Randomized phase III study of S-1 alon Randomized phase III study of S-1 alon e versus S-1 + cisplatin in the treatm e versus S-1 + cisplatin in the treatm ent of advanced gastric cancer ent of advanced gastric cancer ( ( The SPIRITS trial The SPIRITS trial ) ) SPIRITS: SPIRITS: S S -1 plus cis -1 plus cis p p latin vs S-1 latin vs S-1 i i n n R R C C T T i i n the n the t t reatment of reatment of s s tomach cancer tomach cancer H. Narahara 1 , W. Koizumi 2 , T. Hara 3 , A. Takagane 4 , T. Akiya 5 , M. Takagi 6 , K. Miyashita 7 , T. Nishizaki 8 , O. Kobayashi 9 , S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group; 1 Osaka Medical Center for Cancer and CV Diseases, Osaka, JAPAN, 2 Kitasato University East Hospital, Kanagawa, JAPA N, 3 Kouseiren Takaoka Hospital, Toyama, JAPAN, 4 Iwate Med ical University, Iwate, JAPAN, 5 Gunma Prefectural Cancer Center, Gunma, JAPAN, 6 Shizuoka General Hospital, Shizuok a, JAPAN, 7 National Hospital Organization Nagasaki Medica l Center, Nagasaki, JAPAN, 8 Matsuyama Red Cross Hospital, Ehime, JAPAN, 9 Kanagawa Cancer Center, Kanagawa, JAPAN.
Transcript
Randomized phase III study of S-1 alone versus Randomized phase III study of S-1 alone versus S-1 + cisplatin in the treatment of advanced gastS-1 + cisplatin in the treatment of advanced gast
ric cancer ric cancer
((The SPIRITS trialThe SPIRITS trial) )
SPIRITS: SPIRITS: SS-1 plus cis-1 plus cispplatin vs S-1 latin vs S-1 iin n RRCT CT iin the n the ttreatment of reatment of sstomach cancertomach cancer
H. Narahara1, W. Koizumi2, T. Hara3, A. Takagane4, T. Akiya5, M. Takagi6, K. Miyashita7, T. Nishizaki8, O. Kobayashi9,
S-1 Advanced Gastric Cancer (AGC) Clinical Trial Group;
1Osaka Medical Center for Cancer and CV Diseases, Osaka, JAPAN, 2Kitasato University East Hospital, Kanagawa, JAPAN, 3Kouseiren Takaoka Hospital, Toyama, JAPAN, 4Iwate Medical University, Iwate, JAPAN, 5Gunma Prefectural Cancer Center, Gunma, JAPAN, 6Shizuoka General Hospital, Shizuoka, JAPAN, 7National Hospital Organization Nagasaki Medical Center, Nagasaki, JAPAN, 8Matsuyama Red Cross Hospital,Ehime, JAPAN, 9Kanagawa Cancer Center, Kanagawa, JAPAN.
Background-1Background-1 S-1 is :S-1 is : an oral fluoropyrimidine widely used for AGC in Japan.an oral fluoropyrimidine widely used for AGC in Japan. an oral formulation of Tegafur, CDHP, and Oxo at a molaran oral formulation of Tegafur, CDHP, and Oxo at a molar ratio 1:0.4:1.ratio 1:0.4:1. observed high RR and MST of 44-49 % and 207-250 days observed high RR and MST of 44-49 % and 207-250 days in two independent phase II trialsin two independent phase II trials1,21,2
1: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-71: Y Sakata et al. Eur J Cancer 1998; 34: 1715-1720 2: W Koizumi et al. Oncology 2000; 58: 191-7
DPDDPD
TegafurTegafur
CDHPCDHP
OPRTOPRT
OxoOxo
inhibitinhibit inhibitinhibit
Background-2
regimenregimen ptspts RRRR(%)(%)
PFSPFS(M)(M)
OSOS(M)(M)
P value(OS)P value(OS)
5FU5FUUFT+MMCUFT+MMC
5FU+CDDP(FP)5FU+CDDP(FP)
1051057070
105105
11.411.48.68.6
34.334.3
1.91.92.42.43.93.9
7.17.16.06.07.37.3
NS
JCOG9205JCOG92051)1)
1): A. Ohtsu et al. J Clin Oncol 2003; 21:54-591): A. Ohtsu et al. J Clin Oncol 2003; 21:54-59
FP arm demonstrated significantly longer PFS FP arm demonstrated significantly longer PFS than 5FU arm. (P<0.001)than 5FU arm. (P<0.001)
There were no significant differences between There were no significant differences between the arms with respect to OSthe arms with respect to OS
In Japan, recommended regimen for AGC was In Japan, recommended regimen for AGC was 5-FU alone5-FU alone
Day 1Day 1 Day 8Day 8 Day 15Day 15 Day 22Day 22 Day 29Day 29 Day 36Day 36
CDDP 60mg/mCDDP 60mg/m22 on Day 8 on Day 8
S-1S-1
regimenregimen PtsPts(RD)(RD)
RRRR(%)(%)
TTPTTP(Day)(Day)
MSTMST(Day)(Day)
S-1+CDDPS-1+CDDP 2525 76.076.0 162162 383383
1: W Koizumi et al. Br J Cancer 2003; 89:2207-22121: W Koizumi et al. Br J Cancer 2003; 89:2207-2212
Dosage of S-1 was based on patient’s body surface area (BSA)Dosage of S-1 was based on patient’s body surface area (BSA) BSA < 1.25 : 40 mg BIDBSA < 1.25 : 40 mg BID 1.25 - < 1.50 : 50 mg BID1.25 - < 1.50 : 50 mg BID 1.50 - < BSA : 60 mg BID1.50 - < BSA : 60 mg BID
Study DesignStudy Design
AGCAGC
No priorNo priorChemo.Chemo.
