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