1. GASTRIC CANCER 2007 #New Cases (rank) # Deaths (rank)
United States (2007)*
21,260 (#13)
11,210 (#13)
Worldwide (2002)°
934,000 (#4)
700,000 (#2)
* Jemal, et. al. CA Cancer J Clin 2007;57:43
° Parkin, et. al. CA Cancer J Clin 2005;55:75

2. GASTRIC CANCER 2007 Epidemiologic Trends
• worldwide decline in age-adjusted incidence now parallels pattern previously observed in United States
• disease now appearing anatomically in a more proximal pattern

3. International Mortality Trends
GASTRIC CANCER 2007
International Mortality Trends

4. GASTRIC CANCER 2007 Question
• is there a “best” treatment for metastatic disease?

5. GASTRIC CANCER 2007 Active Single Agents fluorouracil
anthracyclines (doxorubicin, epirubicin)
cisplatin
irinotecan
taxanes (docetaxel, paclitaxel)

6. GASTRIC CANCER 2007 Drug Combinations FAM FU, doxorubicin, mitomycin
FAMTX
FU, doxorubicin, methotrexate (high dose)
EAP
etoposide, doxorubicin, cisplatin
ELF
etoposide, FU, leucovorin
ECF
epirubicin, cisplatin, FU (infusional) CF
cisplatin, FU IC
irinotecan, cisplatin IF
irinotecan, FU, leucovorin TC
docetaxel, cisplatin
TCF
docetaxel, cisplatin, FU (infusional)

7. GASTRIC CANCER 2007 Chemotherapy is Superior to Best Supportive Care
Wagner, et. al. JCO 2006;24:2903

8. GASTRIC CANCER 2007 Advanced Disease
Is any one of these various drug combinations superior to the others?

9. Results from Recent Phase III Trials
GASTRIC CANCER 2007
Results from Recent Phase III Trials
regimen
response rate
median TTP (mos)
median OS (mos)
source CF
25%
3.7
8.6
JCO 2006
26%
4.2
8.7
ASCO 2005 IF
32%
5.0
9.0
ECF
45%
7.4
8.9
JCO 1997
42%
7.0
9.4
JCO 2002
TCF
37%
5.6
9.2

10. GASTRIC CANCER 2007 Combination vs Single-Agent Chemotherapy
Wagner, et. al. JCO 2006;24:2903

11. Results from Phase III Trials
GASTRIC CANCER 2007
Results from Phase III Trials
drug (s)
response rate %
median OS (mos)
source
5-FU
1.9
7.3
Gan To Kagaku Ryoho 1989
11.0
7.1
JCO 2003
15.0
7.0
CTR 1986
18.0
JAMA 1985
26.0
Cancer 1993
5-FU/cisplatin
20.0
7.2
JCO 2000
25.0
8.6
JCO 2006
34.0
51.0
9.0
adapted from Wöhrer et. al. Ann Oncol 2004;15:1585

12. GASTRIC CANCER 2007 Treatment of Metastatic Disease
• many active combinations
• none clearly superior
• ECF perhaps best balance between efficacy and tolerability

13. GASTRIC CANCER 2007 Recent Interest in Oral Fluoropyrimidines
• oral preparation of 5-FU was discarded because of erratic absorption thought due to variable concentrations of DPD in the GI mucosa
• three novel forms of oral 5-FU are now available
- capecitabine (Xeloda)
- UFT (uracil and tegafur)
- S-1

14. GASTRIC CANCER 2007
Capecitabine
from: Ajani. Cancer 2006;107:221

15. GASTRIC CANCER 2007 Capecitabine
• phase II data as single agent or when combined with cisplatin similar to results with 5-FU
• phase III comparisons reported at ASCO in showed identical outcomes in treating metastatic disease for:
- ECF vs. ECX (Cunningham, et. al.)
- FP vs. XP (Kang et. al.)

16. GASTRIC CANCER 2007
UFT
• uracil binds to DPD, facilitating the absorption of tegafur, a prodrug of 5-FU
• has been utilized in metastatic gastric cancer as a single agent or in combination with mitomycin or cisplatin
• has been examined in phase III trials in Japan in metastatic and adjuvant settings

17. GASTRIC CANCER 2007 JCOG 9205 5-FU cisplatin UFT mitomycin-C 105 7.1
# pts
OS median (mos)
PFS median (mos) RR
5-FU
800 mg/m2/d x 5
q 4 weeks
105
7.1
1.9
11.4%
stratify:
• PS
• measurable disease +
cisplatin
20 mg/m2/d x 5
7.3
3.9
34.3%
UFT
375mg/m2/d bid
mitomycin-C
5mg/m2 q week 70
6.0
2.4
8.6%
Ohtsu et. al. JCO 2003;21:54

18. GASTRIC CANCER 2007 Adjuvant Phase III Trial # pts OS (4 year) RFS
S U R G E R Y
UFT 93
86.3%
84.5%
p=0.018
p=0.004
observation 95
73.6%
68.1%
median f/u 3.8 years
Kinoshita, et. al. Proc ASCO 2005 (abstract #4021)

19. GASTRIC CANCER 2007
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)
• phase II trials in Japanese patients with advanced gastric cancer were encouraging

20. GASTRIC CANCER 2007 5-FU irinotecan 70mg/m2 d 1,15 cisplatin S-1
JCOG 9912 (Boku, et. al.)
5-FU
800mg/m2/d x 5
q 4 weeks
irinotecan
70mg/m2 d 1,15 +
cisplatin
80mg/m2 d 1
S-1
40mg/m2 bid d 1-28
q 6 weeks

