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

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

International Mortality Trends GASTRIC CANCER 2007 International Mortality Trends

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

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

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)

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

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

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

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

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

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

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

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

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 2006 showed identical outcomes in treating metastatic disease for: - ECF vs. ECX (Cunningham, et. al.) - FP vs. XP (Kang et. al.)

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

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

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)

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

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

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

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)

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

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”

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

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)

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

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

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%

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

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

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

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

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)

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

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

GASTRIC CANCER Stay Tuned!