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.
F-F--Ala-Ala
Neuro ToxicityNeuro Toxicity
GI toxicityGI toxicity
Myelo Myelo toxicitytoxicity
5-FU5-FU
Anti-tumorAnti-tumoractivityactivity
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
Background-3Background-3
JCOG9912JCOG9912
5-FU 5-FU
S-1S-1
CPT-11+CDDPCPT-11+CDDP
Non-inferiorityNon-inferiority
Boku et al. ASCO2007 abstract#: LBA4513
Background-4Background-4
S-1+CDDP Phase I/II StudyS-1+CDDP Phase I/II Study1)1)
S-1 40-60mg BID for 3wksS-1 40-60mg BID for 3wks
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
EndpointsEndpoints Primary EndpointPrimary Endpoint
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
142 pts in each arm142 pts in each arm
Inclusion CriteriaInclusion Criteria Histologically confirmed gastric adenocarcinomaHistologically confirmed gastric adenocarcinoma (unresectable/recurrent gastric cancer)(unresectable/recurrent gastric cancer)
No prior chemotherapyNo prior chemotherapy
PS (ECOG scale) 0-2PS (ECOG scale) 0-2
Age 20-74Age 20-74
Expected survival > 3 monthsExpected survival > 3 months
Adequate organ functionAdequate organ function (bone marrow, liver, renal function)(bone marrow, liver, renal function)
Written informed consentWritten informed consent
Patient Characteristics -1Patient Characteristics -1
Randomized : 305 pts (S-1/S-1+CDDP : 152/153)Randomized : 305 pts (S-1/S-1+CDDP : 152/153) between Mar/2002 and Nov/2004between Mar/2002 and Nov/2004
FAS : 298 pts (S-1/S-1+CDDP : 150/148)FAS : 298 pts (S-1/S-1+CDDP : 150/148)
No. of ptsNo. of pts S-1S-1 S-1+CDDPS-1+CDDP P-valueP-value
Gender M / F Gender M / F 116 / 34116 / 34 108 / 40108 / 40 0.42230.4223
Age, yearsAge, years
Median (range)Median (range) 62.0 (28 – 74)62.0 (28 – 74) 61.5 (33 – 74)61.5 (33 – 74) 0.89330.8933
ECOG PS, 0 / 1 / 2ECOG PS, 0 / 1 / 2 106 / 39 / 5106 / 39 / 5 106 / 38 / 4106 / 38 / 4 0.83470.8347
Primary lesionPrimary lesion
- / +- / + 58 / 9258 / 92 53 / 9553 / 95 0.63320.6332
Patient Characteristics -2Patient Characteristics -2
No. of ptsNo. of pts S-1S-1 S-1+CDDPS-1+CDDP P-valueP-value
DiagnosisDiagnosis UnresectableUnresectable RecurrentRecurrent
1191193131
1181183030
1.00001.0000
Adjuvant chemotherapyAdjuvant chemotherapy - / +- / + 23 / 823 / 8 20 / 1020 / 10 0.80690.8069
HistologyHistology Diffuse Diffuse IntestinalIntestinal UnknownUnknown
8989606011
103103454500
0.07890.0789
No. of organs involvedNo. of organs involved 1 / 2 / 1 / 2 / >>33 39 / 54 / 5739 / 54 / 57 41 / 36 / 7141 / 36 / 71 0.07570.0757
Metastasis of peritoneumMetastasis of peritoneum
- / +- / + 114 / 36114 / 36 97 / 5197 / 51 0.05600.0560
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54
MonthsMonths
Est
imat
ed p
roba
bilit
y E
stim
ated
pro
babi
lity
(%)
(%)
11.011.0 13.013.0
Overall SurvivalOverall SurvivalS-1S-1 S-1+CDDPS-1+CDDP
No. of ptsNo. of pts 150150 148148MST MST 11.011.0 13.013.0
1 yr survival1 yr survival 46.7 %46.7 % 54.1 %54.1 %2 yr survival2 yr survival 15.3 %15.3 % 23.6 %23.6 %
Log-rank p-value:Log-rank p-value: 0.0366 0.0366HR: HR: 0.774 0.774 [ 95% CI: 0.608 – 0.985][ 95% CI: 0.608 – 0.985]Median follow-up time (M): Median follow-up time (M): 34.634.6
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54
Progression-Free SurvivalProgression-Free Survival
Log-rank p-value: Log-rank p-value: <0.0001<0.0001HR:HR: 0.5670.567 [ 95% CI: 0.437 – 0.734] [ 95% CI: 0.437 – 0.734]
Est
imat
ed p
roba
bilit
y E
stim
ated
pro
babi
lity
(%)
(%)
MonthsMonths
6.06.04.04.0
S-1S-1 S-1+CDDPS-1+CDDP
No. of ptsNo. of pts 150150 148148PFSPFS 4.04.0 6.06.0
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9
