A Safety and Efficacy Study in Patients With Gastric Cancer

• Sponsor: Taiho Oncology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00400179
• Collaborator: Quintiles, Inc. (Industry)
• Enrollment: 1,053
• Locations: 33
• Arms: 2
• Duration (Months): 35
• Patients Per Site: 31.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is an open-label, international, two-arm, parallel, randomized, Phase 3 study evaluating the efficacy and safety of S-1/cisplatin versus 5-FU/cisplatin in patients with advanced gastric cancer previously untreated with chemotherapy for advanced disease. Patients will be randomly assigned (1:1) to S-1/cisplatin (experimental arm) or 5-FU/cisplatin (control arm). Patients will be stratified by number of metastatic sites (one vs. more than one), locally advanced or metastatic disease, prior adjuvant therapy (yes or no), measurable or non-measurable disease, and center.

Condition or Disease	Intervention/Treatment	Phase
Gastric Cancer	Drug: S-1/Cisplatin; Drug: 5-FU/cisplatin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1053 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Multicenter, Randomized, Phase 3 Study of S-1 in Combination With Cisplatin Against 5-Fu in Combination W/ Cisplatin in Patients W/ Advanced Gastric Cancer Previously Untreated W/ Chemotherapy for Advanced Disease
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Apr 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A In Arm A, S-1 25 mg/m² was administered orally BID from Day 1 through Day 21 followed by a recovery period from Days 22 through Day 28. On Day 1, the morning dose of S-1 was administered before cisplatin 75 mg/m2 administration as a 1- to 3-hour IV infusion. This regimen was repeated every 4 weeks. S-1 was administered one hour before or one hour after a meal with a glass of water (approximately 100 mL).	Drug: S-1/Cisplatin; In Arm A, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth (NPO 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with approximately 8 ounces of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour IV infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.
Active Comparator: B In Arm B, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion (CIV) over 120 hours (on Days 1 through 5). This regimen was repeated every 4 weeks. 5-FU CIV followed cisplatin infusion on Day 1. All 5-FU used in this study was commercially available product.	Drug: 5-FU/cisplatin; In Arm B, 5-FU 1000 mg/m2/24 hours was administered CIV on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.

Outcome Measures

Primary Outcome Measures

1. Median Survival [The cutoff date for survival analysis was 07 March 2008 (12 months after last patient randomized).]

   Survival was defined as the time from the date of randomization to the time of death (from any cause) for each patient.

Secondary Outcome Measures

1. Overall Response Rate (ORR) [Data cutoff was 07 March 2008 (12 months after last patient randomized).]

   The proportion of patients with objective evidence of complete response (CR) or partial response (PR) based on tumor response assessments. Per the Response Evaluation Criteria in Solid tumors (RECIST), CR was defined as the disappearance of all target lesions for at least 4 weeks, and PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions.

2. Duration of Response (DR) [Data cutoff was 07 March 2008 (12 months after last patient was randomized).]

   Duration of response was defined as the time from date of first confirmed response (CR or PR) to date of first progressive disease (PD) or death. Per the RECIST criteria, definitions were as follows: CR was the disappearance of all target lesions for at least 4 weeks, PR was at least a 30% decrease in the sum of the longest diameter of target lesions, and PD was at least a 20% increase in the sum of the longest diameter of target lesions.

3. Progression-free Survival (PFS) [From date of randomization until date of first documented PD, date of death, or until data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first.]

   The time from randomization to date of first documented PD or date of death, whichever occurred first.

4. Time to Treatment Failure (TTF) [From date of randomization until date of permanent discontinuation of S-1 or 5-FU, first documented PD, death, or data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first.]

   The time from randomization to date of permanent discontinuation of S-1 or 5-FU, first documented PD, or death, whichever occurred first.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

A patient must meet all of the following inclusion criteria to be eligible for enrollment in this study:

• Has given written informed consent

• Has histologically confirmed, unresectable, locally advanced (Stage IV) or metastatic gastric cancer, including adenocarcinoma of the gastro-esophageal junction

• Has measurable or evaluable but non-measurable disease, defined as follows:

• Measurable Disease - Patients with measurable disease as defined by RECIST criteria, i.e., the presence of at least one measurable lesion. A measurable lesion is one that can be accurately measured in at least one dimension with the longest diameter >_ 20 mm using conventional techniques or >_ 10 mm using spiral Computed Tomography (CT)scan. Locally recurrent disease (other than primary) is accepted if there is at least one measurable lesion (i.e. peritoneal mass, lymph node, etc.)

• Evaluable but Non-measurable Disease - Patients with all lesions below the limits defined above for measureable disease (i.e., longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT) excluding those patients with only a primary lesion and/or with only non-evaluable cancer such as bone metastases, ascites, pleural or pericardia effusions, lymphangitic carcinomatosis of the skin or lung, previously irradiated lesions not in progression, or peritoneal carcinomatosis < 10 mm in diameter with conventional imaging techniques.

• No prior palliative chemotherapy is permitted. Adjuvant and /or neo-adjuvant chemotherapy is permitted if more than 12 months have elapsed between the end of adjuvant or neo-adjuvant therapy and first recurrence. This does not qualify as 1st line therapy.

• Is able to take medications orally

• Is >_ 18 years of age

• Is at least 3 weeks from prior major surgery

• Is at least 4 weeks from prior radiotherapy

• Has a ECOG performance status 0 to 1

• Has adequate organ function as defined by the following criteria:

• AST (SGOT) and ALT (SGPT) <_ 2.5 x ULN; if liver function abnormalities are due to underlying liver metastasis, AST (SGOT) and ALT (SGPT) <_ 5 x ULN

• Total serum bilirubin of <_ 1.5 x ULN

• Absolute granulocyte count of >_ 1,500/mm (i.e. >_ 1.5 x 10/L by International Units (IU)

• Platelet count >_ 100,000/mm (IU: >_ 100 x 10/L

• Hemoglobin value of >_ 9.0 g/dL

• Calculated creatinine clearance >_ 60 mL/min (Cockcroft-Gault formula)

• Is willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures

Exclusion Criteria:

Exclude a patient from this study if he/she does not fulfill the inclusion criteria, or if any of the following conditions are observed:

• Has had a treatment with any of the following within the specified timeframe prior to study drug administration:

• Any prior palliative chemotherapy or any previous therapy for malignancy, including any chemotherapy, immunotherapy, biologic or hormonal therapy, within the past 5 years.

