Sutton 2000.

Methods	Phase III Randomised Controlled Trial "Treatment was randomly allocated in an unblinded fashion without concealment"
Participants	194 women with histologically confirmed advanced or recurrent carcinosarcoma no longer amenable to control by surgery and/or radiotherapy. 102 were in arm 1 (ifosfamide) and 92 in arm 2 (ifosfamide + cisplatin). Median age for arm 1 was 67 years (range 32‐84), 66 years for arm 2 (range 35‐83). Inclusion criteria: All patients had to have measurable disease which could be defined in at least two dimensions by palpation, X ray, computed tomography, or ultrasound. White blood count ≥ 3000/mcl, platelet count ≥ 100,000/mcl, blood urea nitrogen level ≥ 30 mg/dL, creatinine ≥ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min, serum bilirubin ≤ 1.5 times normal, SGOT (ALT) ≤ 3 times normal, serum albumin ≥3 g/dL, and a GOG performance status (PS) of 0 to 2 (Karnofsky score ≥60%). Exclusion criteria: Patients must have received no prior chemotherapy. Patients with extensive hepatic metastases, acute hepatitis, septicaemia, severe infection, or gastrointestinal bleeding were ineligible. Patients with previous or concomitant malignancy other than non‐melanoma skin cancer were ineligible. Written informed consent was obtained from all patients prior to study entry, fulfilling all institutional, state, and federal regulations. Slides documenting the primary cancer were submitted for central pathologic review.
Interventions	Arm 1: ifosfamide alone (1.5 g/m2/day) for 5 days with mesna uroprotection , each course given intravenously every 3 weeks. Ifosfamide doses were reduced by 20% to 1.2 g/m2/day in patients who had previous pelvic radiotherapy. Mesna was administered as a continuous infusion in a dose identical to that of ifosfamide. Each patient received eight cycles of therapy unless there was disease progression or undue toxicity. Ifosfamide doses were reduced 20% for grade 4 white blood count or platelet toxicity, grade 3 or 4 hepatic toxicity, or grade 1 renal or neurologic toxicity. Arm 2: Ifosfamide plus cisplatin (20 mg/m2/day) times 5 days. Because of the unexpected toxicity observed early in the trial in patients receiving combination therapy, doses of both drugs were reduced 20% by giving a 4‐day instead of 5‐day course of therapy.
Outcomes	Primary outcome measure: Progression‐free survival (PFS) was defined as the period of time from randomisation until progression of disease or death, whichever occurred first, or the date of last contact for patients remaining alive and progression‐free. Overall survival was measured from the date of study entry to the date of death or date of last contact for patients alive at last contact. Response to treatment defined as: a) Complete response, b) Partial response, c) Increasing disease d) Stable disease, Adverse effects were graded using standard GOG criteria. Eligible patients receiving at least one course of treatment were included in the assessment of adverse effects.
Notes	All eligible patients were included in the analysis of overall and progression‐free survival. All causes of death were considered events in overall and progression‐free survival analysis This randomised Phase III study was designed to detect an increase in response from 34% to 54% or a 50% increase of 2.8 months in median progression‐free survival with 80% power and type I error set at 0.05 for a one‐tailed test. Also, detectable with 76% power and type I error set at 0.05 (one‐tailed) a 50% increase of 6.2 months in median survival was planned. Final analysis required the observation of 136 deaths for survival and 150 failures for PFS. Site of measurable disease appear to be imbalanced between the two treatment arms. 37% of patients on the ifosfamide arm compared to 59% of patients on the combination arm had measurable disease limited to the pelvis. The median number of treatment cycles was 4 with 0‐8 range. Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide– cisplatin therapy was (0.36 versus 0.54) overall, (0.47 versus 0.61) for pelvic, (0.21 versus 0.54) for lung, and (0.33 versus 0.40) for “other” metastatic sites of measurable disease. The median progression‐free survivals for the ifosfamide was 4 months and for the combination arm it was 6 months (relative risk, 0.73; 95% upper confidence limit, 0.94; P 5 0.02). There was no statistically significant difference between the two treatment groups with regard to survival The median duration overall survival for arms was 7.6 and 9.4 months, respectively (relative risk, 0.80, 95% upper confidence limit, 1.03; P 5 0.07).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported, "Treatment was randomly allocated".
Allocation concealment (selection bias)	High risk	"Treatment was randomly allocated ... without concealment".
Blinding (performance bias and detection bias) All outcomes	High risk	"Treatment was randomly allocated in an unblinded fashion".
Incomplete outcome data (attrition bias) All outcomes	Low risk	% analysed: 194/194 (100%) for time‐to‐event outcomes and 191/194 (98%) for all adverse events outcomes. 224 women were randomised, but 30 were found to be ineligible.
Selective reporting (reporting bias)	Low risk	All important survival and adverse event outcomes have been reported. Survival outcomes have been analysed using appropriate statistical techniques to account for censoring.
Other bias	Unclear risk	Insufficient information to assess whether an additional risk of bias exists.