2008, Abstr 4546
Rand Ph II CF +/- cetuximab
66 pts with metastatic SCC esophagus
RR 19 vs. 13%, PFS 5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo
CALGB 80403
Randomized Phase II, met esophagogastric first line
ECF-C, IC-C, FOLFOX-C

31. Trastuzumab ASCO 2008, Abstr 4526, Bang, et al.
Analysis of 2484 gastric cancer samples from the Ph III ToGA trial
21.9% HER2 positivity
ASCO 2009, Abstr LBA 4509, ToGA Trial
Rand Ph III, HER2+ gastric cancer
5-FU/capecitabine + cisplatin +/- trastuzumab
RR 47.3 vs. 34.5%, OS 13.5 vs mo (p = )
HR 0.74 ( )
Practice changing!!!
LOGIC Trial
Rand Ph III, HER 2+ gastric cancer
Capecitabine + oxaliplatin +/- lapatinib

32. Conclusions Localized esophagogastric cancers Metastatic disease
Chemoradiation and chemotherapy options remain
Addition of radiation improves local control
New agents are under investigation
5-FU/Oxaliplatin with radiation could be a reasonable option in the setting of no clear standard
We await more comparison trials to determine role of radiation and optimal timing of treatment
Metastatic disease
S-1 suffers a major setback
Still no clear standard treatment
Quality of life is the issue
Colorectal cancer-type regimens improve side effect profile
New targeted agents are changing how we treat this disease