Neuhaus 2009.

Methods	RCT phase III
Participants	Patients with histologically confirmed lung cancer and intracerebral metastases. Initially only patients with recurrence of lung cancer after first‐line therapy were included in the study. However, due to a slow recruitment, after 1 year an amendment allowing the inclusion of primary diagnosed patients was added. Randomization was performed by considering the parameters SCLC, NSCLC, extracerebral metastases, and a number of BM n = 96; 47 chemoradiotherapy, 49 radiotherapy Sex: 62 male, 34 female Median age: 58/59 years (range: 34 to 75 years) Clinical condition: SCLC: 5 first‐line, 28 recurrence NSCLC: 15 first‐line, 48 recurrence Inclusion criteria: histologically confirmed lung cancer and intracerebral metastases aged 18 to 75 years at least 1 measurable lesion in the brain was confirmed by CT or MRI sufficient bone marrow reserve (neutrophil counts 1500/μL, leukocyte counts ≥ 3500/μL, platelet counts ≥100,000/μL, and hemoglobin ≥ 9 g/dL). adequate renal function (serum creatinine concentration ≤ 1.5 mg% or creatinine clearance > 60 mL/minute performance status of 0 to 2 according to ECOG criteria Exclusion criteria: prior to cerebral radiotherapy, surgery, or both of cerebral metastases (except stereotactic biopsy) missing histologically confirmed nature of cancer solitary intracerebral metastases suitable for neurosurgery meningiosis carcinomatosa active uncontrolled infection concomitant or previous malignancies, except basal or squamous cell carcinoma or carcinoma in situ of the cervix history of therapy with or without known allergy to topoisomerase I inhibitors pregnant or breast‐feeding women
Interventions	Arm A (chemoradiotherapy): topotecan was administered as a 30‐minute infusion with 0.4 mg/m2/day for 5 days over 4 weeks within 2 hours before radiotherapy. WBRT was applied with a fraction size of 2 Gy/day to a total of 40 Gy. Arm B (radiotherapy): WBRT was applied with a fraction size of 2 Gy/day to a total of 40 Gy. Continuation therapy: subsequently, patients with extracerebral cancer lesions from both arms had the option to receive 3 additional cycles of topotecan chemotherapy (1.25 mg/m2/day, days 1 to 5, 4 cycles of 21 days), starting on day 15 after the end of WBRT. Where a patient had not received any kind of chemotherapy or chemoradiotherapy before entering the study, the institutionally preferred chemotherapeutic regimen was allowed to be used instead. Continuation therapy was stopped after 3 cycles or when tumor progression of the extracerebral metastases occurred
Outcomes	Primary end point: OS (minimum clinically relevant therapeutic effect an increase in the survival time to 5.5 months) Secondary end points: PFS rates of complete responses of the cerebral lesions duration of remission status of the extracerebral tumors after continuation therapy and toxicity QoL and safety A complete response was defined as a complete disappearance of all evidence of disease in the brain. A partial response was defined as radiologic response > 50% in all BM. Responses in tumor lesions < 50% or increase in size < 25% was defined as stable disease. A progressive disease was defined as either the occurrence of new lesions or an increase in size of > 25%
Notes	Numerical results for patients with SCLC were not presented in a disaggregated way, but authors reported in a narrative way that in relation with OS and PFS differences between compared groups were not significant either for SCLC and NSCLC Initially only patients with recurrence of lung cancer after first‐line therapy could be included in the study. However, due to a slow recruitment, after 1 year an amendment allowing the inclusion of primary diagnosed patients was added An interim analysis was planned after the death of 150 patients. However, until 6 August 2004, that is, after a study duration of 34 months, only 95 patients in 11 centers had been recruited, and so the interim analysis was performed at that time point. This analysis did not show any benefit of chemoradiotherapy with regard to OS and thus, on the basis of the slow recruitment and the result of the interim analysis, a continuation of the study did no longer appear reasonable. The results described here represent the final analysis, in which 96 patients were included. Study supported by GlaxoSmithKline Competing interests not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgment. Mentioned as "randomized" but sequence generation process is not explained in a detailed way. Probably centralized. Quote: "Randomisation was performed by considering the parameters SCLC, NSCLC, extracerebral metastases and a number of brain metastases". Additional information requested from authors but no answer received
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgment. Additional information requested from authors but no answer received
Blinding of participants and personnel (performance bias) Survival	Low risk	Stated as "open", but main outcome measure (OS) 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	Stated as "open"
Blinding of outcome assessment (detection bias) Survival	Low risk	Stated as "open", but main outcome measure (OS) is it not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) CR, toxicity, quality of life	Unclear risk	Stated as "open"
Incomplete outcome data (attrition bias) Survival	Low risk	Data was not presented for the SCLC subgroup No losses in follow‐up reported. Causes for protocol deviations well reported. Quote: "The reasons for protocol deviations are mainly early deaths, haematological toxicities, dosage failure, worsening of general condition and tumour progression. In detail, in arm A the chemotherapy was delayed or reduced in nine patients because of neutropenia, and in six of them G‐CSF was given at least once. Although no patient stopped topotecan because of neutropenia, one patient left the study because of prolonged thrombocytopenia." Quote: "The treatment was stopped as per the patients' wish, by the decision of the physician, tumour progression, severe side effects according to the NCIC CTCG guidelines or non‐compliance of the patient."
Incomplete outcome data (attrition bias) Toxicity, disease related symptoms, CR	Low risk	Data were not presented for the SCLC subgroup No losses in follow‐up reported. Causes for protocol deviations well reported Quote: "The reasons for protocol deviations are mainly early deaths, haematological toxicities, dosage failure, worsening of general condition and tumour progression. In detail, in arm A the chemotherapy was delayed or reduced in nine patients because of neutropenia, and in six of them G‐CSF was given at least once. Although no patient stopped topotecan because of neutropenia, one patient left the study because of prolonged thrombocytopenia." Quote: "The treatment was stopped as per the patients' wish, by the decision of the physician, tumour progression, severe side effects according to the NCIC CTCG guidelines or non‐compliance of the patient"]
Selective reporting (reporting bias)	Low risk	Authors presented results on all outcome measures that were pre‐specified as relevant Search for protocol in clinical trials registers
Other bias	Low risk	Early termination of the study, but according to previously established criteria Quote: "The whole study was to be stopped in case new therapeutic regimens with superior benefit of either therapy arm were published, if the interim analyses showed that the criteria for stopping the study by using the methods of Pocock (Pocock 1978) and O'Brien and Fleming (O'Brien 1979) were reached and when the number of patients recruited was clearly below the expected value." Quote: "until August 6, 2004, that is, after a study duration of 34 months, only 95 patients in 11 centers had been recruited, and so the interim analysis was performed at that time point. This analysis did not show any benefit of chemoradiotherapy with regard to OS and thus, on the basis of the slow recruitment and the result of the interim analysis, a continuation of the study did no longer appear reasonable. The results described here represent the final analysis, in which 96 patients were included."