Nishikawa 2012.

Methods	Multicentre RCT 4 arms Quality score: D The study was conducted in Japan.
Participants	n = 161 Median age: 67 years ECOG 2‐3: 0 %
Interventions	Group A (sequential 5‐FU + paclitaxel): 5‐FU 800 mg/m² c.i.v. d 1‐5, repeated at 4 weeks, followed by paclitaxel 80 mg/m² d.i.v. d 1, 8, 15, repeated at 4 weeks after progression Group B (sequential S‐1 + paclitaxel): S‐1 80 mg/m² p.o. d 1‐28 , repeated at 6 weeks + paclitaxel 80 mg/m² d.i.v. d 1, 8, 15, repeated at 4 weeks after progression Group C (concomitant 5‐FU +paclitaxel): 5‐FU 600 mg/m² c.i.v. d 1‐5 + paclitaxel 80 mg/m² d.i.v. d 8, 15, 22, repeated at 4 weeks Group D (concomitant S‐1 + paclitaxel): S‐1 80 mg/m² p.o. d1‐14 + paclitaxel 50 mg/m² d.i.v. d1,15, repeated at 3 weeks
Outcomes	Overall survival (10 months overall survival rate) Progression‐free survival Time to treatment failure Response rates Toxicity
Notes	This study was conducted in Japan. After publication of the results of the SPIRITS trial (Koizumi 2008) candidates for accrual were informed about the new treatment standard in Japan and they were offered the alternative to receive the combination therapy instead of participating in the trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Centralised dynamic randomisation
Allocation concealment (selection bias)	Low risk	Centralised dynamic randomisation
Incomplete outcome data (attrition bias) efficacy	Low risk	Only two patients in arm A and two in arm C declined therapies before the start of the assigned treatment
Incomplete outcome data (attrition bias) safety	Low risk	Only two patients in arm A and two in arm C declined therapies before the start of the assigned treatment
Selective reporting (reporting bias)	Low risk	Expected endpoints are reported
Other bias	Unclear risk	An irinotecan‐containing regimen was recommended for use in case if further lines of treatment were given. No information about the percentage of patients receiving second line treatment is provided.
Blinded review of CT/MRI‐scans?	Unclear risk	not stated