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Purpose: BIOEMBRACE was designed to study the impact of biomarkers in addition to clinicopathological factors on disease outcomes in patients treated with chemoradiation and magnetic resonance imaging (MRI)-guided brachytherapy (BT) for locally advanced cervical cancer in the EMBRACE study., Methods and Materials: Between 2018 and 2021, 8 EMBRACE-I sites contributed tumor tissue for the immunohistochemistry of p16, PD-L1, and L1CAM. These biomarkers and clinicopathological factors (International Federation of Gynecology and Obstetrics 2009 stage, nodal status, histology, and necrosis on MRI) were analyzed to predict poor response at BT (high-risk clinical target volume [HR-CTV] ≥ 40 cc) at BT) and 5-year local control, pelvic control, and disease-free survival. Interaction between p16, PD-L1, radiation therapy dose (HR-CTV D90), and disease outcomes was investigated. Univariable and multivariable analyses were performed., Results: Two hundred sixty-four patients were included. The median HR-CTV D90 was 89 Gy (86-95). P-16 positive status, PD-L1 > 1%, and L1CAM ≥ 10% was noted in 86.6%, 20.1%, and 17.8% of patients, respectively. P16 negative status (odds ratio, 2.0; 95% CI, 1.0-5.7; P = .04) and necrosis on MRI (odds ratio, 2.1; 95% CI, 1.1-4.3; P < .02) independently predicted for HR-CTV ≥ 40 cc, as did the International Federation of Gynecology and Obstetrics stage and tumor width >5 cm. PD-L1 > 1% was associated with reduced local (82% vs 94%; P = .02) and pelvic control (79% vs 89%; P = .02). HR-CTV D90 < 85 Gy was associated with inferior 5-year local control in p16-positive patients, especially if PD-L1 was coexpressed. On multivariable analysis, PD-L1 > 1% was the only independent factor for 5-year local control (hazard ratio, 3.3; P = .04) and L1CAM ≥ 50% for pelvic control (hazard ratio, 5.5; 95% CI, 1.3-23.3; P = .02)., Conclusions: P16 negative status and tumor necrosis on MRI are independently associated with poor response to chemoradiation, whereas PD-L1 > 1% and L1CAM ≥ 50% have an independent impact on local and pelvic control, suggesting an impact of biomarker expression on outcomes. Further validation is needed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC., Methods and Materials: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed., Results: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm 3 , were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated., Conclusions: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: A simple scoring system (T-score, TS) for integrating findings from clinical examination and magnetic resonance imaging (MRI) of the primary tumor at diagnosis has shown strong prognostic capability for predicting local control and survival in locally advanced cervical cancer treated with chemoradiation and MRI-guided brachytherapy (BT). The aim was to validate the performance of TS using the multicenter EMBRACE I study and to evaluate the prognostic implications of TS regression obtained during initial chemoradiation., Methods and Materials: EMBRACE I recruited 1416 patients, of whom 1318 were available for TS. Patients were treated with chemoradiation followed by MRI-guided BT. A ranked ordinal scale of 0 to 3 points was used to assess 8 anatomic locations typical for local invasion of cervical cancer. TS was calculated separately at diagnosis (TS D ) and at BT (TS BT ) by the sum of points obtained from the 8 locations at the 2 occasions., Results: Median TS D and TS BT was 5 and 4, respectively. TS regression was observed in 71% and was an explanatory variable for BT technique (intracavitary vs intracavitary/interstitial) and major dose-volume histogram parameters for BT, such as high-risk clinical target (CTV HR ), CTV HR D90 (minimal dose to 90% of the target volume), D2cm 3 bladder (minimal dose to the most exposed 2 cm 3 of the bladder), and D2cm 3 rectum. TS regression (TS BT ≤5) was associated with improved local control and survival and with less morbidity compared with patients with TS BT remaining high (>5) despite initial chemoradiation. TS regression was significant in multivariate analysis for both local control and survival when analyzed in consort with already established prognostic parameters related to the patient, disease, and treatment., Conclusions: TS was validated in a multicenter setting and proven to be a strong multidisciplinary platform for integration of clinical findings and imaging with the ability to quantitate local tumor regression and its prognostic implications regarding BT technique, dose-volume histogram parameters, local control, survival, and morbidity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to evaluate patient- and treatment-related risk factors for late persistent fatigue within the prospective, multicenter EMBRACE-I study., Methods and Materials: Fatigue was prospectively assessed (Common Terminology Criteria for Adverse Events, version 3) at baseline and during regular follow up in 993 patients with locally advanced cervical cancer after treatment with chemoradiotherapy and magnetic resonance