Koizumi 2008.

Methods	Multicentre RCT 2 arms Quality score: A The study was conducted in Japan.
Participants	n = 305 Median age: 62 years Metastatic disease: 100% ECOG 2‐3: 3%
Interventions	S‐1 + cisplatin: S‐1 twice daily d 1‐20 repeated at d 36, dose of S‐1 according to the patient’s body surface area (< 1.25 m²: 40 mg; 1.25–1.5 m²: 50 mg; > 1.5 m²: 60 mg) + cisplatin 60 mg/m² d 8, repeated at d 36 versus S‐1 : S‐1 twice daily d 1‐27 repeated at d 41, dose of S‐1 according to the patient’s body surface area (< 1.25 m²: 40 mg; 1.25–1.5 m²: 50 mg; > 1.5 m²: 60 mg)
Outcomes	Hazard ratio for overall survival Tumour response Toxicity
Notes	This study was conducted in Japan. Due to polymorphic differences in the CYP2A6 gene in Asians and whites, the tolerability of S‐1 is different in whites (Ajani 2006). The dose of S‐1, which was used in this trial may not be used in non‐Asian populations for this reason.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Minimisation by use of biased coin method
Allocation concealment (selection bias)	Low risk	Central allocation
Incomplete outcome data (attrition bias) efficacy	Low risk	298/305 patients included in analysis.
Incomplete outcome data (attrition bias) safety	Low risk	298/305 patients included in analysis.
Selective reporting (reporting bias)	Low risk	Report includes all expected outcomes
Other bias	Low risk	If second‐line treatment was started without progressive disease (i.e. due to adverse events), patients were censored
Blinded review of CT/MRI‐scans?	Low risk	Images were assessed by an extramural review committee