• Adjuvant or neo-adjuvant therapy within the past 12 months

• Concurrent treatment with any investigational anti-cancer agent

• Prior cisplatin as neo-adjuvant and /or adjuvant chemotherapy with cumulative dose > 300 mg/m

• 25% of marrow-bearing bone radiated

• Concurrent treatment with an investigational agent or within 30 days from randomization

• Concurrent enrollment in another clinical study

• Has a serious illness or medical condition(s) including, but not limited to the following:

• Known brain or leptomeningeal metastases

• Uncontrolled ascites requiring drainage at least twice a week

• Other malignancies within the past 5 years, except adequately treated carcinoma-in-situ of the cervix or non-melanoma skin cancer

• Myocardial infarction within the last 6 months, severe/unstable angina, congestive heart failure New York Heart Association (NYHA) class III or IV

• Chronic nausea, vomiting or diarrhea

• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS-related illness

• Psychiatric disorder that may interfere with consent and/or protocol compliance

• Known neuropathy, Grade 2 or higher

• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgement of the Investigator would make the patient inappropriate for entry into this study

• Is receiving concomitant treatment with drugs interacting with S-1. The following drugs are prohibited because there may be an interaction with S-1:

• Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole (may enhance S-1 activity)

• Allopurinol (may diminish S-1 activity

• Phenytoin (S-1 may enhance phenytoin activity)

• Flucytosine, a fluorinated pyrimidine antifungal agent (may enhance S-1 activity)

• Is receiving concomitant treatment with drugs interacting with 5-FU:

• Sorivudine, uracil, cimetidine, folinic acid, and dipyridamole(may enhance 5-FU activity)

• Allopurinol (may diminish 5-FU activity)

• Phenytoin (5-FU may enhance phenytoin activity)

• Is receiving concomitant treatment with drugs interacting with cisplatin:

• Phenytoin (cisplatin may diminish phenytoin activity)

• Aminoglycosides (should be avoided within 8 days after cisplatin administration)

• Ethyol (may diminish cisplatin activity

• Is a pregnant or lactating female

• Has known hypersensitivity to 5-FU or cisplatin

• Patients with reproductive potential who refuse to use an adequate means of contraception (including male patients)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clearview Cancer Center	Huntsville	Alabama	United States	35801
2	Saint Joseph Medical Center	Burbank	California	United States	91505
3	Dr. Ronald Yanagihara	Gilroy	California	United States	95020
4	Norris Cancer Center	Los Angeles	California	United States	90033
5	Comprehensive Cancer Center	Palm Springs	California	United States	92262
6	Saint Francis Memorial Hospital	San Francisco	California	United States	94109
7	Premiere Oncology	Santa Monica	California	United States	90404
8	Western Hematology/Oncology	Lakewood	Colorado	United States	80215
9	Broward Oncology Associates	Fort Lauderdale	Florida	United States	33308
10	Alexandar Rosemurgy	Tampa	Florida	United States	33606
11	Palm Beach Cancer Institute	West Palm Beach	Florida	United States	33401
12	Straub Clinic and Hospital	Honolulu	Hawaii	United States	96813
13	Robert H. Lurie Comprehensive Cancer Center	Chicago	Illinois	United States	60611
14	University of Chicago Medical Center	Chicago	Illinois	United States	60637-1470
15	Oncology and Hematology	Metairie	Louisiana	United States	70006
16	St. Lukes Cancer Care Center	Duluth	Minnesota	United States	55802
17	Neuroscience Center	Saint Louis	Missouri	United States	63110
18	St. Louis University Cancer Center	Saint Louis	Missouri	United States	63110
19	Southern Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
20	AHS Lovelace Medical Group,LLC	Albuquerque	New Mexico	United States	87102
21	New Mexico Cancer Center Associates	Albuquerque	New Mexico	United States	87106
22	University of New Mexico	Albuquerque	New Mexico	United States	87106
23	Hoo Chun, MD	Hawthorne	New York	United States	10532
24	Hematology/Oncology Associates of Rockland	New City	New York	United States	10956
25	New Bern Cancer Care	New Bern	North Carolina	United States	28560
26	Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
27	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
28	Charleston Cancer Center	Charleston	South Carolina	United States	29406
29	Associates in Oncology and Hematology	Chattanooga	Tennessee	United States	37404
30	Lexington Oncology Associates	Chattanooga	Tennessee	United States	37404
31	MD Anderson Cancer Center	Houston	Texas	United States	77030
32	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792
33	CHUM Hopital Saint-Luc	Montreal	Quebec	Canada	H2X3J4

Sponsors and Collaborators

• Taiho Oncology, Inc.
• Quintiles, Inc.

Investigators

• Study Director: Fabio Benedetti, MD, Taiho Oncology, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Taiho Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT00400179
• Other Study ID Numbers: TPU S-1301; NCT00128609
• First Posted: Nov 16, 2006
• Last Update Posted: Aug 14, 2020
• Last Verified: Aug 1, 2020

• Keywords provided by Taiho Oncology, Inc.: Gastric Cancer
• Additional relevant MeSH terms: Stomach Neoplasms; Cisplatin

Study Results

Participant Flow

Recruitment Details	This multicenter study was conducted between May 18, 2005 and March 7, 2008 in 24 countries including the United States. Study centers were also located in Canada, Eastern and Western Europe, South America, Australia, and ex-Soviet Union block of nations.