imaging-guided brachytherapy. Risk factors for baseline and late persistent fatigue were evaluated with multivariable logistic regression. Late persistent fatigue was defined when either grade ≥1 or ≥2 was scored in at least half of the follow ups., Results: The median follow-up time was 57 months. Baseline fatigue grade ≥1/≥2 (35.8%/6.3%, respectively) was associated with preexisting comorbidities, World Health Organization performance status, being underweight, severe pain, and tumor volume. Late persistent grade ≥1/≥2 fatigue (36.3%/5.8%, respectively) was associated with patient-related factors (baseline fatigue, younger age, obesity) along with the size of irradiated volumes and the level of radiation doses from external beam radiation therapy (EBRT) and brachytherapy (EBRT: V43Gy, V57Gy; EBRT + brachytherapy: V60Gy equivalent dose in 2-Gy fractions). Large-volume lymph node (LN) boost increased the risk for late persistent fatigue grade ≥2 by 18% and 5% in patients with and without baseline fatigue, respectively, compared with no LN boost. The risk for late persistent fatigue grade ≥1 increased by 7% and 4% with V43Gy <2000 cm³ versus >3000 cm³ in patients with and without baseline fatigue, respectively. Late persistent grade ≥1 fatigue occurred in 13% of patients without late persistent organ-related symptoms (gastrointestinal, genitourinary, and vaginal) versus 34% to 43%, 50% to 58%, and 73% in patients suffering from persistent symptoms involving 1, 2, or 3 organs, respectively., Conclusions: Late persistent fatigue occurs in a considerable number of patients after chemoradiotherapy, and is associated with patient-related factors, the size of volumes irradiated to intermediate and high EBRT and brachytherapy doses, and other persistent organ-related morbidity. These findings support the importance of ongoing efforts to better tailor the target dose and reduce irradiation of healthy tissue without compromising target coverage, using highly conformal EBRT and brachytherapy techniques., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 D 2cm3 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 D 2cm3 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 D 2cm3 , ICRU RV-RP , and bowel D 2cm3 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer., Methods and Materials: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques., Results: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences., Conclusions: IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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 χ 2 )., 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL)., Methods and Materials: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed., Results: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population., Conclusions: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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 cm 3 versus >3000 cm 3 and 9.4% to 19.0% with V57 Gy <165 cm 3 versus ≥165 cm 3 . Brachytherapy-related bowel and rectum D 2cm3 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 cm 3 ). 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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Current incidence methods for reporting mild or moderate symptoms capture the (first) occurrence of an event and do not allow distinguishing between patients who suffer from long-lasting versus transient morbidity. This paper introduces a new methodological approach that identifies cancer survivors who have clinically relevant, long-lasting symptoms (patients with late, persistent, substantial and treatment-related symptoms, [LAPERS])., Methods and Materials: LAPERS can be evaluated in patients with baseline information and at least 3 late follow-up assessments after treatment. LAPERS identifies individual patients with a given symptom that is substantial (above a predefined clinically relevant threshold) and must be present in at least half of the follow-ups. Baseline morbidity is accounted for by requiring the median of the late symptom score to be worse than the baseline condition. The LAPERS approach was applied to 4 relevant patient-reported genito-urinary/gastrointestinal symptoms within the prospective, longitudinal EMBRACE study (An intErnational study on MRI-guided BRachytherapy in locally Advanced CErvical cancer, www.embracestudy.dk). LAPERS was compared with crude incidence and prevalence rates., Results: Within the EMBRACE cohort, 651/1044 patients (62%) had baseline and long-term follow-up available (median follow-up: 42 months). There was a considerable gap between LAPERS, crude incidence, and prevalence rates. The proportion of patients with LAPERS events was 3.8-4.8 times lower than crude incidences. The highest prevalence rates across follow-up times were 1.8-2.6 times lower than crude incidences., Conclusions: These findings indicate limitations of incidence methods for reporting substantial patient-reported symptoms because a considerable proportion of patients with symptoms do not experience them persistently over time, as they may fluctuate or get successfully treated. In contrast, the