Time to Treatment FailureTime to Treatment Failure
Log-rank p-value: Log-rank p-value: 0.00890.0089HR:HR: 0.6990.699 [ 95% CI: 0.536 – 0.912] [ 95% CI: 0.536 – 0.912]
Est
imat
ed p
roba
bilit
y E
stim
ated
pro
babi
lity
(%)
(%)
MonthsMonths
4.84.83.93.9
S-1S-1 S-1+CDDPS-1+CDDP
No. of ptsNo. of pts 150150 148148TTFTTF 3.93.9 4.84.8
Overall ResponseOverall Response
No. No. ResponseResponse
Overall RR Overall RR CRCR PRPR SDSD PDPD NENE
S-1 S-1 106106 11 3232 3434 3434 55 31 %31 %S-1+CDDPS-1+CDDP 8787 11 4646 1313 2424 33 54 %54 %
Criteria : RECIST (Extramural Review)Criteria : RECIST (Extramural Review)
Fisher’s Exact Test p-value: Fisher’s Exact Test p-value: 0.00180.0018
Adverse Drug Reactions-1Adverse Drug Reactions-1S-1S-1
N = 150N = 150S-1+CDDPS-1+CDDP
N = 148N = 148
All Gr.All Gr.N (%)N (%)
Gr. 3/4Gr. 3/4N (%)N (%)
All GrAll Gr..N (%)N (%)
Gr. 3/4Gr. 3/4N (%)N (%)
Haematological Haematological
LeucopeniaLeucopenia 57 (38)57 (38) 3 (2)3 (2) 104 (70)104 (70) 17 (12)17 (12) NeutropeniaNeutropenia 63 (42)63 (42) 16 (11)16 (11) 110 (74)110 (74) 59 (40)59 (40) AnemiaAnemia 49 (33)49 (33) 6 (4)6 (4) 100 (68)100 (68) 38 (26)38 (26) ThrombocytopeniaThrombocytopenia 27 (18)27 (18) 0 (0)0 (0) 72 (49)72 (49) 8 (5)8 (5)Non-haematological Non-haematological
T-bilT-bil 30 (20)30 (20) 2 (1)2 (1) 36 (24)36 (24) 1 (1)1 (1) ASTAST 17 (11)17 (11) 3 (2)3 (2) 15 (10)15 (10) 0 (0)0 (0) ALTALT 14 (9)14 (9) 1 (1)1 (1) 18 (12)18 (12) 0 (0)0 (0) ALPALP 8 (5)8 (5) 1 (1)1 (1) 8 (5)8 (5) 1 (1)1 (1) CreatinineCreatinine 3 (2)3 (2) 0 (0)0 (0) 32 (22)32 (22) 0 (0)0 (0)
Criteria : NCI-CTC ver. 2.0Criteria : NCI-CTC ver. 2.0
Adverse Drug Reactions-2Adverse Drug Reactions-2S-1S-1
N = 150 N = 150 S-1+CDDPS-1+CDDP
N = 148 N = 148
All Gr.All Gr.N (%)N (%)
Gr. 3/4Gr. 3/4N (%)N (%)
All Gr.All Gr.N (%)N (%)
Gr. 3/4Gr. 3/4N (%)N (%)
GeneralGeneral FatigueFatigue 49 (33)49 (33) 2 (1)2 (1) 84 (57)84 (57) 6 (4)6 (4)GastrointestinalGastrointestinal AnorexiaAnorexia 55 (37)55 (37) 9 (6)9 (6) 107 (72)107 (72) 45 (30)45 (30) NauseaNausea 39 (26)39 (26) 2 (1)2 (1) 99 (67)99 (67) 17 (12)17 (12) VomitingVomiting 21 (14)21 (14) 3 (2)3 (2) 54 (37)54 (37) 6 (4)6 (4) DiarrheaDiarrhea 34 (23)34 (23) 5 (3)5 (3) 51 (35)51 (35) 6 (4)6 (4) StomatitisStomatitis 32 (21)32 (21) 0 (0)0 (0) 43 (29)43 (29) 1 (1)1 (1)SkinSkin PigmentationPigmentation 60 (40)60 (40) 0 (0)0 (0) 53 (36)53 (36) 0 (0)0 (0) RashRash 28 (19)28 (19) 2 (1)2 (1) 32 (22)32 (22) 3 (2)3 (2) Hand-foot syndromeHand-foot syndrome 18 (12)18 (12) 0 (0)0 (0) 14 (10)14 (10) 0 (0)0 (0)
No treatment-related death was observedNo treatment-related death was observedCriteria : NCI-CTC ver. 2.0Criteria : NCI-CTC ver. 2.0
Phase III trials in AGCPhase III trials in AGCGroupGroup regimenregimen ptspts RRRR
(%)(%)PFSPFS(M)(M)
OSOS(M)(M)
P valueP value(OS)(OS)
SPIRITSSPIRITS S-1S-1S-1+CDDPS-1+CDDP
150150148148
31315454
4.04.06.06.0
11.011.013.013.0 0.03660.0366
E Van Cutsem, et alE Van Cutsem, et al1)1)
(2006)(2006)CFCF
DCFDCF224224
2212212525
37373.7*3.7*
5.6*5.6*8.68.6
9.29.20.020.02
D Cunningham, et alD Cunningham, et al2)2)
(2006)(2006)
ECFECF
EOFEOF
ECXECX
EOXEOX
263263
245245
250250
244244
4141
4242
4646
4848
6.26.2
6.56.5
6.76.7
7.07.0
9.99.9
9.39.3
9.99.9
11.211.2
NSNS
YK Kang, et alYK Kang, et al3)3)
(2006)(2006)FPFP
XPXP137137
1391392929
41415.05.0
5.65.69.39.3
10.510.5NSNS
*TTP
3) Proc ASCO 2006; Vol 24, No. 18S: LBA40181) J Clin Oncol 2006; 24: 4991 – 49972) Proc ASCO 2006; Vol 24, No. 18S: LBA4017
ConclusionsConclusions
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
AcknowledgementsAcknowledgementsParticipating Inst.Participating Inst.
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.