Methods	This randomised study was designed to assess whether adjuvant chemotherapy confers an advantage for overall and progression-free survival and on the incidence of local and distant relapses over standard pelvic radiotherapy in high-risk patients without residual tumour
Participants	A total of 491 women with high-risk endometrial carcinoma were consecutively referred to 29 institutions throughout Italy. A total of 345 patients were deemed eligible for this study, with 168 randomly assigned external RT and 177 adjuvant CT Women had histologically confirmed endometrioid, adenoacanthoma or adenosquamous carcinoma and FIGO stage Ic G3, IIa-bG3 with deep myometrial invasion (50% or more) or stage III disease following hysterectomy and bilateral salpingo-oopherectomy. To rule out FIGO stage IV disease all patients underwent chest radiography and abdominal-pelvic ultrasound. Women had to have had surgery as primary treatment and no previous neoadjuvant therapy Approximately 70% of the patients had myometrial invasion deeper than 50%. About one third of the patients had FIGO stage I-II disease. 8% had stage 2b cancer. Two thirds stage 3.22% in each group had stage 3c disease and about 40% had stage 3a disease
Interventions	Women were randomly allocated chemotherapy or radiotherapy after surgical staging and histological evaluation. Chemotherapy had to start within 30 days from surgery. Cyclophosphamide 600mg/m2, adriamycin (doxorubicin) 45mg/m2 and cis-platin 50mgm2 (CAP regimen) were administered every 28 days for five cycles Radiotherapy had to start within 30 days after surgery. External radiation therapy was adopted for a total of 45 to 50 Gray in 5 to 7 weeks (1.7-2 Gray/day, 5 days/week). The upper limit of the pelvic field was at L5, the lower limit at the lower limit of the ischial tuberosity, and the lateral limits fell behind the border of the lateral and common iliac lymph nodes. Patients who had lymph node involvement received additional lumboaortic lymph node irradiation with the upper limit at LI, with 45 Gray in 5 to 7 weeks (1,5-1.8 Gray/day × 5days/ week)
Outcomes	The primary end points for this trial were overall survival, defined as the time from randomisation to death, irrespective of the cause, and progression-free survival, defined as the time from randomisation to the earliest tumour relapse, or death
Results (OS & PFS)	The hazard ratio (HR) for death after a median follow-up of 95.5 months for women in the chemotherapy group as compared with the radiotherapy group was 0.95 (95% confidence interval (CI), 0.66 to 1.36; P = 0.77). The HR for an event was 0.88 (95% CI, 0.63 to 1.23; P = 0.45). The 3, 5 and 7-year overall survivals were 76%, 66% and 62% in the chemotherapy group 78%, 69% and 62% in the radiotherapy group. The 3, 5 and 7-year progression-free survivals were, 68%, 63% and 60% and 69%, 63% and 56% respectively At the median follow-up time of 95.5 months (interquartile range 62 to 122 months), 135 events (recurrences or deaths, whichever came first) had occurred among the 340 randomised patients. There were 56 recurrences and 10 deaths as first event of the 174 patients on chemotherapy and 60 recurrences and nine deaths as first event of the 166 patients on radiotherapy. The overall number of observed deaths was 118 (35%). Fifty-nine in the RT arm and 59 in the CT arm The overall survival of the patients on chemotherapy was 76% (CI = 70% to 83%), 66% (CI = 59% to 73%) and 62% (CI = 55% to 70%) at the third, fifth and seventh year, respectively, and 78% (CI = 71% to 84%), 69% (CI = 61% to 76%) and 62% (CI = 54% to 71%) for patients on radiotherapy at the same time points. The progression-free survival of the patients on chemotherapy was 68% (CI = 61% to 75%), 63% (CI = 55% to 70%) and 60% (01 = 52% to 67%) at the third, fifth and seventh year, respectively and 69% (CI = 62% to 77%), 63% (CI = 55% to 70%) and 56% (CI = 46% to 63%) for patients on radiotherapy
Results (site of recurrence)	Chemotherapy delayed distant metastases and radiotherapy delayed local relapses but these trends did not achieve statistical significance. Among the 174 patients randomised to chemotherapy, the initial site of recurrence was distant in 27 (16%), local in 19 (11%), concurrent local and distant in eight (5%), and of unknown type in two (1%). Among the 166 patients randomised to radiotherapy the initial site of recurrence was distant (extra-abdominal or liver) in 35 (21%), local in 11 (7%), concurrent distant and local in nine (5%), and of unknown type in five (3%). Although this study was not powered to detect clinically significant differences in the incidence of relapses, chemotherapy seemed to prevent or delay distant relapses more than radiotherapy while radiotherapy seemed to prevent or delay local relapses in comparison with chemotherapy
Toxicity	Full details about the toxicity of chemotherapy with CAP is available for 123 women (80% of the 154 patients who had at least one course). Grades 2, 3 and 4 neutropenia occurred in 22 (18%), 38 (31%) and 5 (4%) patients, respectively; 36 patients (29%) had grade 2 anaemia, 5 (4%) had grade 3 anaemia; grade 2 and 3 thrombocytopenia was reported in five (4%) and two patients (2%), respectively. The incidence of nausea and vomiting was relatively low (grade 2 and 3 was reported for 29 (24%) and 12 (10%) patients, respectively, grade 4 for one patient). Other serious toxicities (grade 3) occurred in < 3 % of the patients randomised to CT. There were no treatment-related deaths Toxicity data are available for 146 (97%) of the 150 patients who started radiotherapy. Major late toxic effects were gastrointestinal, including five cases of bowel obstruction with three of these patients requiring surgical intervention, six cases of grade 3 radiation proctitis, and 13 reports of grade 3 diarrhoea (24 patients, 16%). Urinary tract complications (severe cystitis) were recorded in seven patients (5%)
Notes
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was carried out centrally by telephone at the L Mangiagalli Institute (Milan, Italy) and patients were stratified by institution and stage of disease
Allocation concealment (selection bias)	Low risk	It is very unlikely that there was any bias or allocation concealment during analysis of data but this is not clear in the reports
Blinding (performance bias and detection bias) All outcomes	High risk	It is not possible to conceal the treatment allocation from the participants
Incomplete outcome data (attrition bias) All outcomes	Low risk	131 (75%) of the 174 women assigned chemotherapy received five treatment cycles as planned and 154 (89%) received at least one cycle and were assessable for toxicity (six, four, four and nine women received only one, two, three and four courses of CAP, respectively, mainly because of excessive bone marrow toxicity). 12 women (7%) declined adjuvant chemotherapy 146 (88%) of the 166 women assigned radiotherapy completed treatment as planned. Only four women (2%) stopped treatment because of toxicity. Ten women (6%) declined treatment
Selective reporting (reporting bias)	Low risk	The trial is reported according to CONSORT criteria and there is no suggestion of any reporting bias
Other bias	Low risk	The two groups were similar across all categories.
Main problems with the trial as perceived by this analysis	Low risk	Threre are no serious flaws in this trial.