LAPERS method for longitudinal analysis identifies patients with clinically relevant, long-lasting symptoms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To describe the evolution of external beam radiation therapy (EBRT) from EMBRACE-I (general guidelines for EBRT) to the initial phase of the EMBRACE-II study (detailed protocol for EBRT)., Methods and Materials: EMBRACE-I enrolled 1416 locally advanced cervical cancer patients treated with chemoradiation including image-guided adaptive brachytherapy during 2008 to 2015. From March 2016 until March 2018, 153 patients were enrolled in the ongoing EMBRACE-II study, which involves a comprehensive detailed strategy and accreditation procedure for EBRT target contouring, treatment planning, and image guidance. EBRT planning target volumes (PTVs), treated volumes (V43 Gy), and conformity index (CI; V43 Gy/PTV) were evaluated in both studies and compared., Results: For EMBRACE-I, conformal radiation therapy (60% of patients) or intensity-modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT; 40%) was applied with 45 to 50 Gy over 25 to 30 fractions to the elective clinical target volume (CTV). For pelvic CTVs (82%), median PTV and V43 Gy volumes were 1549 and 2390 mL, respectively, and CI was 1.54. For pelvic plus paraortic nodal (PAN) CTVs (15%), median PTV and V43 Gy volumes were 1921 and 2895 mL, and CI was 1.51. For pelvic CTVs treated with 45 to 46 Gy, the use of conformal radiation therapy was associated with a median V43 Gy volume that was 546 mL larger than with IMRT/VMAT. For pelvic CTVs treated with IMRT, the use of a dose prescription ≥48 Gy was associated with a median V43 Gy volumes that was 428 mL larger than with a dose prescription of 45 to 46 Gy. For EMBRACE-II, all patients were treated with: IMRT/VMAT, daily IGRT, 45 Gy over 25 fractions for the elective CTV, and simultaneously integrated boost for pathologic lymph nodes. For pelvic CTVs (61%), median PTV and V43 Gy volumes were 1388 and 1418 mL, and CI was 1.02. For pelvic plus PAN CTVs (32%), median PTV and V43 Gy volumes were 1720 and 1765 mL, and CI was 1.03. From EMBRACE-I to initial II, median V43 Gy was decreased by 972 mL (41%) and 1130 mL (39%), and median CI decreased from 1.54 to 1.02 and 1.51 to 1.03 for pelvic and pelvic plus PAN irradiation, respectively., Conclusions: Application of IMRT/VMAT, IGRT, and a 45-Gy dose provides the potential of higher conformality inducing significant reduction of treated volume. Adherence to a detailed protocol including comprehensive accreditation, as in EMBRACE-II, reduces considerably V43 Gy and V50 Gy and improves conformality and interinstitutional consistency., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the toxicity and efficacy of the combination of external beam radiation therapy (EBRT) followed by high-dose-rate endorectal brachytherapy (HDREBT) boost in elderly and medically inoperable patients with rectal cancer., Methods and Materials: A phase 1 dose-escalation study was performed. Treatment consisted of EBRT (13 × 3 Gy) followed by 3 weekly brachytherapy applications 6 weeks later. The HDREBT dose started at 5 Gy per fraction, increasing with 1 Gy per fraction if dose-limiting toxicity (DLT, defined as grade ≥3 proctitis <6 weeks after HDREBT) occurred in ≤2 patients per dose level. The primary endpoint was the maximum tolerated dose, defined as 1 dose level below the dose at which 3 patients experienced DLT. Secondary endpoints were toxicity, clinical tumor response, freedom from local progression, and local progression-free and overall survival (L-PFS and OS)., Results: Thirty-eight patients with a median age of 83 years were included in the study. Thirty-two were evaluable for DLT and late toxicity and 33 for response evaluation. Maximum delivered dose was 8 Gy per fraction, resulting in a recommended dose of 7 Gy per fraction. Response occurred in 29 of 33 patients (87.9%), with 60.6% complete response (CR). The L-PFS and OS rates were 42% and 63%, respectively, at 2 years. Patients with CR showed a significantly improved L-PFS (60% at 2 years, P=.006) and a trend in improved OS (80% at 2 years, P=.11). Severe late toxicity occurred in 10 of 32 patients., Conclusion: We found that HDREBT after EBRT results in a high overall response rate, with improved L-PFS for patients with a CR. The high observed rate of severe late toxicity requires further evaluation of the risks and benefits of an HDREBT boost., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: This study analyzed functioning and symptom scores for longitudinal quality of life (QoL) from patients with locally advanced cervical cancer who underwent definitive chemoradiation therapy with image guided adaptive brachytherapy in the EMBRACE study., Methods and Materials: In total, 744 patients at a median follow-up of 21 months were included. QoL was prospectively assessed using European Organization for Research and Treatment of Cancer Quality of Life core module 30 (EORTC QLQ-C30) and EORTC cervical cancer module 24 (CX24) questionnaires at baseline, then every 3 months during the first year, every 6 months