Comella 2004.

Methods	Randomized phase III trial Eligibility criteria Histologycally or cytologically confirmed NSCLC Stage IIIB (amenable to local treatment) or IV disease > 70 years old with PS ≤ 2 or ≤ 70 years old with PS = 2 Measurable lesion Charlson score ≤ 4 Adequate bone marrow and renal function Exclusion criteria Brain metastasis Uncontrolled metabolic or infectious disease Cardiac arrhythmia or heart failure Previous exposure to chemotherapy or radiotherapy Diagnosis of malignant tumor within past 5 years
Participants	P arm: 68 randomly assigned and analyzed participants ‐ median age (range): 75 (49 to 86) years; PS 2: 19; stage III: 24/59 elderly G arm: 63 randomly assigned and analyzed participants ‐ median age (range): 72 (50 to 81) years; PS 2: 22; stage III: 16/50 elderly GV arm: 68 randomly assigned and analyzed participants ‐ median age (range): 72 (42 to 82) years; PS 2: 21; stage III: 28/55 elderly GP arm: 65 randomly assigned and analyzed participants ‐ median age (range): 73 (53 to 83) years; PS 2: 15; stage III: 25/56 elderly
Interventions	P arm: paclitaxel 100 mg/m2 over 1‐hour i.v. infusion on days 1, 8, and 15, every 4 weeks. Doses could be increased to 120 mg/m2 on second cycle and to 140 mg/m2 on third cycle, according to tolerance G arm: gemcitabine 1200 mg/m2 over 30‐minute i.v. infusion on days 1, 8, and 15, every 4 weeks. Doses could be increased to 1400 mg/m2 on second cycle and to 1600 mg/m2 on third cycle, according to tolerance GV arm: gemcitabine 1000 mg/m2 over 30‐minute i.v. infusion and vinorelbine 25 mg/m2 over 15‐minute i.v. infusion on days 1 and 8, every 4 weeks. Doses could be increased to gemcitabine 1200 mg/m2 on second cycle and to vinorelbine 30 mg/m2 on third cycle, according to tolerance GP arm: gemcitabine 1000 mg/m2 over 30‐minute i.v. infusion and paclitaxel 80 mg/m2 over 1‐hour i.v. infusion on days 1 and 8 every 4 weeks. Doses could be increased to gemcitabine 1200 mg/m2 on second cycle and to paclitaxel 100 mg/m2 on third cycle, according to tolerance For all arms, in the absence of grade 2 or higher WHO toxicity, intrapatient dose escalation over first 3 cycles was planned and used thereafter
Outcomes	Primary outcome Overall survival (defined as time from randomization to death) ‐ Study was planned to accrue 520 participants to detect improvement in median OS from 5 to 7.5 months for single‐agent vs combination treatment (power 90%; P value < 0.05) Secondary outcomes Time‐to‐treatment failure (defined as time from randomization to progressive disease or failure. Failure defined as early treatment discontinuation or death) Response rate (according to WHO criteria) Toxicity (according to WHO criteria)
Notes	Study prematurely stopped because of poor accrual after results of Gridelli 2003, in which no benefit was observed in favor of gemcitabine‐vinorelbine combination over each drug given as single agent
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were registered by fax at the coordinating centre. After verifying the eligibility criteria, patients were stratified according to stage (IIIB vs IV), PS (0‐1 vs 2) and Charlson index score (0‐2 vs 3‐4) and allocated using a computer‐generated random list one of four arms: gemcitabine (GEM), paclitaxel (PTX), gemcitabine plus paclitaxel (GT) or gemcitabine plus vinorelbine (GV)"
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment analysis
Blinding of outcome assessment (detection bias) OS and 1y OS rate outcome	Unclear risk	Open‐label study considered to have unclear influence on mortality outcomes
Blinding of outcome assessment (detection bias) Other outcomes	Unclear risk	No information on blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Participants analyzed according to intention‐to‐treat principle. 16 participants among whole population not treated because of withdrawal of participant consent (5 cases) or physician's decision (11 cases). These participants not considered for activity and toxicity analyses but included in survival analysis
Selective reporting (reporting bias)	Low risk	No evidence of reporting bias
Other bias	High risk	No planned elderly subgroup analysis (participants > 70 years of age) for any outcome. HR for OS reported for ITT population (doublet vs single agent)