Homesley 2007.

Methods	Phase III Randomised Controlled Trial
Participants	179 women with histologically confirmed stage III or IV, persistent or recurrent uterine carcinosarcoma not amenable to treatment with curative intent by other means. 91 were randomised to arm 1 (ifosfamide alone). 88 were randomised to arm 2 (ifosfamide + paclitaxel). Median age for both arms was 64 years. In arm 1 (single agent ifosfamide) 18% had stage III, 31% stage IV and 52% had recurrent/persistent disease In arm 2 (ifosfamide + paclitaxel) 18% had stage III, 29% had stage IV disease and 52% had recurrent/persistent disease All women had measurable disease by palpation or radiologically (X‐ray, MRI, CT or USS) with minimum measurement of 1 cm. Patients had to have adequate bone marrow function with an absolute neutrophil count > 1,500 mL/uL, platelets >100,000 uL, creatinine clearance of > 50 mL/min, bilirubin < 1.5x normal, AST < 3x normal and serum albumin > 3 g/dL. GOG performance status 0, 1, or 2 At least 6 weeks must have passed since RT to the site of current measurable disease. Exclusion: patients who received prior chemotherapy for uterine carcinosarcoma. Patients with septicaemia, severe infection, acute hepatitis, GI bleed or performance status 3‐4. Patients having other invasive malignancies, prior or current evidence of cancer within the last 5 years, or any cancer therapy determined to be a contraindication for the study protocol. History of congestive cardiac failure unstable angina or myocardial infarction in the last 6 months.
Interventions	Arm 1: Ifosfamide 2 mg/m2 intravenously (IV) daily for three days every 21 days for eight cycles. The starting dose was 1.2 mg/m2 for patients who had received prior radiotherapy (RT). Mesna was administered either IV or orally. The IV administration consisted of 2 g during 12 hours beginning 1 minutes before the ifosfamide infusion; for oral administration, the total dose was 4 g in three divided doses of 1.33 g administered one hour before and eight hours after the ifosfamide infusion for three days Arm 2: Ifosfamide 1.6 mg/m2 daily for three days (or was reduced to 1.2 mg/m2 for patients who had received prior radiotherapy. Paclitaxel 135mg/m2 during three hours IV was administered on day 1. Mesna was to be administered as per Arm 1. The premedication for paclitaxel was dexamethasone 20 mg orally or IV 12 and 6 hours before paclitaxel, diphenhydramine 50 mg IV 30 minutes before paclitaxel. Patients on both arms were to receive a maximum of eight cycles of protocol therapy unless disease progression or adverse effects prohibited additional treatment.
Outcomes	Primary outcome measure: Overall survival (OS) was defined as the observed length of life from study entry to death as a result of any cause or, for the living patients, the date of last contact. Progression‐free survival (PFS) was the length of time a patient survived from study entry without tumour progression (defined as reappearance or increasing disease). Response to treatment defined as: a) Complete response was the disappearance of all gross evidence of disease lasting for at least 4 weeks b) Partial response was a reduction of 50% or greater in the bi‐dimensional measurement of each lesion sustained for at least 4 weeks c) Increasing disease was a 50% or greater increase in any lesion or the appearance of any new lesion (s) within 8 weeks of entry onto the study d) Stable disease was any condition not meeting any of the above criteria Secondary outcomes: Adverse events believed to be related protocol treatment, assessed according to the GOG Common Toxicity Criteria.
Notes	The median duration of follow up was 20 months. Overall the response rate (complete + partial response) was 45% in ifosfamide + paclitaxel arm and 29% in ifosfamide only arm. The odds of response stratified by performance status were 2.21 greater in arm 2 (P = 0.017). The median overall survival was 13.5 months in the combination arm and 8.4 months in the ifosfamide only arm. Median PFS and OS, respectively, for arm 1 compared with arm 2 were 3.6 versus 5.8 months and 8.4 versus 13.5 months, respectively. Intention‐to‐treat principle was applied to the treatment group comparisons of overall survival, progression‐free survival and clinical response. Alog rank test stratified by performance status was used to test the independence of treatment with PFS and OS.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Random assignment was carried out with equal probability of assignment to each treatment regimen using a balanced block randomisation to balance assigned treatment regimens within strata defined by institution and performance status (0 to 1 or 2)".
Allocation concealment (selection bias)	Low risk	"The treatment assignment was concealed from institution and the patient until telephone registration with verification of eligibility".
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	% analysed: 179/179 (100%) for time‐to‐event outcomes and 174/179 (97%) for all adverse events outcomes. 214 women were randomised, but 35 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.