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
Period Title: Overall Study
STARTED	527	526
COMPLETED	521	508
NOT COMPLETED	6	18

Baseline Characteristics

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin	Total
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.	Total of all reporting groups
Overall Participants	521	508	1029
Age (Years) [Median (Full Range) ]
Baseline Measure Data (descriptive stats, median)	59.0	59.0	59.0
Sex: Female, Male (Count of Participants)
Female	139 26.7%	161 31.7%	300 29.2%
Male	382 73.3%	347 68.3%	729 70.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	4 0.8%	6 1.2%	10 1%
Asian	4 0.8%	4 0.8%	8 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 1%	7 1.4%	12 1.2%
White	447 85.8%	438 86.2%	885 86%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	61 11.7%	53 10.4%	114 11.1%
Body surface area (BSA) Categories (Number) [Number]
</=1.29 m2	4 0.8%	5 1%	9 0.9%
1.30-1.49 m2	46 8.8%	44 8.7%	90 8.7%
1.50-1.69 m2	118 22.6%	147 28.9%	265 25.8%
1.70-1.89 m2	208 39.9%	181 35.6%	389 37.8%
1.90-2.09 m2	114 21.9%	93 18.3%	207 20.1%
2.10-2.29 m2	29 5.6%	34 6.7%	63 6.1%
>/=2.30 m2	2 0.4%	4 0.8%	6 0.6%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Number) [Number]
0	226 43.4%	200 39.4%	426 41.4%
1	295 56.6%	308 60.6%	603 58.6%
Tissue Type (Number) [Number]
Papillary adenocarcinoma	15 2.9%	15 3%	30 2.9%
Tubular adenocarcinoma	132 25.3%	113 22.2%	245 23.8%
Well-differentiated	20 3.8%	17 3.3%	37 3.6%
Moderately-differentiated	105 20.2%	91 17.9%	196 19%
Unknown	7 1.3%	5 1%	12 1.2%
Poorly differentiated adenocarcinoma	210 40.3%	189 37.2%	399 38.8%
Signet-ring cell carcinoma	75 14.4%	95 18.7%	170 16.5%
Mucinous adenocarcinoma	28 5.4%	32 6.3%	60 5.8%
Other	97 18.6%	94 18.5%	191 18.6%
Adenocarcinoma NOS	87 16.7%	87 17.1%	174 16.9%
Poorly differentiated cancer	7 1.3%	2 0.4%	9 0.9%
Unknown/not specified	1 0.2%	1 0.2%	2 0.2%
Other types	2 0.4%	4 0.8%	6 0.6%
Anatomical Location of Primary Lesion (Number) [Number]
Stomach	438 84.1%	417 82.1%	855 83.1%
Gastroesophageal junction	82 15.7%	88 17.3%	170 16.5%
Stomach and gastroesophageal junction	1 0.2%	3 0.6%	4 0.4%
Extent of Disease (Number) [Number]
Locally advanced	23 4.4%	20 3.9%	43 4.2%
1 metastatic site	157 30.1%	161 31.7%	318 30.9%
>/=2 metastatic sites	340 65.3%	327 64.4%	667 64.8%
Not assessed	1 0.2%	0 0%	1 0.1%
Disease Measurability (Number) [Number]
Measureable disease	499 95.8%	485 95.5%	984 95.6%
Non-measurable disease	21 4%	22 4.3%	43 4.2%
Nonevaluable disease	0 0%	1 0.2%	1 0.1%
No disease present	1 0.2%	0 0%	1 0.1%

