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slide1

Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer: A randomized phase III trial of intraperitonealcisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)(AMC 0101) (NCT00296322)

Yoon-Koo Kang, Heung-Moon Chang, Dae Young Zang,

Jae-Lyun Lee, Tae Won Kim, Dae Hyun Yang, Se Jin Jang,

Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim

Asan Medical Center, Seoul, Hallym University Hospital, Anyang, Korea

disclosure
Disclosure
  • Yoon-Koo Kang, M.D., Ph.D.
  • I have no relevant relationships to disclose.
slide4
Mitomycin-C based adjuvant chemotherapy: shown effective in a meta-analysis of 10 studies conducted in Japan in 1960s – 1980s

Nakajima, et al. Gan To Kagaku Ryoho 1994

mmc short term oral fluoropyrimidine effective adjuvant chemotherapy for agc
MMC + short-term oral fluoropyrimidine: effective adjuvant chemotherapy for AGC

Tegafur 400 mg po bid

for 3 months

MMC 20 mg/m2 iv

R

None

N=148

Stage III

Ciera, et al. J Clin Oncol 1999

to improve adjuvant chemotherapy with mmc short term oral fluoropyrimidine
To improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidine
  • Add cisplatin
  • Prolong the administration of low dose oral fluoropyrimidine
slide7

AMC0201

Curatively Resected PS II – IV(M0) Gastric Cancer

3-6 weeks after surgery

RANDOMIZATION

Stratified by center, stage

MFP arm

Mf arm

MMC

MMC

CDDP

DFUR

DFUR

CDDP

DFUR

DFUR

CDDP

DFUR

DFUR

CDDP

DFUR

CDDP

DFUR

CDDP

DFUR

MMC 20 mg/m2 iv

DFUR 460 – 600 mg/m2 po daily

Cisplatin 60 mg/m2 iv D1 every 4 weeks

DFUR

DFUR

DFUR

DFUR

DFUR

DFUR

DFUR

Kang, et al. 2008 ASCO-GI

Chang, etal. 2008 ASCO Abst #4531

to improve adjuvant chemotherapy with mmc short term oral fluoropyrimidine1
To improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidine
  • Add cisplatin
  • Prolong the administration of low dose oral fluoropyrimidine
  • Early start of chemotherapy
  • Intraperitoneal chemotherapy
    • For cases with gross serosa involvement
objectives of the study amc 0101
Objectives of the study (AMC 0101)
  • To determine if addition of these 4 strategies can improve the outcome of adjuvant chemotherapy with mitomycin-C plus short-term oral fluoropyrimidine (Mf) in patients with grossly serosa positive AGC
    • Primary endpoint: RFS
    • Secondary endpoints: OS, safety
eligibility criteria
Eligibility criteria
  • Histologically proven gastric adenocarcinoma
  • Curative gastrectomy with D2 dissection
  • Gross involvement of serosa
  • Age 18 – 70 years
  • No prior chemotherapy
  • No contraindication for chemotherapy
  • Informed consent
slide11

Treatment Schema

Grossly Serosa(+), Non-Metastatic Gastric Cancer

At surgery

RANDOMIZATION

Stratified by center

iceMFP arm

Mf arm

100 mg for 2h

before closure

Intraperitoneal CDDP

3 - 6 weeks

after surgery

MMC

15 mg/m2 iv D1

Stage I,

IV(M1)

MMC

4 weeks later

20 mg/m2 iv

Protocol off

CDDP

DFUR

DFUR

CDDP

DFUR

DFUR

CDDP

DFUR

DFUR

CDDP

DFUR

CDDP

DFUR

CDDP

DFUR

DFUR

DFUR

DFUR 460 – 600 mg/m2 po daily

Cisplatin 60 mg/m2 iv D1 every 4 weeks

DFUR

DFUR

DFUR

DFUR

DFUR

sample size calculation
Sample size calculation
  • Primary endpoint = 3yRFSR
  • Estimated 3yRFSR for Mf = 55%
  • Improvement of 3yRFSR to 67.5% by iceMFP
  • HR = 0.6574
  • Two-sided a=0.05, b=0.2
  • Considering 10% of FU loss
  • Total 527 patients (192 events) are needed
interim analysis
Interim analysis
  • In Feb 2004
  • Increased the dose of doxifluridine
    • To 600 mg/m2/d because of good safety
study summary
Study summary
  • Accrual period: Oct 2001 - Apr 2007
  • Total patients entered: 640
    • 119 (60 in Mf, 59 in iceMFP) excluded after surgery because of stage I (90), IV (M1) (13), positive RM (10), others (6)
  • Total patients analyzed: 521
  • Final analysis: Mar 2008
  • Follow-up, median: 3.5 years
  • Total events: 229 (planned 192)
    • For HR = 0.6574 (3yRFSR 55% vs 67.5%)
    • Power = 0.8785
recurrence free survival
Recurrence Free Survival

1.00

0.75

Recurrence free proportion

0.50

0.25

HR 0.695 [ 95% C.I.: 0.536 - 0.902 ]

P = 0.006 by log-rank test

0

0

12

24

36

48

60

72

months after randomization

slide18

RFS: Subgroup analysis

Subgroup N H.R. (95% C.I.)

Favor iceMFP

Favor Mf

overall survival
Overall Survival

1.00

0.75

Surviving proportion

0.50

0.25

HR 0.710 [ 95% C.I.: 0.531-0.950 ]

P = 0.02 by log-rank test

0

0

12

24

36

48

60

72

months after randomization

dose of doxifluridine 460 vs 600 mg m 2 d

1.0

0.8

0.6

Surviving proportion

0.4

460 mg/m2/d

600 mg/m2/d

460 mg/m2/d

600 mg/m2/d

1.0

0.2

0.8

0.0

0

12

24

36

48

60

72

0.6

Months

Recurrence free proportion

0.4

0.2

0.0

0

12

24

36

48

60

72

Months

Dose of doxifluridine460 vs. 600 mg/m2/d

RFS

OS

conclusion
Conclusion
  • Postoperative iceMFP chemotherapy was safe and could significantly improve the RFS and OS in patients with grossly serosa-positive AGC, compared with Mf chemotherapy.
  • Considering no benefit of adding cisplatin and prolongation of oral doxifluridine to Mf chemotherapy in curatively resected AGC patients (AMC 0201), early start of chemotherapy and/or intraperitoneal cisplatin seemed to be responsible for the improved efficacy of iceMFP chemotherapy in this study.
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