Zukin 2013.

Methods	Randomized multi‐center phase III trial Inclusion criteria Cytological or histological confirmation of stages IIIB (malignant effusion) and IV NSCLC (6 ed AJCC) Measurable disease PS: 2 on ECOG scale Initially, patients with all histologic subtypes were eligible. A protocol amendment was implemented in May 2009 to exclude patients with squamous cell histology, when 14 such patients had been enrolled. Prior chemotherapy was not allowed Prior irradiation, with toxicities resolved before study entry Brain metastases if neurologically stable and no longer receiving corticosteroids after appropriate therapy Adequate organ function required, including glomerular filtration rate > 45 mL/min Exclusion criteria Locally advanced disease amenable to combined modality therapy not eligible Concurrent active malignancies, except in situ carcinoma of the cervix and basal cell carcinoma of the skin
Participants	P arm: 109 participants (ITT population)/36 elderly participants CP arm: 108 participants (ITT population)/38 elderly participants
Interventions	P arm: pemetrexed 500 mg/m2 i.v. on day 1, every 21 days for up to 4 cycles CP arm: carboplatin AUC5 and pemetrexed 500 mg/m2, both administered i.v. on day 1, every 21 days for up to 4 cycles All participants received premedications with dexamethasone, vitamin B12, and folic acid according to the pemetrexed label. Maintenance therapy was not allowed
Outcomes	Primary outcome Overall survival (measured from date of first treatment dose to date of death or last date participant was known to be alive, in which case participant was censored as of that date) Secondary outcomes Response rate (using RECIST criteria) Progression‐free survival (measured from date of first treatment dose to date participant was first recorded as having disease progression or date of death) Toxicity
Notes	"The study was designed with 80% power and a two‐sided type I error of 0.05, assuming that pemetrexed plus carboplatin would result in a median survival of at least 4.3 months and pemetrexed alone would result in a median survival of at least 2.9 months (hazard ratio [HR], 0.674) Despite multiple attempts to contact study authors, no information about subgroup analysis of the elderly was retrieved
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Random assignment was performed by an independent provider not involved in the study and stratified by stage (IIIB v IV), weight loss (< 5% v ≥ 5%), and age (< 70 v ≥70 years)"
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	"Twelve patients—seven in the P arm and five in the CP arm—were deemed ineligible because of stage IIIB disease without a malignant pleural effusion (n = 4), uncontrolled CNS disease (n = 2), non measurable disease (n = 1), glomerular filtration rate < 45 mL/min (n = 2), transaminases > 5x the upper limit of normal range (n = 2), and prior chemotherapy" No information about number of elderly participants excluded
Selective reporting (reporting bias)	High risk	Data for the elderly provided only for OS outcome
Other bias	High risk	Elderly subgroup analysis not planned. Study authors presented a post hoc analysis for OS only