in the second and third years, and finally yearly thereafter in patients with no evidence of disease. Outcomes were evaluated over time and compared to those from an age-matched female reference population., Results: General QoL and emotional and social functioning were impaired at baseline but improved during the first 6 months after treatment, to reach a level comparable to that of the reference population, whereas cognitive functioning remained impaired. Both social and role functioning showed the lowest scores at baseline but which increased after treatment to reach a plateau at 6 months and then declined slightly at 3 and 4 years. The overall symptom experience was elevated at baseline and decreased to a level within the range of that of the reference population. Similarly, tumor-related symptoms (eg, pain, appetite loss, and constipation), which were present before treatment, decreased substantially at the first follow-up after treatment. Several treatment-related symptoms developed either immediately after and persisted over time (diarrhea, menopausal symptoms, peripheral neuropathy, and sexual functioning problems) or developed gradually after treatment (lymphedema and dyspnea)., Conclusions: This longitudinal prospective QoL analysis showed that patients' general QoL and functioning were impaired before treatment compared to those of reference data. Several tumor-related symptoms resolved after treatment, and functioning and general QoL returned to that of the level of the reference population, indicating a transient impact of diagnosis and treatment. However, several treatment-related symptoms and problems did develop and persist, either immediately or gradually after treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the long-term health-related quality of life (HRQL) after external beam radiation therapy (EBRT) or vaginal brachytherapy (VBT) among PORTEC-2 trial patients, evaluate long-term bowel and bladder symptoms, and assess the impact of cancer on these endometrial cancer (EC) survivors., Patients and Methods: In the PORTEC-2 trial, 427 patients with stage I high-intermediate-risk EC were randomly allocated to EBRT or VBT. The 7- and 10-year HRQL questionnaires consisted of EORTC QLQ-C30; subscales for bowel and bladder symptoms; the Impact of Cancer Questionnaire; and 14 questions on comorbidities, walking aids, and incontinence pads. Analysis was done using linear mixed models for subscales and (ordinal) logistic regression with random effects for single items. A two-sided P value <.01 was considered statistically significant., Results: Longitudinal HRQL analysis showed persisting higher rates of bowel symptoms with EBRT, without significant differences in global health or any of the functioning scales. At 7 years, clinically relevant fecal leakage was reported by 10.6% in the EBRT group, versus 1.8% for VBT (P=.03), diarrhea by 8.4% versus 0.9% (P=.04), limitations due to bowel symptoms by 10.5% versus 1.8% (P=.001), and bowel urgency by 23.3% versus 6.6% (P<.001). Urinary urgency was reported by 39.3% of EBRT patients, 25.5% for VBT, P=.05. No difference in sexual activity was seen between treatment arms. Long-term impact of cancer scores was higher among the patients who had an EC recurrence or second cancer., Conclusions: More than 7 years after treatment, EBRT patients reported more bowel symptoms with impact on daily activities, and a trend for more urinary symptoms, without impact on overall quality of life or difference in cancer survivorship issues., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Postoperative radiation therapy for stage I endometrial cancer improves locoregional control but is without survival benefit. To facilitate treatment decision support for individual patients, accurate statistical models to predict locoregional relapse (LRR), distant relapse (DR), overall survival (OS), and disease-free survival (DFS) are required., Methods and Materials: Clinical trial data from the randomized Post Operative Radiation Therapy for Endometrial Cancer (PORTEC-1; N=714 patients) and PORTEC-2 (N=427 patients) trials and registered group (grade 3 and deep invasion, n=99) were pooled for analysis (N=1240). For most patients (86%) pathology review data were available; otherwise original pathology data were used. Trial variables which were clinically relevant and eligible according to data constraints were age, stage, given treatment (pelvic external beam radiation therapy (EBRT), vaginal brachytherapy (VBT), or no adjuvant treatment, FIGO histological grade, depth of invasion, and lymph-vascular invasion (LVSI). Multivariate analyses were based on Cox proportional hazards regression model. Predictors were selected based on a backward elimination scheme. Model results were expressed by the c-index (0.5-1.0; random to perfect prediction). Two validation sets (n=244 and 291 patients) were used., Results: Accuracy of the developed models was good, with training accuracies between 0.71 and 0.78. The nomograms validated well for DR (0.73), DFS (0.69), and OS (0.70), but validation was only fair for LRR (0.59). Ranking of