Havemann 1987.

Methods	STUDY DESIGN: Parallel study LOCATION, NUMBER OF CENTRES: Germany, multicentre DURATION OF STUDY: July 1981 to November 1983. CONCEALMENT OF ALLOCATION: C DESCRIBED AS RANDOMISED: Yes DESCRIBED AS DOUBLE BLIND: No METHOD OF RANDOMISATION WELL‐DESCRIBED/APPROPRIATE: Not described METHOD OF BLINDING WELL‐DESCRIBED/APPROPRIATE: Not described DESCRIPTION OF WITHDRAWALS/DROP‐OUTS: Yes GRADE ASSESSMENT QUALITY RATING: High TYPE OF ANALYSIS (AVAILABLE CASE/TREATMENT RECEIVED/ ITT): ITT
Participants	INCLUSION CRITERIA: Histologic proof of SCLC ‐ positive cytologic findings were not considered histologic confirmation; signs of measurable or evaluable disease; performance status of 50% or more according to the Karnofsky scale; age of 70 years or younger; and informed patient consent. EXCLUSION CRITERIA: prior radiotherapy, chemotherapy or surgical treatment received; existence of an accessory malignant disease; evidence of renal dysfunction (creatinine > 1.5 mg/dL), chronic haptic disease (bilirubin > 2.0 mg/dL); or advanced respiratory or cardiac insufficiency. N RANDOMISED: 306 (302 evaluable) (sequential ‐ 155, alternating ‐ 151) ASSESS STAGE: Yes (N LIMITED): 104 (N EXTENSIVE): 198 M: 254 F: 48 AGE:
Interventions	TYPE: Chemotherapy REGIMENS: Sequential chemotherapy consisted of 8 cycles of CAV ‐ cyclophosphamide 1000 mg/m2 intravenously (IV) on day 1, Adriamycin 50 mg/m2 IV on day 1, and vincristine 2 mg IV on day 1, all administered in 3‐week intervals. Alternating chemotherapy consisted of 3 cycles of EVI (cycles 1, 3 and 5) ‐ etoposide 80 mg/m2 IV on days 1 to 3, vindesine 3 mg/m2 IV on day 1, and iphosphamide 1500 mg/m2 IV on days 1 to 5 alternating with 3 cycles (cycles 2, 4 and 6) of PAV ‐ cisplatin 90 mg/m2 IV on day 1, Adriamycin 60 mg/m2 IV on day 1, and vincristine 2 mg IV on day 1, all administered in 3‐week intervals and followed by application of CMC ‐ cyclophosphamide 1000 mg/m2 IV on days 1 and 22, methotrexate 15 mg/m2 orally on days 1, 4, 8 and 11; and CCNU 100 mg/m2 orally on day 1 in a 6‐week cycle. CO‐INTERVENTIONS: Responsive patients received prophylactic cranial irradiation after 3 cycles. Patients without distant metastases after 8 cycles of chemotherapy received chest irradiation. Patients with brain metastases received cranial irradiation immediately. Accessory painful metastatic sites were irradiated as necessary.
Outcomes	OUTCOMES MEASURED: Tumour response (defined as best response at any time during treatment) Survival Progression‐free survival Tumour progression or relapse Toxicity FOLLOW UP ASSESSMENT POINTS: OUTCOMES INCLUDED IN ANALYSES: Tumour response (defined as best response at any time during treatment) Survival Toxicity
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation reported and adequate
Allocation concealment (selection bias)	High risk	Allocation concealment not adequate
Blinding (performance bias and detection bias) Participants	Unclear risk	Not reported
Blinding (performance bias and detection bias) Investigators	Unclear risk	Not reported
Blinding (performance bias and detection bias) Survival	Unclear risk	Not reported
Blinding (performance bias and detection bias) Tumour Response	Unclear risk	Not reported
Blinding (performance bias and detection bias) Toxicity	Unclear risk	N/A
Blinding (performance bias and detection bias) Quality of Life	Unclear risk	N/A
Incomplete outcome data (attrition bias) Survival	Low risk	Reasons for withdrawals, drop‐outs and exclusions reported
Incomplete outcome data (attrition bias) Tumour Response	Low risk	Reasons for withdrawals, drop‐outs and exclusions reported
Incomplete outcome data (attrition bias) Toxicity	Unclear risk	N/A
Incomplete outcome data (attrition bias) Quality of Life	Unclear risk	N/A
Selective reporting (reporting bias)	Low risk	Adequate
Other bias	Low risk	Adequate