Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer:

A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term

doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short-term doxifluridine (Mf)

(AMC 0101) (NCT00296322)

Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer:

A randomized phase III trial of intraperitoneal cisplatin 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.

Meta-analyses suggested small but significant benefit of adjuvant chemotherapy in AGC

Meta-analyses suggested small but significant benefit of adjuvant chemotherapy in AGC

Author Journal No. of

Study

No. of

Pts

O.R. for death

(95% C.I.)

Hermans JCO 1993 11 2,096 0.88 ( 0.78 – 1.08 )

Earle Eur J Cancer 1999 13 1,990 0.80 ( 0.66 – 0.97 )

Mari Ann Oncol 2000 21 3,658 0.82 ( 0.75 – 0.89 )

Janunger Eur J Surg 2002 20 3,962 0.84 ( 0.74 – 0.96 )

Panzini Tumori 2002 17 3,118 0.72 ( 0.62 – 0.84 )

O.R.=odds ratio, C.I.=confidence interval

Mitomycin-C based adjuvant chemotherapy : shown effective in a meta-analysis of 10 studies

conducted in Japan in 1960s – 1980s

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

Ciera, et al. J Clin Oncol 1999

N 5yDFSR 5yOSR

Treatment 76 55% 56%

Control 72 31% 36%

R

N=148Stage III

MMC 20 mg/m2 ivTegafur 400 mg po bid

for 3 months

None

To improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidineTo improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidine

• Add cisplatin

• Prolong the administration of low dose oral

fluoropyrimidine

CDDP DFUR

MMC

CDDPCDDP

CDDPCDDP

CDDP

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFUR

MMC

MMC 20 mg/m2 ivDFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks

Curatively Resected PS II – IV(M0) Gastric Cancer

RANDOMIZATION

Mf armMFP arm

Stratified by center, stage

3-6 weeks after surgery

AMC 0201AMC 0201

Kang, et al. 2008 ASCO-GIChang, et al. 2008 ASCO Abst #4531

To improve adjuvant chemotherapy with MMC + short-term oral fluoropyrimidineTo 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 criteriaEligibility 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

Grossly Serosa(+), Non-Metastatic Gastric Cancer

RANDOMIZATION

Intraperitoneal CDDP

MMC

CDDP DFUR

MMC

CDDPCDDP

CDDPCDDP

CDDP

Stage I, IV(M1)

Protocol off

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFURDFUR

DFUR

Mf armMf armiceMFP armiceMFP arm

Stratified by center

Treatment SchemaTreatment Schema

At surgery

DFUR 460 – 600 mg/m2 po daily Cisplatin 60 mg/m2 iv D1 every 4 weeks

100 mg for 2h before closure

15 mg/m2 iv D1

4 weeks later

3 - 6 weeks after surgery

20 mg/m2 iv

Sample size calculationSample size calculation

• Primary endpoint = 3yRFSR

• Estimated 3yRFSR for Mf = 55%• Improvement of 3yRFSR to 67.5% by iceMFP• HR = 0.6574 • Two-sided =0.05, =0.2• Considering 10% of FU loss

• Total 527 patients (192 events) are needed

Interim analysisInterim analysis

• In Feb 2004

• Increased the dose of doxifluridine – To 600 mg/m2/d because of good safety

Study summaryStudy 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

Patients Characteristics (1)Patients Characteristics (1)

Mf iceMFP p-value

Patient No. 258 263

Age (years), median 56 53 0.11

Sex: Male (%) 68.2 66.5 0.68

ECOG PS 0-1 (%) 95.7 94.3 0.45

Primary site (%)

Proximal

Distal

Multiple / diffuse

16.6

80.2

3.2

15.0

83.8

1.2

0.11

Surgery (%)

Total gastrectomy

Distal gastrectomy

54.7

45.3

50.2

49.8

0.31

No. of LNs, median 29 30 0.43

Patients Characteristics (2)Patients Characteristics (2)Mf iceMFP p-value

Overall stage (%)

II

IIIA

IIIB

IV

34.5

31.4

17.1

17.1

32.3

32.3

17.9

17.5

0.96

Pathology, WHO (%)

Tubular adenoca

Signet ring cell ca

Mucinous adenoca

Papillary adenoca

85.7

8.9

4.3

0.4

81.4

13.7

4.6

0.0

0.34

Days to chemo, median 22 1 < 0.0001

Dose of doxifluridine (%)