21. GASTRIC CANCER 2007 Study Design • OS represented the primary endpoint
JCOG 9912 (Boku, et. al.)
Study Design
• OS represented the primary endpoint
• dual comparisons to 5-FU
- superiority of irinotecan/cisplatin
- non-inferiority of S-1
• three stratifications (PS, de novo vs. recurrence, center)
• 704 randomized patients well balanced
- only 3 had received prior adjuvant chemotherapy
- equal proportion intestinal/diffuse histologies

22. GASTRIC CANCER 2007 Results JCOG 9912 (Boku, et. al.) 234 2.9 mos
#pts
response rate
median
PFS
survival
TTF
one-sided
p value
5-FU
234 9%
2.9 mos
10.8 mos
2.3 mos -
irinotecan +
cisplatin
236
38%
4.8 mos
12.3 mos
3.7 mos
0.055 (superiority)
S-1
231
28%
4.2 mos
11.4 mos
4.0 mos
<0.001
(non-inferiority)

23. GASTRIC CANCER 2007 Observations
JCOG 9912 (Boku, et. al.)
Observations
• neither the 5-FU nor the irinotecan/cisplatin regimens as given in this trial are commonly used in the US or Europe
• toxicity led to the withdrawal of 32.1% of the irinotecan/cisplatin cohort compared to a 9.4% and 7.7% withdrawal rate for patients randomized to S-1 or 5-FU respectively
• in retrospect, a prospective stratification for “measurable vs. non-measurable” disease would have been useful

24. GASTRIC CANCER 2007 Conclusions
JCOG 9912 (Boku, et. al.)
Conclusions
• results with S-1 are impressive (11.4 month median survival)
• however – premature to annoint S-1 as “the standard chemotherapy for unresectable or recurrent gastric cancer”

25. GASTRIC CANCER 2007 S-1 cisplatin SPIRITS Trial (Narahara, et. al.)
40-60mg bid x 28 days q 5 weeks
40-60mg bid x 28 days +
cisplatin
60 mg/m2 d 8 q 5 weeks

26. GASTRIC CANCER 2007 Study Design • OS represented the primary endpoint
SPIRITS Trial (Narahara, et. al.)
Study Design
• OS represented the primary endpoint
• three stratifications (PS, de novo vs. recurrent, center)
• 298 evaluable patients
- S-1/cisplatin cohort contained a greater proportion of patients with diffuse histology (p=0.079) and peritoneal carcinomatosis (p=0.056)

27. GASTRIC CANCER 2007 Results SPIRITS Trial (Narahara, et. al.) 150 31%
# pts
response rate
median PFS
median survival
median TTF
S-1
150
31%
4.0 mos
11.0 mos
3.9 mos
p=<0.0001
p=0.037
p=0.009 +
cisplatin
148
54%
6.0 mos
13.0 mos
4.8 mos

28. GASTRIC CANCER 2007 Conclusions
SPIRITS Trial (Narahara, et. al.)
Conclusions
• S-1/cisplatin regimen:
- was well tolerated
- was superior to single agent S-1, even though it was given to patients with more ominous prognostic features
- merits further study

29. Comparative Recent Japanese Experience
GASTRIC CANCER 2007
Is S-1 a Superior Fluoropyrimidine?
Comparative Recent Japanese Experience
Response Rate
Trial
5-FU
UFT
S-1 FP
S-1/P
9205
11.4%
8.6%
34.4%
9912
9.0%
28%
SPIRITS
31%
54%

30. Comparative Recent Japanese Experience
GASTRIC CANCER 2007
Is S-1 a Superior Fluoropyrimidine?
Comparative Recent Japanese Experience
Median Survival
(mos)
Trial
5-FU
UFT
S-1 FP
S-1/P
9205
7.1
6.0
7.3
9912
10.8
11.4
SPIRITS
11.0
13.0

31. GASTRIC CANCER 2007 Adjuvant Phase III Trial # pts OS (3 year) RFS
S U R G E R Y
S-1
529
81.1%
72.2%
p=0.0015
p=<0.0001
observation
530
70.1%
60.1%
median f/u 3 years
Sasako, et. al.;Proc GI ASCO 2007

32. GASTRIC CANCER 2007
would S-1 be a superior form of fluoropyrimidine therapy if used outside of Japan?

33. GASTRIC CANCER 2007 American Experience with S-1
• Asian and white individuals have different rates of activation of tegafur to 5-FU
- such activation is dependent on an hepatic cytochrome P450 enzyme (CYP2A6)
- different polymorphisms of the CYP2A6 gene exist among Asians and whites

34. GASTRIC CANCER 2007 American Experience with S-1
• a phase I study in 16 American patients suggested a “25mg/m2 bid” dose being optimal for “Westerners” rather than the “40mg/m2 bid” dose utilized in Japan
(Ajani, et. al. JCO 2005;23:6957)

35. GASTRIC CANCER 2007 American Experience with S-1
• multicenter phase II trial involving 72 American patients (74% white, 15% black or Latino) previously untreated for metastatic disease
S-1 (25mg/m2 bid d 1-21) +
cisplatin (75mg/m2 d 1)
q 28 days
• report: 55% response rate
5.6 month median PFS
10.4 month median OS
Ajani, et. al. JCO 2006;24:663
Lenz, et. al. Cancer 2007;109:33

36. GASTRIC CANCER 2007 First-Line Advanced Gastric Cancer Study (FLAGS)
• ongoing worldwide phase III trial involving >1000 patients
• comparison of:
5-FU/cisplatin
S-1/cisplatin
• hopefully will be addressing cost and quality of life as well as efficacy

37. GASTRIC CANCER
Stay Tuned!