Wolfson 2007.

Methods	Phase III Randomised Controlled Trial
Participants	232 enrolled in the study, 25 were excluded based on review of histology and one patient was excluded due to inappropriate residual disease at determined by GOG Gyne/oncology committee review. All were previously untreated patients with stages I, II, III, and IV primary carcinosarcomas of the uterus or cervix (without any demonstrable parenchymal hepatic involvement or extra‐abdominal distant disease) 206 patients were in the study, 105 were randomised to whole abdominal irradiation (WAI) arm and 101 to Cispltain, Ifosfamide with mesna (CIM) arm. 43% of patients randomised to WAI arm had stage III, and 46% in the CIM arm had stage III Median age for WAI was 68 years and 65 years for CIM arm. Eligibility required a patient to have a TAH, BSO, and maximal resection of all gross intra‐abdominal/pelvic disease, including macroscopically involved pelvic and para‐aortic nodes, leaving no residual disease any larger than 1 cm. Peritoneal cytology and RPLND were optional if there were no intraoperative clinical manifestations of residual disease within the abdomen and pelvis. Adequate hematologic (WBC ≥ 3000/μL, platelets ≥1 00,000/μL, and granulocytes ≥ 1500/μL), renal (serum creatinine ≤ 1.5 mg% or creatinine clearance ≥ 50 mL/min), and hepatic (serum bilirubin ≤1.5 × the institutional value, serum AST≤3 × the institutional value, and serum albumin ≥ 3) functions were required. In addition, eligible patients were required to have a GOG Performance Status of 0, 1, or 2 and a normal chest X‐ray (no other imaging studies were required).patients who had received prior hormonal manipulation (not evaluated in this study) were also eligible for entry. Exclusion criteria: patients who had a prior history of receiving radiotherapy and/ or chemotherapy or who had a concomitant malignancy (other than non‐melanoma skin cancer) within 5 years of being diagnosed with uterine CS were ineligible.
Interventions	Arm 1: Whole Abdominal Irradiation (WAI) was to be delivered by external beam radiation therapy (EBRT) to the abdomen and pelvis that involved a minimum beam energy of 4 MV photons and utilised an anterior/posterior (AP) and posterior/anterior (PA) summated technique. The field borders for WAI involved 1 cm margins on the diaphragm superiorly, the inguinal ligament inferiorly, and the lateral aspect of the peritoneal margin laterally. At the outset of this protocol, the whole abdomen was treated to a total dose of 30 Gy at 1 Gy per fraction, two fractions per day, and 5 days each week with a minimum of 6 h between morning and afternoon fractions (hyperfractionation). Due to slow patient accrual, in August of 1996, the dose fractionation schedule was changed to once‐daily fractions of 1.5 Gy for 5 days each week to the same total dose to the whole abdomen of 30 Gy. Whole abdominal irradiation (WAI). The true pelvis was treated with a boost requiring a four‐field “box” set‐up that included not only AP/PA beam portals but also opposed lateral fields. The pelvic field borders included the S1/S2 interspace superiorly, the mid‐level portion of the obturator foramen inferiorly, and 1 cm beyond the widest aspect of the true pelvic laterally. At the initiation of this study, the true pelvis as a boost was treated to a total dose of 20 Gy at 1 Gy per fraction, two fractions per day for 5 days each week with the same 6 h time interval between fractions as was initially done for the WAI (cumulative true pelvic dose of 50 Gy). As stated above, the fractionation schedule was also changed in August of 1996 for this portion of radiotherapy to once‐daily fractions of 1.8 Gy for 5 days each week to a total dose of 19.8 Gy (cumulative true pelvic dose of 49.8 Gy). Arm 2: Cispltain, Ifosfamide with mesna (CIM) comprised intravenous (IV) cisplatin (20 mg/m2/day × 4 days) that was to be followed by a 1 h IV administration of ifosfamide (1.5g/m2/day IV × 4 days) with mesna (120 mg/m2 IV bolus over 15 min on day one, followed by 1.5 g/m2/day IV continuous infusion × 4 days beginning with day one) every 3 weeks for three cycles. It was recommended that hydration be maintained by IV administration of 1 L over several hours preferably with either normal or one‐half normal saline prior to initiation of chemotherapy in order to maintain urine output of at least 100 mL/h. IV fluid and electrolyte repletion was permitted as medically indicated during the 4‐day course of chemotherapy. Cisplatin administration was required prior to ifosfamide therapy and was to be reconstituted at a concentration of approximately 1 mg/mL and infused at a rate of 1 mg/min. Dose modifications for toxicities of cisplatin and ifosfamide were permitted but not for mesna administration. Protocol therapy was to be started within 8 weeks following initial surgery.
Outcomes	The primary outcome measures for assessing treatment efficacy Death: An individual’s survival is assessed from the date she was registered onto the study to the date of death from any cause or, for living patients, the date of last contact. Recurrence rate: The recurrence‐free interval was assessed from the date of entry onto the protocol to date when clinically evident disease was observed. Secondary measures: Adverse events of treatment were classified as being either acute or late toxicities. A toxicity that occurred during study therapy was identified as acute, while those that either persisted or developed after completion of treatment were separately identified as late or chronic toxicities.
Notes	After protocol treatment, patients were evaluated every 3 months for the first 2 years and then every 6 months thereafter by a treating physician with CBC, serum creatinine, serum bilirubin, serum AST, and CA‐125 level (required prior to study entry). A chest X‐ray was required every 6 months following completion of study treatment for the first 2 years and then yearly thereafter. The estimated crude probability of recurring within 5 years was 58% (WAI) and 52% (CIM). The estimated crude probability of surviving at least 5 years following diagnosis was approximately 35% for those randomised to WAI vs. 45% for those randomised to CIM. The median duration of follow‐up for patients alive at last contact was 5 years and 3 months.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The list of treatment assignments was created by concatenating randomly selected balanced blocks of permuted treatments".
Allocation concealment (selection bias)	Low risk	"The complete list of treatment assignments remained concealed and only the next unassigned treatment was revealed after each patient was successfully registered onto the study".
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	% analysed: 206/206 (100%) for time‐to‐event outcomes and 197/206 (96%) for all adverse events outcomes. 232 women were randomised, but 26 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.

ALT: alanine transaminase
 AP: anterior/posterior
 AST: aspartate aminotransferase (SGOT)
 BSO: bilateral salpingo‐oophorectomy
 CIM: cisplatin and Ifosfamide with mesna
 CT: computed tomography
 EBRT: external beam radiation therapy
 GI: gastrointestinal
 GOG: Gynecologic Oncology Group
 MRI: magnetic resonance imaging
 OS: overall survival
 PA: posterior/anterior
 PFS: progression‐free survival
 RPLND: Retroperitoneal Lymph Node Dissection
 SGOT: glutamic oxaloacetic transaminase (AST)
 TAH: total abdominal hysterectomy
 USS: ultrasound scan
 WAI: whole abdominal irradiation
 WBC: white blood cell count