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GASTRIC CANCER 2007

GASTRIC CANCER 2007

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GASTRIC CANCER 2007

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  1. GASTRIC CANCER 2007

  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. 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)

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  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?

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

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  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 2006 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

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  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

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  21. 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

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  23. 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

  24. 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”

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  26. 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)

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  28. 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

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  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!