Patients characteristics and compliance with treatment
Between January 1, 1990 and December 31, 1997, 491 patients 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 ().
Figure 1 Flow chart of the progress of patients through the trial (Adapted from Begg C, Cho M, Eastwood S, et al. proving the quality of reporting of randomised controlled trials: the CONSORT statement. JAMA 1996;276;637–639). * Lower risk profile=FIGO (more ...)
lists the distribution by treatment group of patients according to age, FIGO stage, grading, degree of myometrial invasion and type of primary surgery. The two groups were similar across all categories. About one third of the patients had FIGO stage I–II disease and two thirds stage III, and approximately 70% of the patients had myometrial invasion deeper than 50%. Of the 340 patients analysed, 315 (93%) underwent TAH-BSO.
Clinical and tumour characteristics
Of the 166 patients assigned RT, 146 (88%) completed treatment as planned (); only four patients (2%) stopped treatment because of toxicity (investigators were not required to report the specific toxic effect that prompted treatment cessation); 10 patients (6%) declined treatment. Of the 174 patients assigned CT, 131 (75%) received five treatment cycles as planned and 154 (89%) received at least one cycle and were assessable for toxicity (six, four, four and nine patients received only one, two, three and four courses of CAP, respectively, mainly because of excessive bone marrow toxicity). In all, 12 patients (7%) declined adjuvant CT.
We had toxicity data for 146 (97%) of the 150 patients who started RT (RT). 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 actinic cystitis) were recorded in seven patients (5%).
We collected full details about the toxicity of CAP for 123 patients (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.
Recurrence and survival
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: 60 recurrences and nine deaths as first event of the 166 patients on RT, and 56 recurrences and 10 deaths as first event of the 174 patients on CT. The overall number of observed deaths was 118 (35%), 59 in the RT arm and 59 in the CT arm. Comparison of the Kaplan–Meier curves for death () or first event () gave nonsignificant HRs of 0.95 (CI=0.66–1.36, P=0.78) and 0.88 (CI=0.63–1.23, P=0.45), respectively ().
Figure 2 Overall survival of patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receiving adjuvant radiotherapy (Radio) or chemotherapy (Chemio). Five-year overall survival was 69% and (more ...)
Figure 3 Progression-free survival of patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receiving adjuvant radiotherapy (Radio) or chemotherapy (Chemio). Five-year progression-free survival (more ...)
The overall survival of the patients on CT was 76% (CI=70–83%), 66% (CI=59–73%) and 62% (CI=55–70%) at the third, fifth and seventh year, respectively, and 78% (CI=71–84%), 69% (CI=61–76%) and 62% (CI=54–71%) for patients on RT at the same time points. The progression-free survival of the patients on CT was 68% (CI=61–75%), 63% (CI=55–70%) and 60% (CI=52–67%) at the third, fifth and seventh year, respectively, and 69% (CI=62–77%), 63% (CI=55–70%) and 56% (CI=46–63%) for patients on RT.
In the multivariate proportional hazard model () age, grading, depth of myometrial invasion and FIGO stage were all significantly associated with progression-free and overall survival. Multivariate analysis confirmed there was no real difference between CT and RT in progression-free and overall survival. and depict the cumulative incidence, after adjusting for competing risks, of distant or local relapses by treatment arm. Among the 166 patients randomised to RT, 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%). Among the 174 patients randomised to CT, 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%). Although this study was not powered to detect clinically significant differences in the incidence of relapses, CT seemed to prevent or delay distance relapses more than RT () while the RT seemed to prevent or delay local relapses in comparison with CT ().
Multivariable Cox proportional hazards analysis for progression-free and overall survival
Cumulative incidence of distant relapses for patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receiving adjuvant radiotherapy (Radio) or chemotherapy (Chemo).
Figure 5 Cumulative incidence of local (central pelvic, including vaginal cuff recurrence, lateral pelvic and vaginal) relapses for patients with high-risk endometrial carcinoma (stage IcG3, IIG3 with myometrial invasion >50%, and III) receiving (more ...)