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!