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

Abstract

PurposeTo 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 methodAll patients were treated with curative intent according to institutional protocols with chemoradiation and IGABT. Reporting followed the GEC-ESTRO recommendations (D0.1cm3, D2cm3), applying bioeffect modeling (linear quadratic model) with equieffective doses (EQD23). 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. Results960 patients were included. The median follow-up was 25.4months. 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 DICRU, D0.1cm3, and D2cm3 were respectively: 66.2±9.1Gy, 72.9±11.9Gy, and 62.8±7.6Gy. 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 D2cm3, D0.1cm3, and DICRU and the probability of grade 1–4, 2–4, and 3–4 rectal events. The equieffective D2cm3 for a 10% probability for overall rectal grade⩾2 morbidity was 69.5Gy (p<0.0001). After sorting patients according to 6 D2cm3 levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A D2cm3⩾75Gy was associated with a 12.5% risk of fistula at 3years versus 0–2.7% for lower doses (p>0.001). A D2cm3<65Gy was associated with a two times lower risk of proctitis than D2cm3⩾65Gy. ConclusionsSignificant correlations were established between late rectal morbidity, overall and single endpoints, and dose–volume (D2cm3, D0.1cm3) and dose-point (DICRU) parameters. A D2cm3⩽65Gy is associated with more minor and less frequent rectal morbidity, whereas a D2cm3⩾75Gy is associated with more major and more frequent rectal morbidity.