Postmus 2000.

Methods	RCT, parallel, open, multicentric, phase III 11 centers in Europe (EORTC)
Participants	N = 120; 60 teniposide, 60 teniposide + WBRT Sex: 95 male, 25 female Median age: 60/61 years (range: 38 to 75 years) Inclusion criteria: histologic or cytologic evidence of  SCLC BM confirmed by contrast‐enhanced CT evidence of extracranial tumor deposits no previous treatment with either chemotherapy or radiotherapy (prophylactic or therapeutic) for BM no prior treatment with teniposide age less than 76 years WBC count > 3000/mL platelet count > 100,000/mL creatinine concentration < 150 mmol/L bilirubin concentration < 25 mmol/L Exclusion criteria: uncontrolled infection serious nonmalignant disease expected difficulty with follow‐up
Interventions	Intervention teniposide alone Control teniposide + WBRT Teniposide 120 mg/m2 intravenous infusion on days 1, 3, and 5 every 3 weeks. Patients underwent treatment until they had received the maximum number of courses (n = 12) or until the disease had progressed inside or outside the brain. If the WBC count was ≤ 3000 /mL or the platelet count was ≤ 100.000/mL on the day of scheduled retreatment, treatment was delayed. Counts were measured weekly, and treatment was given at full doses when the WBC and platelet counts returned to ≥ 3000 /mL and ≥100.000/mL, respectively. If recovery was still incomplete after 2 weeks, the patient went off study. In the event of WHO grade 4 leukocytopenia, thrombocytopenia, or both during 2 subsequent courses, a 25% dose reduction for subsequent courses was advised WBRT consisted of 30 Gy (midplane dose) in 10 fractions in 2 weeks with parallel opposing fields. Both fields were treated each day. WBRT had to be started within 3 weeks after the start of teniposide and continued during administration of teniposide. All cranial meningeal surfaces, including the anterior, middle, and posterior cranial fossae, were included with a minimum 1‐cm margin. Treatment was given with megavoltage equipment with a minimum source‐to‐skin distance or target‐to‐skin distance of 80 cm. Corticosteroids (dexamethasone 2 mg, 4 times) were given during irradiation and tapered off as soon as possible after WBRT
Outcomes	Primary end point: duration of survival Secondary end points: response rates TTP duration of response (complete and partial responders were considered together)
Notes	Analysis was performed on all eligible patients according to the intent‐to‐treat principle. The analysis of toxicity was based on the treatment patients actually received Competing interests and information on funding sources not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was done using minimization techniques with patients stratified according to their institution, number of BM (> 2), and prior chemotherapy (naive/pretreated)
Allocation concealment (selection bias)	Unclear risk	No further description in the manuscript. Probably central allocation. Additional information requested to authors but no answer received
Blinding of participants and personnel (performance bias) Survival	Low risk	No information was provided, but main outcome measure (duration of survival) is it not likely to be influenced by lack of blinding
Blinding of participants and personnel (performance bias) Toxicity and disease related symptoms	Unclear risk	No information was provided
Blinding of outcome assessment (detection bias) Survival	Low risk	No information provided, but main outcome measure (duration of survival) is it not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) CR, toxicity, quality of life	Unclear risk	No information was provided
Incomplete outcome data (attrition bias) Survival	High risk	Only 1 participant in the teniposide + WBRT was lost to follow‐up. However, only 6 patients completed all 12 courses of protocol therapy in the combined group compared with 0 in the teniposide group. Reasons for stopping protocol therapy were reported in both groups. Tumor progression was the principal cause for stopping protocol therapy
Incomplete outcome data (attrition bias) Toxicity, disease related symptoms, CR	High risk	Only 1 participant in the teniposide + WBRT was lost to follow‐up. However, only 6 patients completed all 12 courses of protocol therapy in the combined group compared with 0 in the teniposide group. Reasons for stopping protocol therapy were reported in both groups. Tumor progression was the principal cause for stopping protocol therapy
Selective reporting (reporting bias)	Low risk	Authors presented results on all outcome measures that were prespecified as relevant
Other bias	Low risk	The study seems to be free of other sources of bias

BM: brain metastases; CR: complete remission; CT: computer tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; ECT: emission computer tomography; G‐CSF: granulocyte colony‐stimulating factor; EORTC: European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group; ICTRP: International Clinical Trials Registry Platform; MRI: magnetic resonance imaging; NC: no change; NSCLC: non‐small cell lung cancer; OS: overall survival; PD: progressive disease; PFS: progression‐free survival; PR: partial remission; QoL: quality of life; RCT: randomized controlled trial; RECIST: Response Evaluation Criteria In Solid Tumors; SCLC: small cell lung cancer; TTO: time to progression; WBRT: whole brain radiotherapy.