Sekine 2014.

Methods	STUDY DESIGN: Parallel group LOCATION, NUMBER OF CENTRES: Japan DURATION OF STUDY: July 2006 – September 2007; December 2007 – April 2008 CONCEALMENT OF ALLOCATION: Not described DESCRIBED AS RANDOMISED: Yes DESCRIBED AS DOUBLE BLIND: No METHOD OF RANDOMISATION WELL DESCRIBED/APPROPRIATE: Yes METHOD OF BLINDING WELL DESCRIBED/APPROPRIATE: N/A DESCRIPTION OF WITHDRAWALS/DROPOUTS: Yes GRADE ASSESSMENT QUALITY RATING: Low TYPE OF ANALYSIS (AVAILABLE CASE/TREATMENT RECEIVED/ ITT): ITT COMPLIANCE: CONFOUNDERS:
Participants	INCLUSION CRITERIA: The eligibility criteria were histologically or cytologically proven SCLC; no previous chemotherapy; measurable disease; age >= 70 years; Eastern Cooperative Oncology Group performance status (PS) of 0 to 2; life expectancy of >= 2 months; adequate bone marrow function (white blood cell count of 4.0 x 10^9 to 12 x 10^9/L, neutrophil count >= 2.0x10^9/L, hemoglobin >=9.5 g/dL, and platelet count >=100x10^9/L); adequate liver function (aspartate aminotransferase and alanine aminotransferase <= 2.5 times the upper limit of the normal range and total bilirubin < 1.5 mg/dL); adequate renal function (serum creatinine <= 1.5 mg/dL and glomerular filtration rate [GFR] calculated using the Cockcroft‐Gault method >= 30 mL/min); adequate pulmonary function (PaO2 >= 60 Torr under room air); adequate cardiac function (electrocardiogram without abnormal findings requiring treatment and left ventricular ejection fraction measured using echocardiography >= 60%); and written informed consent. Patients who received radiation or surgery for metastatic sites other than the primary site were eligible if they received these treatments two weeks or more before registration for this study. EXCLUSION CRITERIA: Patients were excluded if they had symptomatic brain metastases; pleural or pericardial effusion or ascites that required drainage; superior vena cava syndrome; abnormal cardiac function that required treatment or a history of this condition; interstitial pneumonitis or lung fibrosis identified on chest radiograph; severe infection; serious syndrome of inappropriate secretion of antidiuretic hormone or uncontrolled diabetes mellitus; gastric or duodenal ulcer; or active prior malignancies with a disease‐free interval of less than five years, except for carcinoma in situ. Pregnant or lactating women, men who had no intention of using contraception, and patients who had participated in registration‐directed clinical trials in the previous six months were also ineligible. N SCREENED: 62 N RANDOMISED: 62 (32 in Arm A ‐ non‐platinum (amrubicin) and 30 in Arm B ‐ platinum (carboplatin/etoposide) N COMPLETED: 61 (31 for amrubicin and 30 carboplatin/etoposide) ASSESS STAGE: Yes (N LIMITED): NA (N EXTENSIVE): 62 M: 24 (amrubicin), 24 carboplatin/etoposide F: 8 (amrubicin), 6 (carboplatin/etoposide) MEAN AGE: Median Age: [Amrubicin –76years (70‐88); EP ‐ 75 years (70‐82)]
Interventions	TYPE: Chemotherapy REGIMENS AND DOSE: The patients were randomly assigned to receive amrubicin monotherapy (arm A) or carboplatin/etoposide (arm B). In arm A, amrubicin dissolved in 20 mL normal saline was administered once intravenously as a 5‐minute infusion on days 1 to 3, every 3 weeks. At the start of the study, the dose of amrubicin was set at 45 mg/m2/ d for 3 days in patients aged < 75 years and at 40 mg/m2/d for 3 days in patients aged >= 75 years. However, 2 of the first 21 patients in arm A who received amrubicin at 45 mg/m2/d died of severe infection associated with serious myelosuppression, and dose reduction was also required in subsequent cycles in 4 of 8 patients who started at 45 mg/m2/d. CYCLES: In both arms chemotherapy was repeated every 3 weeks for a total of 4‐6 cycles DELIVERY: IV CO‐INTERVENTIONS PERMITTED: Nil CO‐INTERVENTIONS: Nil
Outcomes	OUTCOMES MEASURED: Primary endpoint: overall survival Secondary endpoints: objective response rate, toxicity, time to progression and quality of life. FOLLOW‐UP ASSESSMENT POINTS: Objective tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, using CT or MRI for target and nontarget lesions performed every 4 weeks, and every 2 months after the best tumor response was established. OUTCOMES INCLUDED IN ANALYSES: Survival Response rate Toxicity Quality of Life SUB‐GROUPS INDENTIFIED: Nil – Extensive Stage SCLC (ED‐SCLC) only
Notes	Trial terminated early due to treatment‐related deaths in non‐platinum (amrubicin) arm Between July 4, 2006, and September 5, 2007, 21 and 22 patients were enrolled in arms A and B, respectively. Two patients in arm A treated with amrubicin at 45 mg/m2/d died from severe infection associated with grade 4 neutropenia (sepsis in the first cycle in one patient and pneumonia in the third cycle in the other). There were no treatment‐related deaths in arm B. The dose of amrubicin was reduced to 40 mg/m2/d in subsequent cycles in 4 of 8 patients who started at 45 mg/m2/d. After a recommendation from the Data Monitoring Committee (DMC), the protocol was amended and amrubicin was administered at 40 mg/m2/d in all patients registered in arm A thereafter. From December 2007 to April 2008, 11 and 8 patients were added to arms A and B, respectively. Of these patients, one in arm A died of amrubicin‐ induced pneumonitis. Enrollment of patients was then terminated early after a DMC recommendation.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Described and appropriate
Allocation concealment (selection bias)	Low risk	Described and appropriate
Blinding (performance bias and detection bias) Participants	Unclear risk	Not described
Blinding (performance bias and detection bias) Investigators	Unclear risk	Not described
Blinding (performance bias and detection bias) Survival	Unclear risk	Not described
Blinding (performance bias and detection bias) Tumour Response	Unclear risk	Not described
Blinding (performance bias and detection bias) Toxicity	Unclear risk	Not described
Blinding (performance bias and detection bias) Quality of Life	Unclear risk	Not described
Incomplete outcome data (attrition bias) Survival	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Incomplete outcome data (attrition bias) Tumour Response	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Incomplete outcome data (attrition bias) Toxicity	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Incomplete outcome data (attrition bias) Quality of Life	Low risk	All randomised patients accounted for; withdrawals and dropouts adequately described
Selective reporting (reporting bias)	Low risk	Adequate
Other bias	Unclear risk	Trial initially interrupted (to allow for a dose reduction) and then terminated early due to treatment related deaths in non‐platinum (amrubicin) arm