Outcome Measures

1. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	The proportion of patients with objective evidence of complete response (CR) or partial response (PR) based on tumor response assessments. Per the Response Evaluation Criteria in Solid tumors (RECIST), CR was defined as the disappearance of all target lesions for at least 4 weeks, and PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions.
Time Frame	Data cutoff was 07 March 2008 (12 months after last patient randomized).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
Measure Participants	402	385
Number (95% Confidence Interval) [Percentage of patients in each group]	29.1	31.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-1/Cisplatin, 5-FU/Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3952
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Duration of Response (DR)
Description	Duration of response was defined as the time from date of first confirmed response (CR or PR) to date of first progressive disease (PD) or death. Per the RECIST criteria, definitions were as follows: CR was the disappearance of all target lesions for at least 4 weeks, PR was at least a 30% decrease in the sum of the longest diameter of target lesions, and PD was at least a 20% increase in the sum of the longest diameter of target lesions.
Time Frame	Data cutoff was 07 March 2008 (12 months after last patient was randomized).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
Measure Participants	402	385
Median (95% Confidence Interval) [Months]	6.5	5.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-1/Cisplatin, 5-FU/Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0808
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	The time from randomization to date of first documented PD or date of death, whichever occurred first.
Time Frame	From date of randomization until date of first documented PD, date of death, or until data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
Measure Participants	521	508
Median (95% Confidence Interval) [Months]	4.8	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-1/Cisplatin, 5-FU/Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.9158
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.86 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Time to Treatment Failure (TTF)
Description	The time from randomization to date of permanent discontinuation of S-1 or 5-FU, first documented PD, or death, whichever occurred first.
Time Frame	From date of randomization until date of permanent discontinuation of S-1 or 5-FU, first documented PD, death, or data cutoff on 07 March 2008 (12 months after last patient randomized), whichever came first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
Measure Participants	521	508
Median (95% Confidence Interval) [Months]	3.8	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-1/Cisplatin, 5-FU/Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0320
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.77 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Median Survival
Description	Survival was defined as the time from the date of randomization to the time of death (from any cause) for each patient.
Time Frame	The cutoff date for survival analysis was 07 March 2008 (12 months after last patient randomized).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-1/Cisplatin	5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.	In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
Measure Participants	521	508
Median (95% Confidence Interval) [Months]	8.6	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-1/Cisplatin, 5-FU/Cisplatin
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1983
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From the start of study drug administration until 12 months after last patient randomized
Arm/Group Title	S-1/Cisplatin		5-FU/Cisplatin
Arm/Group Description	In the S-1/cisplatin arm, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with a glass of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour intravenous (IV) infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment.		In the 5-FU/cisplatin arm, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles.
All Cause Mortality
	S-1/Cisplatin		5-FU/Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	S-1/Cisplatin		5-FU/Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	257/521 (49.3%)		248/508 (48.8%)
Blood and lymphatic system disorders
Anaemia	33/521 (6.3%)	37	31/508 (6.1%)	38
Anaemia megaloblastic	1/521 (0.2%)	2	0/508 (0%)	0
