Laack 2004.

Methods	Randomized multi‐center phase III trial Eligible patients Cytologically or histologically confirmed NSCLC Stage IIIB with malignant pleural effusion or stage IV disease No previous chemotherapeutic regimen Objective bi‐dimensionally measurable disease defined as larger than 20 × 20 mm Life expectancy ≥ 12 weeks PS by Karnofsky Performance Scale > 70% 18 to 75 years of age No symptoms of brain metastasis, no hearing loss, no uncontrolled infection No prior malignancy except adequately controlled basal cell carcinoma of the skin Adequate hepatic and renal function Exclusion criteria History of cancer within the past 5 years (except adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix) Pre‐existing sensory or motor neuropathy ≥ WHO grade 1 History of myocardial infarction, coronary heart disease > grade 3 according to Canadian Cardiovascular Society Scale, ventricular cardiac arrhythmia > IIIB according to Lown scale, cardiac insufficiency > grade 3 according to New York Heart Association Scale Active infection Pregnancy, breast‐feeding, inadequate contraceptive precautions Brain metastasis
Participants	GV arm: 143 participants (ITT population) ‐ median age (range): 60.8 (41 to 75.9) years/16 elderly participants with the following characteristics: stage IIB: 2, and stage IV: 14; male: 14, and female: 2; KPS: 100%: 2, 90%: 3, 80%: 8, and 70%: 3 GVP arm: 144 participants (ITT population) ‐ median age (range): 61.1 (40.6 to 75.9)/27 elderly participants with the following characteristics: stage IIIB: 2, and stage IV: 26; male: 22, and female: 5; KPS: 100%: 4, 90%: 10, 80%: 8, and 70%: 5
Interventions	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 3 weeks GVP 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 and cisplatin 75 mg/m2 on day 2 over 1‐hour infusion with standard pre‐hydration and post‐hydration, every 3 weeks Obs: prophylaxis for febrile neutropenia with use of granulocyte‐colony stimulating factor at physician's decision on an individual basis
Outcomes	Primary outcome Overall survival defined from date of randomization to death or last follow‐up of living participants ‐ "The study was designed as a superiority trial to evaluate whether cisplatin‐based GVP chemotherapy prolongs overall survival in comparison to cisplatin‐free GV chemotherapy as first‐ line therapy" Secondary outcomes Objective response rate according to WHO criteria Toxicity by WHO criteria Quality of Life (QoL) assessment by EORTC QLQ‐C30 with annexed LC13 questionnaire at baseline and before each therapy cycle
Notes	Elderly subgroup analysis not planned in the original protocol. Unpublished post hoc analysis of participants older than 70 years obtained upon direct request to study author
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly assigned to receive either GV or GVP. Before random assignment, patients were stratified according to participating centre. Randomization (stratified block randomisation with enclosed block length) was performed centrally by the Department of Biostatistics of the German Cancer Research Center (Heidelberg, Germany) using facsimile forms"
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment
Blinding of outcome assessment (detection bias) OS and 1y OS rate outcome	Unclear risk	Open‐label study considered to have unclear impact on mortality outcomes
Blinding of outcome assessment (detection bias) Other outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"Thirteen randomly assigned patients (4.3%) did not fulfil the eligibility criteria and were excluded from the full analysis set. Four patients had a stage IIIB disease without malignant pleural effusion, one patient was staged as stage IIIA disease, two patients had brain metastases, two patients did not have NSCLC (one patient had small cell lung cancer and one patient a malignant melanoma), two patients revealed a Karnofsky performance status of lower than 70%, one patient did not fulfil the eligibility criteria concerning tumor size, and one patient refused treatment after randomisation" No further details on attrition bias provided for elderly subgroup
Selective reporting (reporting bias)	Low risk	No evidence of selective reporting bias
Other bias	High risk	Study designed for the general population; elderly subgroup analysis not planned. Unpublished post hoc elderly subgroup analysis obtained upon direct request to study authors