Late complications after postoperative radiotherapy in endometrial cancer: Analysis of 317 consecutive cases with application of linear- quadratic model

Purpose: To evaluate the incidence and risk factors for late complications after postoperative radiotherapy in endometrial cancer patients. Methods and Material: We performed a detailed retrospective analysis of 317 endometrial cancer patients given postoperative radiotherapy. A total of 247 patients (78%) received both intracavitary (BRT) and external beam irradiation (XRT); 49 patients (15%) received only BRT, and 21 (7%) only XRT. BRT included radium (Ra) and cesium (Cs). The mean dose rate for both isotopes at 0.5 cm from the applicator surface was 0.47 ± 0.06 and 1.42 ± 0.41 Gy/h, and the mean total dose was 50.5 ± 10.3 and 48.4 ± 15.0 Gy, respectively. Mean BRT dose at 0.5 cm was 50.1 ± 11.7 Gy (range 14.5-71.0). Mean XRT dose in the International Commission on Radiation Units and Measurements (ICRU) reference point was 49.0 ± 3.7 Gy (range 22.0-66.0) given in fractions of 1.54-2.49 Gy (mean 2.0 ± 0.17) with a two- or four- field technique. Follow-up ranged from 4 to 21 years (median 7.3). Normalized total dose (NTD) including XRT and BRT doses was calculated based on a linear quadratic equation. Results: Five-year overall survival rate was 75%, and 5- year disease-free survival (censored for noncancer deaths) was 81%. Late radiotherapy complications of any grade occurred in 158 patients (51%), including bowel complications in 41% and urinary bladder complications in 21%. A total of 37 grade 3 or 4 complications were observed in 33 patients (11%), of whom 32 were treated with both XRT and BRT. Severe bowel and/or urinary bladder complications occurred in 24 patients: in 14 of 72 patients (19.4%) who received XRT and Cs BRT, and in 10 of 172 patients (6.0%) applied XRT and Ra BRT. The higher proportion of severe bowel and/or bladder complications in the former group was due to the particularly frequent rate of these events (30.0%) in a subset of 47 patients who received XRT combined with Cs BRT at the dose rate of 1.7 Gy/h and the total BRT dose of 60 Gy. Higher NTD, XRT fraction dose, BRT dose rate, Cs BRT, two-field XRT technique, short overall radiotherapy time, and older age were correlated with increased late-event risk in univariate analysis. Multivariate Cox analysis demonstrated that the independent risk factors for late bowel complications were NTD (p = 0.000) and BRT dose rate (p = 0.036), whereas for bladder complications they were BRT dose rate (p = 0.005) and XRT fraction dose (p = 0.041). Neither clinical factor (age, parity, prior abdominal surgery, FIGO stage, diabetes mellitus, or hypertension) nor the surgery-to- radiotherapy interval, nor overall radiotherapy time was independently associated with the risk of late bladder or bowel complications. Conclusions: The risk of late complications after postoperative radiotherapy in endometrial cancer depends mainly on treatment-related factors: NTD, BRT dose rate, and XRT fraction dose. The use of combined XRT and BRT increases the risk of late effects. NTD calculations including BRT dose rate and XRT fraction dose enable estimation of radiobiologically equivalent dose and can decrease the risk of mistakes when the radiotherapy regimen is changed.