Bone marrow failure	1/521 (0.2%)	1	1/508 (0.2%)	1
Disseminated intravascular coagulation	0/521 (0%)	0	1/508 (0.2%)	1
Febrile neutropenia	8/521 (1.5%)	8	31/508 (6.1%)	34
Haemorrhagic anaemia	0/521 (0%)	0	1/508 (0.2%)	1
Haemorrhagic diathesis	0/521 (0%)	0	1/508 (0.2%)	1
Leukopenia	4/521 (0.8%)	4	5/508 (1%)	5
Neutropenia	8/521 (1.5%)	8	31/508 (6.1%)	34
Pancytopenia	2/521 (0.4%)	5	4/508 (0.8%)	4
Thrombocytopenia	11/521 (2.1%)	11	17/508 (3.3%)	18
Cardiac disorders
Acute left ventricular failure	1/521 (0.2%)	1	0/508 (0%)	0
Acute myocardial infarction	3/521 (0.6%)	3	0/508 (0%)	0
Angina pectoris	1/521 (0.2%)	1	2/508 (0.4%)	2
Atrial fibrillation	2/521 (0.4%)	2	1/508 (0.2%)	1
Cardiac Arrest	0/521 (0%)	0	1/508 (0.2%)	1
Cardiac failure	1/521 (0.2%)	1	0/508 (0%)	0
Cardiopulmonary failure	0/521 (0%)	0	2/508 (0.4%)	2
Myocardial infarction	1/521 (0.2%)	1	0/508 (0%)	0
Myocardial ischaemia	0/521 (0%)	0	1/508 (0.2%)	1
Pericardial effusion	1/521 (0.2%)	1	0/508 (0%)	0
Ventricular fibrillation	0/521 (0%)	0	1/508 (0.2%)	1
Ventricular tachycardia	0/521 (0%)	0	1/508 (0.2%)	1
Ear and labyrinth disorders
Deafness	0/521 (0%)	0	1/508 (0.2%)	1
Hypoacusis	0/521 (0%)	0	1/508 (0.2%)	1
Endocrine disorders
Adrenal haemorrhage	1/521 (0.2%)	1	0/508 (0%)	0
Eye disorders
Visual acuity reduced	0/521 (0%)	0	1/508 (0.2%)	1
Vitreious floaters	0/521 (0%)	0	1/508 (0.2%)	1
Gastrointestinal disorders
Abdominal distension	0/521 (0%)	0	1/508 (0.2%)	1
Abdominal pain	12/521 (2.3%)	13	7/508 (1.4%)	7
Abdominal pain upper	1/521 (0.2%)	1	0/508 (0%)	0
Ascites	4/521 (0.8%)	5	3/508 (0.6%)	3
Constipation	3/521 (0.6%)	3	3/508 (0.6%)	3
Diarrhoea	9/521 (1.7%)	9	13/508 (2.6%)	13
Dysphagia	4/521 (0.8%)	4	1/508 (0.2%)	1
Enteritis	1/521 (0.2%)	1	0/508 (0%)	0
Gastric haemorrhage	5/521 (1%)	5	4/508 (0.8%)	4
Gastric perforation	4/521 (0.8%)	4	4/508 (0.8%)	4
Gastric stenosis	0/521 (0%)	0	1/508 (0.2%)	1
Gastric ulcer haemorrhage	0/521 (0%)	0	1/508 (0.2%)	1
Gastrointestinal haemorrhage	13/521 (2.5%)	13	8/508 (1.6%)	8
Gastrointestinal hypomotility	1/521 (0.2%)	1	0/508 (0%)	0
Gastrointestinal motility disorder	0/521 (0%)	0	1/508 (0.2%)	1
Gastrointestinal obstruction	1/521 (0.2%)	1	3/508 (0.6%)	3
Gastrointestinal perforation	0/521 (0%)	0	1/508 (0.2%)	1
Haematemesis	2/521 (0.4%)	2	0/508 (0%)	0
Ileus	5/521 (1%)	6	1/508 (0.2%)	1
Ileus paralytic	1/521 (0.2%)	1	0/508 (0%)	0
Intestinal haemorrhage	1/521 (0.2%)	1	0/508 (0%)	0
Intestinal ischaemia	2/521 (0.4%)	2	1/508 (0.2%)	1
Intestinal obstruction	6/521 (1.2%)	6	3/508 (0.6%)	3
Mechanical ileus	1/521 (0.2%)	1	1/508 (0.2%)	1
Melaena	1/521 (0.2%)	1	0/508 (0%)	0
Nausea	17/521 (3.3%)	18	10/508 (2%)	13
Obstruction gastric	6/521 (1.2%)	6	1/508 (0.2%)	1
Odynophagia	0/521 (0%)	0	1/508 (0.2%)	1
Oesophageal obstruction	1/521 (0.2%)	1	0/508 (0%)	0
Oesophageal spasm	1/521 (0.2%)	1	0/508 (0%)	0
Oesophagitis	1/521 (0.2%)	1	1/508 (0.2%)	1
Pancreatitis acute	0/521 (0%)	0	3/508 (0.6%)	4
Periproctitis	1/521 (0.2%)	1	0/508 (0%)	0
Peritonitis	1/521 (0.2%)	1	2/508 (0.4%)	2
Prepyloric stenosis	1/521 (0.2%)	1	0/508 (0%)	0
Retroperitoneal fibrosis	1/521 (0.2%)	1	0/508 (0%)	0
Small intestinal obstruction	5/521 (1%)	5	3/508 (0.6%)	4
Stomatitis	3/521 (0.6%)	3	24/508 (4.7%)	30
Subileus	2/521 (0.4%)	2	1/508 (0.2%)	1
Thrombosis mesenteric vessel	1/521 (0.2%)	1	0/508 (0%)	0
Upper gastrointestinal haemorrhage	5/521 (1%)	8	4/508 (0.8%)	4
Vomiting	23/521 (4.4%)	23	17/508 (3.3%)	21
General disorders
Asthenia	4/521 (0.8%)	4	4/508 (0.8%)	4
Catheter site pain	0/521 (0%)	0	2/508 (0.4%)	2
Catheter thrombosis	1/521 (0.2%)	1	2/508 (0.4%)	2
Chest pain	1/521 (0.2%)	1	1/508 (0.2%)	1
Chills	1/521 (0.2%)	1	0/508 (0%)	0
Death	9/521 (1.7%)	9	1/508 (0.2%)	1
Disease progression	53/521 (10.2%)	53	34/508 (6.7%)	34
Fatigue	8/521 (1.5%)	10	6/508 (1.2%)	7
Generalised Oedema	0/521 (0%)	0	1/508 (0.2%)	1
Hyperthermia	0/521 (0%)	0	1/508 (0.2%)	1
Malaise	1/521 (0.2%)	1	0/508 (0%)	0
Mucosal inflammation	2/521 (0.4%)	2	10/508 (2%)	11
Multi-organ failure	0/521 (0%)	0	1/508 (0.2%)	1
Non-cardiac chest pain	1/521 (0.2%)	1	0/508 (0%)	0
Oedema peripheral	0/521 (0%)	0	1/508 (0.2%)	1
Pain	0/521 (0%)	0	1/508 (0.2%)	1
Performance status decreased	3/521 (0.6%)	3	1/508 (0.2%)	1
Pyrexia	10/521 (1.9%)	10	1/508 (0.2%)	1
Sudden death	2/521 (0.4%)	2	3/508 (0.6%)	3
Hepatobiliary disorders
Bile duct obstruction	2/521 (0.4%)	2	0/508 (0%)	0
Bile duct stenosis	0/521 (0%)	0	1/508 (0.2%)	1
Cholangitis	1/521 (0.2%)	1	1/508 (0.2%)	1
Hepatic failure	1/521 (0.2%)	1	0/508 (0%)	0
Hepatic function abnormal	2/521 (0.4%)	2	0/508 (0%)	0
Hyperbilirubinaemia	4/521 (0.8%)	5	1/508 (0.2%)	1
Jaundice cholestatic	1/521 (0.2%)	1	1/508 (0.2%)	1
