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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]

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: The purpose of this review was to evaluate the current status of reporting prospectively assessed late morbidity after curative radiation therapy in large clinical studies.Methods and Materials: A descriptive review on publications from 10 high-impact journals with a primary or partial focus on radiation therapy published between December 1, 2015, and November 30, 2017, was conducted. Publications were considered eligible if they reported prospectively assessed late morbidity after curative radiation therapy and included ≥200 patients with cancer of any type. Full text publication and supplementary material were analyzed according to items based on extensions to the Consolidated Standards of Reporting Trials (CONSORT) statement regarding reporting of harms and patient reported outcomes.Results: Overall, 802 publications were identified in PubMed; of these, 69 met the eligibility criteria. Mild and moderate morbidity were reported in 40% and 57% of publications; aggregated endpoints instead of individual endpoints were reported in 23%. In 43% of publications, crude incidence of worst grade of morbidity was used as the only statistical method for summarizing physician-assessed morbidity. Duration of morbidity or recurrent events were not reported in any of the publications.Conclusions: Comprehensive, quantitative reporting of late morbidity after radiation therapy is challenging because of the high dimensionality and time evolution of the range of normal tissue effects. The following suggestions and recommendations are proposed: (1) report on individual severity grades, including moderate and mild; (2) use patient reported outcomes in complement to physician-assessed morbidity; (3) report on individual symptoms/endpoints on top of aggregated endpoints; (4) report on duration of morbidity or recurrent events; (5) take steps toward a consensus on severity grading scales/patient questionnaires; (6) use time to event analysis and prevalence rates; (7) report or use statistical methods accounting for pretreatment morbidity when relevant. [ABSTRACT FROM AUTHOR]

Purpose To validate the feasibility and use of dose points to characterize the bladder wall dose distribution and investigate potential impact of the applicator position in cervical cancer brachytherapy. Methods and Materials One hundred twenty-eight optimized MRI plans were evaluated. The International Commission of Radiation Units and Measurements (ICRU-38) point doses (B ICRU ), surrogate for bladder base doses, were compared with D 2cc . Vaginal source to superior–anterior border of the symphysis distances were measured and compared within two groups, namely Group 1—B ICRU / D 2cc ≥1 and Group 2—B ICRU / D 2cc <1. Additionally, points at 1.5 and 2 cm cranial to the B ICRU , parallel to the tandem and the body axis were analyzed. Results Thirty-seven percent of the patients had the ratio B ICRU / D 2cc of 1 or higher, with the 2cc subvolume at the bladder base (Group 1). In 63%, B ICRU / D 2cc ratio was lower than 1 and the 2cc, cranial to the bladder base (Group 2). Median vaginal source-to-superior–anterior border of the symphysis line distance was −2 cm (range, −3.7 to +1.2 cm) in Group 1 and +1.8 cm (range, −2 to +4.8 cm) in Group 2 (+ cranial/− caudal direction). There was a high correlation between vaginal sources near the symphysis and the 2cc subvolume at the bladder base. The additional points provided no added value. Conclusions Location of the 2cc subvolume varies in cervical cancer brachytherapy. Maximum doses are at the bladder base if vaginal sources are also in the vicinity of the bladder base indicated by B ICRU / D 2cc ratio of 1 or higher. Such variation should be considered in dose–effect analyses and intercomparisons, as the same D 2cc at different bladder locations may correlate with different morbidity profiles and severity Reporting D 2cc and B ICRU doses together therefore remains essential. [ABSTRACT FROM AUTHOR]