RR
S-1 aloneS-1 aloneS-1: 40-60 mg BID for 28 days q6wksS-1: 40-60 mg BID for 28 days q6wks
S-1 + CDDPS-1 + CDDPS-1: 40-60 mg BID for 21 days q5wksS-1: 40-60 mg BID for 21 days q5wksCDDP: 60 mg/mCDDP: 60 mg/m22 iv on day 8 iv on day 8
Central RandomizationCentral Randomization (dynamic balancing)(dynamic balancing)Adjustment Factors:Adjustment Factors: InstituteInstitute PSPS Unresectable vs RecurrentUnresectable vs Recurrent
Overall SurvivalOverall Survival• Estimated OS (S-1/S-1+CDDP) : 8/12 monthsEstimated OS (S-1/S-1+CDDP) : 8/12 months• N=142 in each arm for 90% power to establish N=142 in each arm for 90% power to establish superiority in OS (Two-sided log-rank superiority in OS (Two-sided log-rank =0.05).=0.05).• Follow up: 2 yearsFollow up: 2 years
Secondary EndpointsSecondary Endpoints Progression Free SurvivalProgression Free Survival Time to Treatment FailureTime to Treatment Failure Overall ResponseOverall Response SafetySafety
The OS ofThe OS of S-1+CDDP is superior to S-1 aloneS-1+CDDP is superior to S-1 alone
The median survival time of S-1 was 11.0 M11.0 M,, moreover, that of S-1+CDDP was 13.0 M13.0 M
S-1+CDDP is well tolerated and no treatment- related death was observed
S-1+CDDP regimen can be regarded as the first-line standard treatment for AGC
Future PerspectivesFuture Perspectives
In RedIn Red : FP vs : FP vs S-1+CDDPS-1+CDDP (FLAGS: on-going) (FLAGS: on-going) In YellowIn Yellow : S-1 vs : S-1 vs S-1+CDDPS-1+CDDP (SPIRITS) (SPIRITS)
In near future, the clinical characteristics of In near future, the clinical characteristics of S-1+CDDP for AGC will become clear S-1+CDDP for AGC will become clear
Kitasato University East HospitalOsaka Medical Center for Cancer and CV DiseasesKouseiren Takaoka HospitalIwate Medical UniversityGunma Prefectural Cancer CenterShizuoka General HospitalNational Hospital Organization Nagasaki Medical CenterMatsuyama Red Cross HospitalKanagawa Cancer Center (Department of Gastrointestinal Surgery)Hiroshima City Asa HospitalNational Hospital Organization Kyushu Cancer CenterAso Iizuka HospitalKanagawa Cancer Center(Department of Gastroenterology)Aichi Cancer CenterWakayama Medical UniversitySaga Prefectural Hospital KOSEIKANNational Hospital Organization Tokyo Medical Center
Osaka Saiseikai Nakatsu HospitalAichi Cancer Center Aichi HospitalThe Fraternity Memorial HospitalUniversity of Tokai School of MedicineGifu Municipal HospitalToranomon HospitalKumamoto Rosai Hospital Showa University Northern Yokohama HospitalKobe City Medical Center General Hospital Kawaguchi Municipal Medical CenterNara Prefectural Nara Hospital Chikushi Hospital, Fukuoka University Kanto Medical Center, NTT ECKyoto UniversityKinki University School of MedicineYamagata Prefectural Central HospitalNational Hospital Organization Fukuoka-Higashi Medical CenterKouri Hospital, Kansai Medical UniversitySendai Kousei HospitalTokyo Women's Medical University Medical Center EastKokura Memorial HospitalNiigata City General Hospital
This study was sponsored by TAIHO Pharmaceutical, co. ltd.This study was sponsored by TAIHO Pharmaceutical, co. ltd.
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