Infections and infestations
Anal abscess	1/521 (0.2%)	1	0/508 (0%)	0
Appendicitis	3/521 (0.6%)	3	0/508 (0%)	0
Bacteraemia	2/521 (0.4%)	2	1/508 (0.2%)	1
Bronchitis	3/521 (0.6%)	3	1/508 (0.2%)	1
Broncopneumonia	0/521 (0%)	0	2/508 (0.4%)	2
Catheter related infection	0/521 (0%)	0	4/508 (0.8%)	4
Catheter sepsis	1/521 (0.2%)	1	0/508 (0%)	0
Catheter site cellulitis	0/521 (0%)	0	1/508 (0.2%)	1
Cellulitis	0/521 (0%)	0	2/508 (0.4%)	2
Central line infection	0/521 (0%)	0	1/508 (0.2%)	1
Clostridium difficile colitis	1/521 (0.2%)	1	1/508 (0.2%)	1
Enterocolitis infectious	1/521 (0.2%)	1	0/508 (0%)	0
Gastroenteritis	1/521 (0.2%)	1	0/508 (0%)	0
Gastrointestinal infection	1/521 (0.2%)	1	1/508 (0.2%)	1
Genital candidiasis	1/521 (0.2%)	1	0/508 (0%)	0
Infection	1/521 (0.2%)	1	0/508 (0%)	0
Lobar pneumonia	3/521 (0.6%)	3	3/508 (0.6%)	3
Neutropenic sepsis	3/521 (0.6%)	3	5/508 (1%)	5
Oesophageal candidiasis	0/521 (0%)	0	1/508 (0.2%)	1
Oral candidiasis	0/521 (0%)	0	3/508 (0.6%)	3
Oral herpes	0/521 (0%)	0	1/508 (0.2%)	1
Parotitis	0/521 (0%)	0	1/508 (0.2%)	1
Peritonitis bacterial	1/521 (0.2%)	1	1/508 (0.2%)	1
Pharyngitis streptococcal	0/521 (0%)	0	1/508 (0.2%)	1
Pharyngotonsillitis	0/521 (0%)	0	1/508 (0.2%)	1
Pneumonia	6/521 (1.2%)	6	6/508 (1.2%)	6
Pneumonia bacterial	1/521 (0.2%)	1	0/508 (0%)	0
Postoperative wound infection	0/521 (0%)	0	1/508 (0.2%)	1
Pyelonephritis acute	0/521 (0%)	0	1/508 (0.2%)	1
Pyothorax	1/521 (0.2%)	1	0/508 (0%)	0
Respiratory tract infection	1/521 (0.2%)	1	0/508 (0%)	0
Sepsis	4/521 (0.8%)	4	3/508 (0.6%)	3
Septic shock	3/521 (0.6%)	3	10/508 (2%)	10
Staphylococcal infection	0/521 (0%)	0	1/508 (0.2%)	1
Tooth infection	0/521 (0%)	0	1/508 (0.2%)	1
Upper respiratory tract infection	1/521 (0.2%)	1	0/508 (0%)	0
Urinary tract infection	1/521 (0.2%)	1	0/508 (0%)	0
Urosepsis	0/521 (0%)	0	1/508 (0.2%)	1
Vaginal infection	0/521 (0%)	0	1/508 (0.2%)	1
Wound abscess	1/521 (0.2%)	1	0/508 (0%)	0
Injury, poisoning and procedural complications
Anastomotic complication	0/521 (0%)	0	1/508 (0.2%)	1
Confusion	0/521 (0%)	0	1/508 (0.2%)	1
Device migration	1/521 (0.2%)	1	0/508 (0%)	0
Drug toxicity	0/521 (0%)	0	1/508 (0.2%)	1
Femoral neck fracture	0/521 (0%)	0	2/508 (0.4%)	2
Femur fracture	1/521 (0.2%)	1	0/508 (0%)	0
Head Injury	0/521 (0%)	0	1/508 (0.2%)	1
Humerus fracture	0/521 (0%)	0	1/508 (0.2%)	1
Incorrect dose administered	1/521 (0.2%)	1	0/508 (0%)	0
Stent occlusion	1/521 (0.2%)	1	0/508 (0%)	0
Traumatic brain injury	0/521 (0%)	0	1/508 (0.2%)	1
Investigations
Alanine aminotransferase increased	1/521 (0.2%)	1	1/508 (0.2%)	1
Aspartate aminotransferase increased	1/521 (0.2%)	1	1/508 (0.2%)	1
Blood alkaline phosphatase increased	0/521 (0%)	0	1/508 (0.2%)	1
Blood bilirubin increased	1/521 (0.2%)	1	1/508 (0.2%)	1
Blood creatinine increased	5/521 (1%)	5	4/508 (0.8%)	4
Blood potassium decreased	0/521 (0%)	0	1/508 (0.2%)	1
Creatinine renal clearance decreased	0/521 (0%)	0	2/508 (0.4%)	2
Glomerular filtration rate decreased	0/521 (0%)	0	2/508 (0.4%)	2
Haemoglobin decreased	3/521 (0.6%)	3	1/508 (0.2%)	1
Platelet count decreased	0/521 (0%)	0	2/508 (0.4%)	2
Urine electrolytes increased	0/521 (0%)	0	1/508 (0.2%)	1
Weight decreased	0/521 (0%)	0	1/508 (0.2%)	1
Metabolism and nutrition disorders
Alkalosis hypochloraemic	1/521 (0.2%)	1	0/508 (0%)	0
Anorexia	7/521 (1.3%)	8	2/508 (0.4%)	2
Cachexia	1/521 (0.2%)	2	1/508 (0.2%)	1
Decreased appetite	1/521 (0.2%)	1	0/508 (0%)	0
Dehydration	21/521 (4%)	21	32/508 (6.3%)	41
Diabetes mellitus	1/521 (0.2%)	1	0/508 (0%)	0
Diabetic ketoacidosis	2/521 (0.4%)	2	0/508 (0%)	0
Failure to thrive	1/521 (0.2%)	1	1/508 (0.2%)	1
Hyperglycaemia	0/521 (0%)	0	3/508 (0.6%)	3
Hyperkalaemia	2/521 (0.4%)	2	0/508 (0%)	0
Hyperuricaemia	0/521 (0%)	0	1/508 (0.2%)	1
Hypoalbuminaemia	1/521 (0.2%)	1	0/508 (0%)	0
Hypocalcaemia	0/521 (0%)	0	4/508 (0.8%)	4
Hypoglycaemia	1/521 (0.2%)	1	1/508 (0.2%)	1
Hypokalaemia	4/521 (0.8%)	4	8/508 (1.6%)	8
Hypomagnesaemia	1/521 (0.2%)	1	2/508 (0.4%)	2
Hyponatraemia	1/521 (0.2%)	2	6/508 (1.2%)	6
Hypophosphataemia	0/521 (0%)	0	3/508 (0.6%)	3
Hypovolaemia	0/521 (0%)	0	1/508 (0.2%)	1
Malnutrition	0/521 (0%)	0	1/508 (0.2%)	1
Metabolic acidosis	0/521 (0%)	0	1/508 (0.2%)	1
Musculoskeletal and connective tissue disorders
Back pain	6/521 (1.2%)	6	1/508 (0.2%)	1
Bone pain	0/521 (0%)	0	1/508 (0.2%)	1
Musculoskeletal chest pain	1/521 (0.2%)	1	0/508 (0%)	0
Pathological fracture	1/521 (0.2%)	1	1/508 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant ascites	1/521 (0.2%)	1	0/508 (0%)	0
Malignant pleural effusion	1/521 (0.2%)	1	0/508 (0%)	0
Metastases to bladder	0/521 (0%)	0	1/508 (0.2%)	1
