Legha 1996.

Study characteristics
Methods	Phase II parallel‐group RCT. Open label study.
Participants	Untreated metastatic melanoma. Randomised participants:102.
Interventions	Two‐arm study: Chemotherapy and biotherapy regimens were alternating integrated initially (6‐week intervals), (N = 40); Subsequently, regiments were sequentially administered (participants were randomised to receive either chemotherapy immediately followed by biotherapy or the reverse sequence), (N = 62). Treatment schedules: Chemotherapy: cisplatin 20 mg/m² IV daily for 4 days, vinblastine 1.6 mg/m² IV daily x 5 days, and dacarbazine 800 mg/m² IV daily, repeated every 3 weeks; Biotherapy: IL‐2,9 x 106 IU/mVd for 4 days and IFN‐a 5 x 10^6 U/m² daily SC for 5 days.
Outcomes	Progression‐free survival. Overall survival. Tumour response. Toxicity.
Notes	Cross‐over: not allowed. Quality of life: not reported. Participants with brain metastasis: participants with symptomatic brain metastasis were excluded. Median follow‐up: 45 months. Note: Both biochemotherapy schedules were compared with a non‐randomised group of participants who received chemotherapy alone.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomly assigned". Comment: There was insufficient information about the sequence generation process to permit judgment.
Allocation concealment (selection bias)	Unclear risk	There was insufficient information to permit judgment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	As an open label study, no blinding of participants or personnel was possible. However, we believe that in this setting (metastatic melanoma), with the treatments tested and outcomes assessed, the knowledge of which intervention was received or administered (rather than the intervention itself), could not affect the outcomes under investigation. Therefore, we judged the risk of performance bias as low.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	There was insufficient information to permit judgement.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing outcome data were balanced across intervention groups, with similar reasons for missing data across groups.
Selective reporting (reporting bias)	Unclear risk	Published reports included all expected outcomes. However, no protocol was available so it was unclear if all planned outcomes were reported.
Other bias	Low risk	The study appeared to be free of other sources of bias.