Frasci 2001.

Methods	Randomized phase II trial Inclusion criteria Chemotherapy‐naive ≥ 70 years of age Histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic NSCLC ECOG PS: 0 to 2 No prior chemotherapy nor thoracic radiotherapy Adequate bone marrow and liver function and creatinine clearance > 60 mL/min CNS metastases not considered an exclusion criterion, if asymptomatic Life expectancy ≥ 12 weeks Exclusion criterion Severe cardiac arrhythmia or heart failure, second‐ or third‐degree heart block, and acute myocardial infarction within 4 months before study entry
Participants	V arm: 60/median age of included participants: 74 (range 71 to 81) years; 13% ECOG 2; 16.7% Charlson score > 2 VG arm: 60/median age of included participants: 75 (range 71 to 83) years; 16% ECOG 2; 20% Charlson score > 2
Interventions	V arm: vinorelbine 30 mg/m2 i.v. infusion on days 1 and 8, every 3 weeks for maximum of 6 cycles VG arm: vinorelbine 30 mg/m2 i.v. infusion plus gemcitabine 1200 mg/m2 i.v. infusion on days 1 and 8, every 3 weeks for maximum of 6 cycles All participants received antiemetic prophylaxis consisting of HT3‐receptor antagonist
Outcomes	Primary outcomes Overall survival Response rate Toxicity Quality of life (QoL assessment with Lung Cancer Symptoms questionnaire)
Notes	Study prematurely stopped after first interim analysis showed increased risk of death for participants in V arm Evaluation of co‐morbidities using Charlson score before start of treatment. Quality of life assessment using Lung Cancer Symptom Scale (LCSS) questionnaire at diagnosis, after third and sixth cycles of chemotherapy. Response rate and toxicity classified according to World Health Organization (WHO) criteria
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was performed centrally at the Division of Medical Oncology of the National Tumor Institute of Naples". "(...) procedure that used the centre, stage IIIB vs IV and performance (ECOG 0 or 1 vs 2) as stratifying variables". "Patients were assigned to one of the two arms by computer‐driven minimization"
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	High risk	Open‐label study
Incomplete outcome data (attrition bias) All outcomes	High risk	Five patients excluded because no information sent to co‐ordination center. After early trial interruption, additional 21 patients included and outcome data not reported
Selective reporting (reporting bias)	High risk	Study not planned for PFS analysis. Therefore, no data on this outcome. Absence of important outcome associated with reporting bias, despite lack of inclusion in study design
Other bias	High risk	Study closed prematurely because planned interim analysis showed that magnitude of survival gain achieved by combination therapy met chosen criteria for early discontinuation. However, additional 21 participants included after that and outcome data not reported