Metastases to central nervous system	1/521 (0.2%)	1	0/508 (0%)	0
Metastases to liver	0/521 (0%)	0	1/508 (0.2%)	1
Metastases to ovary	0/521 (0%)	0	1/508 (0.2%)	1
Metastases to spine	1/521 (0.2%)	1	0/508 (0%)	0
Tumour associated fever	0/521 (0%)	0	1/508 (0.2%)	2
Tumour haemorrhage	7/521 (1.3%)	9	3/508 (0.6%)	4
Tumour lysis syndrome	0/521 (0%)	0	1/508 (0.2%)	1
Tumour pain	2/521 (0.4%)	2	0/508 (0%)	0
Tumour perforation	0/521 (0%)	0	1/508 (0.2%)	1
Nervous system disorders
Acoustic neuritis	0/521 (0%)	0	1/508 (0.2%)	1
Cerebellar infarction	1/521 (0.2%)	1	0/508 (0%)	0
Cerebral infarction	1/521 (0.2%)	1	0/508 (0%)	0
Cerebral ischaemia	0/521 (0%)	0	2/508 (0.4%)	2
Cerebral thrombosis	0/521 (0%)	0	1/508 (0.2%)	1
Cerebrovascular accident	3/521 (0.6%)	3	3/508 (0.6%)	4
Cerebrovascular disorder	1/521 (0.2%)	1	1/508 (0.2%)	1
Convulsion	5/521 (1%)	6	2/508 (0.4%)	2
Encephalopathy	0/521 (0%)	0	1/508 (0.2%)	1
Grand mal convulsion	0/521 (0%)	0	1/508 (0.2%)	1
Hypotonia	0/521 (0%)	0	1/508 (0.2%)	1
Ischaemic cerebral infarction	1/521 (0.2%)	1	0/508 (0%)	0
Ischaemic stroke	3/521 (0.6%)	3	0/508 (0%)	0
Metabolic encephalopathy	1/521 (0.2%)	1	0/508 (0%)	0
Neuropathy peripheral	0/521 (0%)	0	1/508 (0.2%)	1
Peripheral sensory neuropathy	0/521 (0%)	0	1/508 (0.2%)	1
Speech disorder	0/521 (0%)	0	1/508 (0.2%)	1
Spinal cord compression	3/521 (0.6%)	3	2/508 (0.4%)	2
Syncope	1/521 (0.2%)	1	1/508 (0.2%)	1
Syncope vasovagal	1/521 (0.2%)	1	1/508 (0.2%)	1
Psychiatric disorders
Confusional state	1/521 (0.2%)	1	1/508 (0.2%)	1
Disorientation	1/521 (0.2%)	1	1/508 (0.2%)	1
Psychotic disorder	1/521 (0.2%)	1	0/508 (0%)	0
Renal and urinary disorders
Calculus urinary	0/521 (0%)	0	1/508 (0.2%)	1
Hydronephrosis	0/521 (0%)	0	1/508 (0.2%)	1
Incontinence	1/521 (0.2%)	1	0/508 (0%)	0
Renal colic	0/521 (0%)	0	1/508 (0.2%)	1
Renal disorder	0/521 (0%)	0	2/508 (0.4%)	2
Renal failure	5/521 (1%)	5	9/508 (1.8%)	9
Renal failure acute	4/521 (0.8%)	4	11/508 (2.2%)	11
Renal failure chronic	0/521 (0%)	0	1/508 (0.2%)	1
Renal impairment	2/521 (0.4%)	2	3/508 (0.6%)	3
Renal tubular disorder	0/521 (0%)	0	1/508 (0.2%)	1
Ureteric stenosis	0/521 (0%)	0	1/508 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	0/521 (0%)	0	1/508 (0.2%)	1
Dyspnoea	4/521 (0.8%)	4	1/508 (0.2%)	1
Haemoptysis	1/521 (0.2%)	1	1/508 (0.2%)	1
Hydrothorax	1/521 (0.2%)	1	0/508 (0%)	0
Pharyngeal inflammation	0/521 (0%)	0	1/508 (0.2%)	1
Pleural effusion	4/521 (0.8%)	5	4/508 (0.8%)	4
Pneumonia aspiration	0/521 (0%)	0	1/508 (0.2%)	1
Pneumothorax	1/521 (0.2%)	1	0/508 (0%)	0
Pulmonary artery thrombosis	1/521 (0.2%)	1	0/508 (0%)	0
Pulmonary embolism	12/521 (2.3%)	12	8/508 (1.6%)	8
Respiratory failure	1/521 (0.2%)	1	0/508 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/521 (0.2%)	1	0/508 (0%)	0
Vascular disorders
Aortic thrombosis	1/521 (0.2%)	1	0/508 (0%)	0
Arterial thrombosis limb	2/521 (0.4%)	2	0/508 (0%)	0
Circulatory collapse	0/521 (0%)	0	1/508 (0.2%)	1
Deep vein thrombosis	5/521 (1%)	5	17/508 (3.3%)	18
Haemorrhage	1/521 (0.2%)	1	2/508 (0.4%)	2
Hypertension	1/521 (0.2%)	1	0/508 (0%)	0
Hypertensive crisis	0/521 (0%)	0	1/508 (0.2%)	1
Hypotension	4/521 (0.8%)	4	3/508 (0.6%)	4
Hypovolaemic shock	4/521 (0.8%)	4	1/508 (0.2%)	1
Iliac artery thrombosis	1/521 (0.2%)	1	0/508 (0%)	0
Pelvis venous thrombosis	1/521 (0.2%)	1	0/508 (0%)	0
Peripheral embolism	1/521 (0.2%)	1	1/508 (0.2%)	1
Subclavian vein thrombosis	2/521 (0.4%)	2	1/508 (0.2%)	1
Thrombophlebitis	0/521 (0%)	0	1/508 (0.2%)	1
Vena cava thrombosis	1/521 (0.2%)	1	0/508 (0%)	0
Venous thrombosis	0/521 (0%)	0	1/508 (0.2%)	1
Other (Not Including Serious) Adverse Events
	S-1/Cisplatin		5-FU/Cisplatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	514/521 (98.7%)		504/508 (99.2%)
Blood and lymphatic system disorders
Anaemia	229/521 (44%)	404	234/508 (46.1%)	380
Neutropenia	149/521 (28.6%)	383	240/508 (47.2%)	588
Thrombocytopenia	92/521 (17.7%)	174	116/508 (22.8%)	190
Leukopenia	91/521 (17.5%)	224	117/508 (23%)	254
Lymphopenia	26/521 (5%)	54	34/508 (6.7%)	126
Granulocytopenia	18/521 (3.5%)	60	10/508 (2%)	19
Febrile neutropenia	10/521 (1.9%)	10	35/508 (6.9%)	38
Leukocytosis	8/521 (1.5%)	13	15/508 (3%)	22
Ear and labyrinth disorders
Tinnitus	29/521 (5.6%)	76	44/508 (8.7%)	75
Deafness	11/521 (2.1%)	12	24/508 (4.7%)	27
Eye disorders
Lacrimation increased	32/521 (6.1%)	62	6/508 (1.2%)	8
Vision blurred	18/521 (3.5%)	81	9/508 (1.8%)	13
Gastrointestinal disorders
Nausea	321/521 (61.6%)	778	342/508 (67.3%)	913
Vomiting	260/521 (49.9%)	616	281/508 (55.3%)	693
Diarrhoea	152/521 (29.2%)	329	195/508 (38.4%)	331
Abdominal pain	131/521 (25.1%)	219	114/508 (22.4%)	205
Constipation	120/521 (23%)	296	133/508 (26.2%)	219