variables as to their predictive power showed that age, tumor grade, and LVSI were highly predictive for all outcomes, and given treatment for LRR and DFS. The nomograms were able to significantly distinguish low- from high-probability patients for these outcomes., Conclusions: The nomograms are internally validated and able to accurately predict long-term outcome for endometrial cancer patients with observation, pelvic EBRT, or VBT after surgery. These models facilitate decision support in daily clinical practice and can be used for patient counseling and shared decision making, selecting patients who benefit most from adjuvant treatment, and generating new hypotheses., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate the psychological consequences of high-dose-rate brachytherapy with 2 fractions in 1 application under spinal/epidural anesthesia in the treatment of locally advanced cervical cancer., Methods and Materials: In 50 patients with locally advanced cervical cancer, validated questionnaires were used for prospective assessment of acute and posttraumatic stress disorder (ASD/PTSD) (Impact of Event Scale-Revision), anxiety/depression (Hospital Anxiety and Depression Scale), quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30/Cervical Cancer 24), physical functioning (World Health Organization performance status), and pain (visual analogue scale), before and during treatment and 1 week and 3 months after treatment. Qualitative interviews were recorded in open format for content analysis., Results: Symptoms of ASD occurred in 30% of patients 1 week after treatment; and of PTSD in 41% 3 months after treatment in association with this specific brachytherapy procedure. Pretreatment predictive variables explain 82% of the variance of PTSD symptoms. Helpful experiences were the support of the treatment team, psychological support, and a positive attitude. Stressful factors were pain, organizational problems during treatment, and immobility between brachytherapy fractions., Conclusions: The specific brachytherapy procedure, as performed in the investigated mono-institutional setting with 2 fractions in 1 application under spinal/epidural anesthesia, bears a considerable risk of traumatization. The source of stress seems to be not the brachytherapy application itself but the maintenance of the applicator under epidural anesthesia in the time between fractions. Patients at risk may be identified before treatment, to offer targeted psycho-social support. The patients' open reports regarding helpful experiences are an encouraging feedback for the treatment team; the reported stressful factors serve as a basis for improvement of patient management, especially regarding pain control., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: Brachytherapy in the treatment of locally advanced cervical cancer has changed substantially because of the introduction of combined intracavitary/interstitial applicators and an adaptive target concept, which is the focus of the prospective, multi-institutional EMBRACE study (www.embracestudy.dk) on image-guided adaptive brachytherapy (IGABT). So far, little has been reported about the development of early to late vaginal morbidity in the frame of IGABT. Therefore, the aim of the present EMBRACE analysis was to evaluate the manifestation pattern of vaginal morbidity during the first 2 years of follow-up., Methods and Materials: In total, 588 patients with a median follow-up time of 15 months and information on vaginal morbidity were included. Morbidity was prospectively assessed at baseline, every 3 months during the first year, and every 6 months in the second year according to the Common Terminology Criteria for Adverse Events, version 3, regarding vaginal stenosis, dryness, mucositis, bleeding, fistula, and other symptoms. Crude incidence rates, actuarial probabilities, and prevalence rates were analyzed., Results: At 2 years, the actuarial probability of severe vaginal morbidity (grade ≥3) was 3.6%. However, mild and moderate vaginal symptoms were still pronounced (grade ≥1, 89%; grade ≥2, 29%), of which the majority developed within 6 months. Stenosis was most frequently observed, followed by vaginal dryness. Vaginal bleeding and mucositis were mainly mild and infrequently reported., Conclusion: Severe vaginal morbidity within the first 2 years after definitive radiation (chemo)therapy including IGABT with intracavitary/interstitial techniques for locally advanced cervical cancer is limited and is significantly less than has been reported from earlier studies. Thus, the new adaptive target concept seems to be a safe treatment with regard to the vagina being an organ at risk. However, mild to moderate vaginal morbidity is still pronounced with currently applied IGABT, and it needs further attention., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers., Patients and Methods: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat., Results: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02)., Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC., (Copyright © 2011 Elsevier Inc. All rights reserved.)