Purpose This study evaluated the dose delivered to lymph nodes (LNs) by brachytherapy (BT) and the effect of BT image–guided optimization on the LN dose. Methods and Materials Twenty-five patients with locally advanced cervical cancer were retrospectively analyzed, 16 patients of them had LN involvement. The patients received whole pelvis intensity-modulated radiation therapy (45–50 Gy/25–30 fx) to whole pelvis and two fractions of MRI pulsed-dose-rate BT. The delineated LN groups were para-aortic, inguinal, common iliac (CI), external iliac, internal iliac, obturator, and presacral. For each LN group, D 98% , D 50% , and D 2% (the dose that covers 98%, 50%, and 2% of the volume, respectively) were evaluated for optimized and standard BT plans. The correlation between total reference air kerma (TRAK) and D 50% of the LN groups was evaluated. Results BT contributed considerable dose (mean D 50% was 3.8–6.2 Gy equivalent total dose in 2-Gy fractions) to the pelvic LN (external iliac, internal iliac, obturator, and presacral) in optimized plans, whereas less-dose contribution to CI, para-aortic, and inguinal (mean D 50% was 0.5–1.9 Gy equivalent total dose in 2-Gy fractions) was observed. Optimized plans delivered less dose to the LNs as compared with standard plans, although differences only amounted to a mean of 0.2–0.9 Gy ( D 50% ). TRAK showed a significant correlation with LN D 50% for all LN groups except CI, although only 19–38% of the dose variation could be explained by the TRAK. Conclusions BT contributes considerable dose to pelvic LNs and should be considered in the evaluation of total LN doses. [ABSTRACT FROM AUTHOR]

Purpose: The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer.Methods and Materials: Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups.Results: The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D2cm3 and the International Commission on Radiation Units and Measurements recto-vaginal reference point (ICRU RV-RP) correlated with G ≥3 anus/rectum events and moderate/persistent diarrhea, proctitis, bleeding, abdominal cramps, and difficulty in bowel control. Bowel D2cm3 correlated with G ≥3 sigmoid and colon/small bowel events and moderate/persistent diarrhea and flatulence. For external beam radiation therapy (EBRT), prescription dose correlated with G ≥3 anus/rectum, diarrhea, and difficulty in bowel control. Patients with large lymph-node boost (V57Gy) were at higher risk for G ≥3 sigmoid events, moderate/persistent diarrhea, proctitis, and cramps.Conclusions: The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D2cm3, ICRU RV-RP , and bowel D2cm3 are risk factors for GI morbidity. The risk for various symptoms was lower with an EBRT prescription of 45 Gy than 50 Gy and increased with larger V57Gy. [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]

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]

Purpose: To evaluate patient- and treatment-related risk factors associated with incidence and persistence of late diarrhea after radiochemotherapy and image guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer.Materials and Methods: Of 1416 patients from the EMBRACE I study, 1199 were prospectively evaluated using physician-reported (Common Terminology Criteria for Adverse Events version 3 [CTCAEv3]) assessment for diarrhea; median follow-up 48 months. Patient-reported outcome (EORTC) was available in 900 patients. Incidence of CTCAE G≥2, G≥3, and EORTC "very much" diarrhea was analyzed with Cox proportional hazards regression. Binary logistic regression was used for analysis of persistent G≥1 and EORTC "quite a bit" - "very much" (≥"quite a bit") diarrhea, defined if present in at least half of all follow-ups.Results: Crude incidences of G≥2 and G≥3 diarrhea were 8.3% and 1.5%, respectively, and 8% of patients reported "very much" diarrhea. Persistent G≥1 and ≥"quite a bit" diarrhea was present in 16% and 7%, respectively. Patient-related risk factors were baseline diarrhea, smoking, and diabetes with hazard ratios of 1.4 to 7.3. Treatment-related risk factors included prescribed dose, V43 Gy, V57 Gy (lymph node boost), and para-aortic irradiation for external beam radiation therapy (EBRT). G≥2 diarrhea at 3 years increased from 9.5% to 19.9% with prescribed dose 45 Gy versus 50 Gy, 8.7% to 14.0% with V43 Gy <2500 cm3 versus >3000 cm3 and 9.4% to 19.0% with V57 Gy <165 cm3 versus ≥165 cm3. Brachytherapy-related bowel and rectum D2cm3 were also associated with diarrhea.Conclusion: Dose and volume effects have been established for late diarrhea after radiochemotherapy and IGABT in both CTCAE and EORTC reporting. The risk of diarrhea was lower with a pelvic EBRT prescription of 45 Gy, and higher with larger lymph node boosts volumes (ie, ≥165 cm3). The importance of EBRT volumes as determinants of late toxicity underline the need for continuous quality assurance of target contouring, dose planning, and conformity. The findings of brachytherapy dosimetric factors related to the intestines may become more important with highly conformal EBRT. [ABSTRACT FROM AUTHOR]

Purpose: This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC).Methods and Materials: Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated.Results: Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event.Conclusions: Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors. [ABSTRACT FROM AUTHOR]