460 mg/m2/d

600 mg/m2/d

53.9

46.1

52.9

47.1

0.81

Recurrence Free SurvivalRecurrence Free Survival

0 12 24 36 48 60 720

0.25

0.50

0.75

1.00

months after randomization

Rec

urr

ence

fre

e p

rop

orti

on

N Event 3yRFSR 5yRFSR

iceMFP 263 103 60.2% 50.5%

Mf 258 126 50.0% 43.8%

HR 0.695 [ 95% C.I.: 0.536 - 0.902 ]P = 0.006 by log-rank test

0.824 (0.513- 1.323)0.633 (0.461- 0.871)0.894 (0.148- 5.409)

0.398 (0.164- 0.97)0.779 (0.485- 1.25)0.874 (0.565- 1.352)0.401 (0.234- 0.687)

0.494 (0.298- 0.818)0.702 (0.504- 0.977)

0.695 (0.536- 0.902)

0.747 (0.543- 1.027)0.606 (0.384- 0.956)

0.629 (0.439- 0.901)0.754 (0.516- 1.101)

0.662 (0.472- 0.929)0.728 (0.483- 1.098)

0.553 (0.394- 0.776)0.977 (0.644- 1.481)

0.677 (0.372- 1.23)0.665 (0.425- 1.039)1 (0.567- 1.762)0.427(0.252- 0.724)

0.65 (0.352- 1.201)0.73 (0.457- 1.167)0.774 (0.516- 1.16)

T stage pT2 193 pT3 316 pT4 11

N stage pN0 63 pN1 227 pN2 148 pN3 83

Lauren classification Intestinal 161 Diffuse 301

Total 521

Sex Male 351 Female 170

Age < 55 yr 260 > 55 yr 261

Dose of doxifluridine

460 mg/ m2/ day 278

600 mg/ m2/ day 243

Type of surgery Total gastrectomy 273 Distal gastrectomy 248

TNM stage II 174 IIIA 166 IIIB 93 IV 90

Primary site Upper 1/ 3 79 Middle 1/ 3 180 Lower 1/ 3 230

0.0 0.5 1.0 1.5 2.0

RFS: Subgroup analysisRFS: Subgroup analysis

Favor iceMFP Favor Mf

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

Overall SurvivalOverall Survival

0 12 24 36 48 60 720

0.25

0.50

0.75

1.00

months after randomization

Su

rviv

ing

pro

por

tion

N Event 3yOSR 5yOSR

iceMFP 263 82 71.2% 56.2%

Mf 258 103 59.6% 47.0%

HR 0.710 [ 95% C.I.: 0.531-0.950 ]P = 0.02 by log-rank test

Dose of doxifluridine460 vs. 600 mg/m2/d

Dose of doxifluridine460 vs. 600 mg/m2/d

RFS OS

460 mg/m2/d600 mg/m2/d

460 mg/m2/d600 mg/m2/d

0 12 24 36 48 60 72

Months

0.0

0.2

0.4

0.6

0.8

1.0

Re

cu

rre

nc

e f

ree

pro

po

rtio

n

0 12 24 36 48 60 72Months

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

ing

pro

po

rtio

n

Surgery related complicationsSurgery related complications Mf

(N=258)

iceMFP

(N=263)

Total

(N=521)

Wound problem 11 9 20

Ileus

Immediate postop

Adhesive

2

7

0

10

2

17

Intraabdominal abscess 12 3 15

Bleeding

Intraluminal

Intraperitoneal

0

1

2

0

2

1

Anastomotic leakage 0 2 2

Anastomotic stenosis 1 0 1

Pneumonia 1 0 1

Others 1 1 2

RecurrencesRecurrences

P=0.02

Toxicities of chemotherapyGrade 3 & 4 (%)

Toxicities of chemotherapyGrade 3 & 4 (%)

• 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.

ConclusionConclusion

AcknowledgementsAcknowledgementsAsan Medical Center Hallym University

HospitalLife Stat Korea

Yoon-Koo Kang Byung Sik Kim Dae Young Zang Young Jack Lee

Tae-Won Kim Sung Tae Oh Dae Hyun Yang Ik Seong Choi

Heung-Moon Chang Jeong Hwan Yook Se Won Hwang Young Chol Lee

Min-Hee Ryu Su Mi Park

Jae-Lyun Lee Yeon Hong Seo

Se Jin Jang Young Ae Kim

Eun Mi Kim