Abdominal pain upper	66/521 (12.7%)	125	67/508 (13.2%)	85
Dyspepsia	46/521 (8.8%)	86	30/508 (5.9%)	41
Stomatitis	33/521 (6.3%)	74	153/508 (30.1%)	321
Flatulence	31/521 (6%)	49	10/508 (2%)	11
Dysphagia	26/521 (5%)	29	42/508 (8.3%)	54
Ascites	25/521 (4.8%)	27	13/508 (2.6%)	15
Gastrointestinal haemorrhage	19/521 (3.6%)	19	14/508 (2.8%)	15
Abdominal distension	16/521 (3.1%)	23	18/508 (3.5%)	20
Gastrooesophageal reflux disease	16/521 (3.1%)	21	8/508 (1.6%)	9
General disorders
Fatigue	205/521 (39.3%)	505	200/508 (39.4%)	329
Asthenia	88/521 (16.9%)	124	96/508 (18.9%)	152
Pyrexia	72/521 (13.8%)	112	61/508 (12%)	80
Disease progression	55/521 (10.6%)	55	35/508 (6.9%)	35
Oedema peripheral	53/521 (10.2%)	81	46/508 (9.1%)	56
Performance status decreased	35/521 (6.7%)	36	42/508 (8.3%)	49
Chest pain	27/521 (5.2%)	38	23/508 (4.5%)	30
Mucosal inflammation	20/521 (3.8%)	27	152/508 (29.9%)	330
Chills	16/521 (3.1%)	20	10/508 (2%)	13
Injection site reaction	5/521 (1%)	11	15/508 (3%)	21
Hepatobiliary disorders
Hyperbilirubinaemia	32/521 (6.1%)	47	15/508 (3%)	21
Infections and infestations
Nasopharyngitis	16/521 (3.1%)	19	9/508 (1.8%)	9
Oral candidiasis	3/521 (0.6%)	3	22/508 (4.3%)	31
Investigations
Weight decreased	148/521 (28.4%)	157	164/508 (32.3%)	173
Creatinine renal clearance decreased	37/521 (7.1%)	43	61/508 (12%)	72
Blood creatinine increased	35/521 (6.7%)	45	62/508 (12.2%)	78
Haemoglobin decreased	26/521 (5%)	35	22/508 (4.3%)	31
Aspartate aminotransferase increased	25/521 (4.8%)	29	18/508 (3.5%)	25
Blood alkaline phosphatase increased	23/521 (4.4%)	25	28/508 (5.5%)	32
Neutrophil count decreased	22/521 (4.2%)	41	29/508 (5.7%)	61
Alanine aminotransferase increased	16/521 (3.1%)	18	19/508 (3.7%)	25
Blood LDH increased	16/521 (3.1%)	22	19/508 (3.7%)	24
Blood urea increased	15/521 (2.9%)	28	30/508 (5.9%)	35
Platelet count decreased	15/521 (2.9%)	28	27/508 (5.3%)	46
White blood cell count decreased	14/521 (2.7%)	22	24/508 (4.7%)	44
Glomerular filtration rate decreased	6/521 (1.2%)	6	15/508 (3%)	18
Metabolism and nutrition disorders
Anorexia	164/521 (31.5%)	306	177/508 (34.8%)	310
Dehydration	63/521 (12.1%)	81	79/508 (15.6%)	114
Hypomagnesaemia	52/521 (10%)	91	52/508 (10.2%)	74
Hyponatraemia	38/521 (7.3%)	55	41/508 (8.1%)	51
Hypokalaemia	36/521 (6.9%)	52	85/508 (16.7%)	133
Decreased appetite	26/521 (5%)	31	30/508 (5.9%)	62
Hypoalbuminaemia	26/521 (5%)	36	46/508 (9.1%)	63
Hypocalcaemia	23/521 (4.4%)	26	36/508 (7.1%)	45
Hyperglycaemia	19/521 (3.6%)	28	21/508 (4.1%)	32
Hyperkalaemia	17/521 (3.3%)	18	19/508 (3.7%)	20
Hypophosphataemia	10/521 (1.9%)	12	30/508 (5.9%)	43
Musculoskeletal and connective tissue disorders
Back pain	45/521 (8.6%)	58	44/508 (8.7%)	57
Pain in extremity	24/521 (4.6%)	29	19/508 (3.7%)	21
Myalgia	16/521 (3.1%)	31	8/508 (1.6%)	11
Nervous system disorders
Dizziness	53/521 (10.2%)	128	36/508 (7.1%)	72
Headache	50/521 (9.6%)	127	51/508 (10%)	72
Dysgeusia	48/521 (9.2%)	128	50/508 (9.8%)	79
Peripheral sensory neuropathy	42/521 (8.1%)	80	44/508 (8.7%)	59
Paraesthesia	18/521 (3.5%)	23	21/508 (4.1%)	29
Neuropathy peripheral	14/521 (2.7%)	18	33/508 (6.5%)	35
Psychiatric disorders
Insomnia	40/521 (7.7%)	173	67/508 (13.2%)	129
Depression	14/521 (2.7%)	16	17/508 (3.3%)	17
Anxiety	10/521 (1.9%)	11	31/508 (6.1%)	39
Respiratory, thoracic and mediastinal disorders
Hiccups	37/521 (7.1%)	98	45/508 (8.9%)	99
Cough	30/521 (5.8%)	37	36/508 (7.1%)	38
Dyspnoea	29/521 (5.6%)	89	33/508 (6.5%)	46
Epistaxis	18/521 (3.5%)	19	15/508 (3%)	20
Pulmonary embolism	17/521 (3.3%)	17	15/508 (3%)	15
Skin and subcutaneous tissue disorders
Alopecia	31/521 (6%)	50	104/508 (20.5%)	111
Palmar-plantar erythrodysaesthesia	28/521 (5.4%)	52	13/508 (2.6%)	27
Skin hyperpigmentation	27/521 (5.2%)	29	17/508 (3.3%)	21
Rash	27/521 (5.2%)	53	21/508 (4.1%)	29
Hyperhidrosis	20/521 (3.8%)	62	13/508 (2.6%)	22
Vascular disorders
Hypotension	24/521 (4.6%)	26	24/508 (4.7%)	27
Hypertension	21/521 (4%)	31	20/508 (3.9%)	25
Deep vein thrombosis	14/521 (2.7%)	14	22/508 (4.3%)	24
Phlebitis	8/521 (1.5%)	10	23/508 (4.5%)	35

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Taiho agreements vary with individual investigators, but do not prohibit any from publishing. Taiho is provided time to review material discussing trial results (generally 30 to 120 days with possible extension), and can remove undisclosed confidential, proprietary and intellectual property rights-related information. Authors have final control and approval of publication content of final study results. The investigator agrees not to publish any results before the first multicenter publication.