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• Urinary morbidity after treatment of locally advanced cervical cancer is prevalent. • Bladder dose constraints based on a high level clinical evidence are not available. • EMBRACE I provides prospective morbidity data for analysis in a large cohort. • Individual physician and patient reported urinary endpoints were analysed in EMBRACE I. • Bladder fistula, bleeding and cystitis showed dose–effect with bladder D 2cm3. To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3–120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D 2cm3 correlated with G ≥ 2 fistula, bleeding and cystitis, while ICRU bladder point dose correlated with EORTC pain "quite a bit" or worse. An increase from 75 Gy to 80 Gy in bladder D 2cm3 resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis. Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose–effect was established with bladder D 2cm3 , reinforcing the importance of continued optimization during individualized IGABT planning. [ABSTRACT FROM AUTHOR]

• Urinary side effects after radiotherapy can rely on different bladder substructures. • EMBRACE I provides prospective morbidity data to study individual urinary symptoms. • Frequency and incontinence are frequent side effects in cervix cancer radiotherapy. • Limited clinical evidence supports the predictive value of ICRU Bladder point dose. • This analysis showed correlation of ICRU Bladder point dose with incontinence. To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups. Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D 2cm3. The 5-year actuarial estimate of G ≥ 2 incontinence increased from 11% to 20% with ICRU-BP doses > 75 Gy compared to ≤ 65 Gy. Frequency showed weaker associations with dose. ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose–effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes. [ABSTRACT FROM AUTHOR]

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 0.1 cm 3 , D 2 cm 3 ), 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 0.1 cm 3 , and D 2 cm 3 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 2 cm 3 , D 0.1 cm 3 , and D ICRU and the probability of grade 1–4, 2–4, and 3–4 rectal events. The equieffective D 2 cm 3 for a 10% probability for overall rectal grade ⩾ 2 morbidity was 69.5 Gy ( p < 0.0001). After sorting patients according to 6 D 2 cm 3 levels, less favorable outcome was observed in the high dose subgroups, for bleeding, proctitis, fistula, and overall rectal morbidity. A D 2 cm 3 ⩾ 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 2 cm 3 < 65 Gy was associated with a two times lower risk of proctitis than D 2 cm 3 ⩾ 65 Gy. Conclusions Significant correlations were established between late rectal morbidity, overall and single endpoints, and dose–volume ( D 2 cm 3 , D 0.1 cm 3 ) and dose-point (D ICRU ) parameters. A D 2 cm 3 ⩽ 65 Gy is associated with more minor and less frequent rectal morbidity, whereas a D 2 cm 3 ⩾ 75 Gy is associated with more major and more frequent rectal morbidity. [ABSTRACT FROM AUTHOR]

Cervical cancer, IGABT, Urinary morbidity, Risk factors, Dose-effect relationship, Clinical study. [Extracted from the article]

Abstract: Purpose: This study explores the feasibility of limiting dose optimisation to the first brachytherapy fraction (BT1) and applying the same plan for the second fraction (BT2). Material and methods: Seventy one consecutive patients were analysed. Pulsed dose rate (PDR) BT was initiated after about 4weeks of external beam radiotherapy (EBRT). Thirty eight patients had only intracavitary applicator (IC), and 33 had combined IC with interstitial needles (IC/IS). The optimised BT1 plan was copied to BT2 images with no further optimisation (single plan scenario) and dose volume histogram (DVH) parameters were compared with those of full dose optimisation for every fraction (optimised plan scenario). Results: 31/38 IC patients had similar applicator geometry in both fractions and mean DVH parameters were comparable between full optimisation and single plan. The mean HR CTV D90 in total EQD2 with optimisation was 94.5Gy and with single plan scenario was 94.4Gy (p =0.89). Organs at risk (OARs) planning aims were fulfilled with the single plan, although 5/31 patients would receive 3–10Gy extra to the . The mean doses in total EQD2 for the of the bladder, rectum, sigmoid and bowel were respectively 68.5, 61.0, 64.9 and 60.6Gy for the optimised plan, and for the single plan scenario were 69.0, 61.3, 65.1 and 60.8Gy respectively. The difference was statistically not significant. The standard deviation (SD) of the difference between the single plan and the optimised plan was 3.2Gy for HR CTV and 2.9, 1.4, 1.2, 1.6Gy for the bladder, rectum, sigmoid and bowel , respectively. Only 4/33 IC/IS patients had the same applicator geometry and single plan was therefore not feasible for the majority of these patients. Conclusion: For IC BT in small volume tumours (primarily stage IB-IIB) with mean HR CTV volume at BT1=24±12cm3, comparable mean DVH parameters resulted when applying a single plan, but with considerable variations in individual patients. Yet since in our population the applied target doses are high and the OARs doses are lower than the dose volume constraints these variations may not have considerable clinical consequences. Individual optimisation for each BT fraction is recommended when interstitial needles are used. [Copyright &y& Elsevier]