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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]

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

Simple Summary: Primary vaginal cancer is a rare disease and, consequently, evidence about the outcome of treatment is scarce. The aim of our retrospective, observational multicenter study was to assess the oncological outcome of the nowadays standing treatment for vaginal cancer, namely radio(chemo)therapy, followed by image-guided adaptive brachytherapy (IGABT). Our study confirms the results of the earlier published small monocentric IGABT studies, showing a high local control with acceptable morbidity. Notably, patients with large (T3/T4) tumors especially seem to benefit from volumetric (3D) image-guided brachytherapy, as compared to two-dimensional-based radiotherapy. In addition, although interpreted with caution, as for cervical cancer, a higher dose seems to lead to better local control. These results should, however, be further investigated in a prospective trial. Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%; disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if >80 Gy EQD2α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer. [ABSTRACT FROM AUTHOR]

Purpose To evaluate an image-guided and adaptive EBRT workflow in locally advanced cervical cancer (LACC) patients treated according to EMBRACE II guidelines in terms of individualized ITV margins and new criteria for dose coverage. Interfractional target-(cervix/uterus) and organ filling was monitored on a daily basis and investigated along with the impact of patient feedback on organ fillings. Methods Patients treated with definitive radiochemotherapy were included. Pretreatment MRI- and (PET)-CT scans with full and empty bladders were performed and a bladder-filling protocol applied. Contouring was according to EMBRACE II guidelines with individualized ITV margin and 5 mm PTV margin. VMAT plans were used to deliver 45Gy/25 fractions with daily onboard cone beam CT (CBCT) scans. Trained RTTs monitored the interfractional target motion and organ fillings, and provided patients with daily feedback on organ-filling. A clinical workflow including thresholds for re-planning if target was not inside PTV was designed and followed. CBCTs were retrospectively reviewed, and the accuracy of the RTT scorings analyzed. Minimum doses to CTV-T HR(aim 42,75 Gy) and CTV-T LR(aim 40 Gy) were retrospectively estimated for replanned patients. Results Twenty-three patients were evaluated. RTT scoring of target coverage was correct in 90% of the CBCTs (505/563), incorrect in <1%, and in 7% of the CBCTs the RTTs could not score primary due to compromised image quality. Seven patients were re-planned based on lack of target coverage. Minimum dose assessment indicated that delivered dose had been within aims without re-planning for 3/7 patients. One patient had considerable benefit of re-planning with an improvement of 12.7 Gy to CTV-T LR vagina. Re-planning improved CTV-T LR uterus by 1.2–1.8 Gy in 4 patients, and 3 patients gained less than 1 Gy. Lack of coverage was more often caused by rectal/bowel than bladder-filling. Conclusions The study proposes a practical adaptive approach for EBRT in LACC patients with daily IGRT monitoring supporting the EMBRACE II guidelines. The strategy allowed safe treatment with relatively tight ITV margins. In patients with unpredictable interfractional target- and organ motion, the compromised coverage benefitted from re-planning. The approach has limited workload and can be performed with high accuracy by RTTs. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate patient-reported sexual outcomes after chemoradiation therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer in the observational, prospective, multicenter EMBRACE-I study.Methods and Materials: Sexual outcomes were assessed prospectively with the European Organization for Research and Treatment of Cancer Qualify of Life Questionnaire (EORTC-QLQ-CX24) at baseline and follow-up. Crude incidence and prevalence rates of sexual activity, vaginal functioning problems (dryness, shortening, tightening, pain during intercourse), and sexual enjoyment were evaluated. Associations between pain during intercourse and vaginal functioning problems or sexual enjoyment were calculated, pooling observations over all follow-ups (Spearman correlation coefficient). In patients who were frequently sexually active (≥50% of follow-ups), the effects of regular hormonal replacement therapy (HRT) on vaginal functioning problems were evaluated (Pearson χ2).Results: The analysis involved 1045 patients with a median follow-up of 50 months. Sexual activity was reported by 22% of patients at baseline and by 40% to 47% of patients during follow-up (prevalence rates). Vaginal functioning problems in follow-up were dryness (18%-21%), shortening (15%-22%), tightening (16%-22%), pain during intercourse (9%-21%), and compromised enjoyment (37%-47%). Pain during intercourse was significantly associated with vaginal tightening (r = 0.544), shortening (r = 0.532), and dryness (r = 0.408) and negatively correlated with sexual enjoyment (r = -0.407). Regular HRT was associated with significantly less vaginal dryness (P = .015), shortening (P = .024), pain during intercourse (P = .003), and borderline higher sexual enjoyment (P = .062).Conclusions: Vaginal functioning problems are associated with pain and compromised sexual enjoyment. Further effort is required for the primary prevention of vaginal morbidity with dose optimization and adaptation. Secondary prevention strategies, including HRT for vaginal and sexual health after radiation therapy in locally advanced cervical cancer, should be considered and sexual rehabilitation programs should be developed further. [ABSTRACT FROM AUTHOR]