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GASTRIC CANCER 2007. 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. - PowerPoint PPT Presentation
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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
GASTRIC CANCER 2007International 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?
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 ASCO 2005
ECF 45% 7.4 8.9 JCO 1997
42% 7.0 9.4 JCO 2002
TCF 37% 5.6 9.2 JCO 2006
GASTRIC CANCER 2007Combination vs Single-Agent Chemotherapy
Wagner, et. al. JCO 2006;24:2903
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 7.0 JAMA 1985
26.0 7.0 Cancer 1993
5-FU/cisplatin 20.0 7.2 JCO 2000
25.0 8.6 JCO 2006
34.0 7.3 JCO 2003
51.0 9.0 Cancer 1993adapted 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
# 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
5-FU 800 mg/m2/d x 5
+
cisplatin 20 mg/m2/d x 5
q 4 weeks
105 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
(4 year)
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 2007JCOG 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
q 4 weeks
S-1 40mg/m2 bid d 1-28
q 6 weeks
GASTRIC CANCER 2007JCOG 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 2007JCOG 9912 (Boku, et. al.)
Results
#pts response rate
median
PFS
median
survival
median
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
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 2007JCOG 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.)
S-1 40-60mg bid x 28 days q 5 weeks
S-1 40-60mg bid x 28 days
+
cisplatin 60 mg/m2 d 8 q 5 weeks
GASTRIC CANCER 2007SPIRITS 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.)
Results
# 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
S-1
+
cisplatin
148 54% 6.0 mos 13.0 mos 4.8 mos
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
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%
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
(3 year)
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 2007American 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!