Freedman 1980.

Methods	Randomised Phase II trial 1975
Participants	59 women with recurrent squamous cell cervical cancer
Interventions	Arm 1: sequential cyclophosphamide 8 mg/kg iv d1‐5 q28 then adriamycin 80 mg/m2 iv d1 q28 then hexamethylmelamine 8 mg/kg po daily continuously Arm 2: sequential adriamycin 80 mg/m2 iv d1 q28 then cyclophosphamide 8 mg/kg iv d1‐5 q28 then hexamethylmelamine 8 mg/kg po daily continuously Arm 3: sequential hexamethylmelamine 8 mg/kg po daily continuously then cyclophosphamide 8 mg/kg iv d1‐5 q28 then adriamycin 80 mg/m2 iv d1 q28 Not stated prospectively what criteria would be for switching treatment (i.e. number of cycles versus progressive disease)
Outcomes	Response rates Survival time after chemotherapy start Survival from time of treatment change
Notes	1 patient excluded (died prior to starting chemotherapy). No ITT analysis performed. Cross‐over between arms allowed. Reasons for switching chemotherapy agents varied and included disease progression, toxicity and cumulative doxorubicin dose
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stratified by ease of disease evaluation then randomised
Allocation concealment (selection bias)	Unclear risk	Not documented
Blinding (performance bias and detection bias) All outcomes	Low risk	Not documented, but OS unlikely to be affected by blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Low risk	Published report included all pre‐specified outcomes
Other bias	High risk	Patients allowed to switch between arms for variety of reasons including toxicity, cumulative doxorubicin dose and disease progression