Dose-volume effect relationships for late rectal morbidity in patients treated with chemoradiation and MRI-guided adaptive brachytherapy for locally advanced cervical cancer: Results from the prospective multicenter EMBRACE study

Purpose: To establish dose volume-effect relationships predicting late rectal morbidity in cervix cancer patients treated with concomitant chemoradiation and MRI-guided adaptive brachytherapy (IBABT) within the prospective EMBRACE study. Material and method: All patients were treated with curative intent according to institutional protocols with chemoradiation and IGABT. Reporting followed the GEC-ESTRO recommendations (D-0.1cm3, D-2cm3), applying bioeffect modeling (linear quadratic model) with equieffective doses (EQD2(3)). Morbidity was scored according to the CTC-AE 3.0. Dose-effect relationships were assessed using comparisons of mean doses, the probit model and log rank tests on event-free periods. Results: 960 patients were included. The median follow-up was 25.4 months. Twenty point one percent of the patients had grade 1 events, 6.0% grade 2, 1.6% grade 3 and 0.1%, grade 4. The mean D-ICRU, D-0.1cm3 and D-2cm3 were respectively: 66.2 +/- 9.1 Gy, 72.9 +/- 11.9 Gy, and 62.8 +/- 7.6 Gy. Increase of dose was associated with increase in severity of single endpoints and overall rectal morbidity (grade 1-4) (p < 0.001-0.026), except for stenosis (p = 0.24-0.31). The probit model showed significant relationships between the D-2cm3, D-0.1cm3, and DICRU and the probability of grade 1-4, 2-4, and 3-4 rectal events. The equieffective D-2cm3 for a 10% probability for overall rectal grade >= 2 morbidity was 69.5 Gy (p < 0.0001). After sorting patients according to 6 D-2cm3 levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A D-2cm3 >= 75 Gy was associated with a 12.5% risk of fistula at 3 years versus 0-2.7% for lower doses (p > 0.001). A D-2cm3 < 65 Gy was associated with a two times lower risk of proctitis than D-2cm3 >= 65 Gy. Conclusions: Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose-volume (D-2cm3, D-0.1cm3) and dose-point (D-ICRU) parameters. A D-2cm3 <= 65 Gy is associated with more minor and less frequent rectal morbidity, whereas a D-2cm3 >= 75 Gy is associated with more major and more frequent rectal morbidity. (C) 2016 Elsevier Ireland Ltd. All rights reserved.