Stages I-III Inoperable Endometrial Carcinoma: A Retrospective Analysis by the Gynaecological Cancer GEC-ESTRO Working Group of Patients Treated with External Beam Irradiation and 3D-Image Guided Brachytherapy.

BACKGROUND/PURPOSE: Analyse the outcomes of stages I-III inoperable endometrial cancer (IEC) patients treated with external-beam-irradiation (EBRT) and 3D-image-guided-brachytherapy (IGBT). MATERIAL AND METHODS: Medical records of IEC patients receiving EBRT + IGBT in eight European and one Canadian centres (2004-2019) were examined, including: pelvic ± para-aortic EBRT and lymph node boost; anaesthetic procedure, applicators, BT-planning imaging, clinical target volume (CTV), brachytherapy schedule, and EQD2 to the CTV(α/ß=4.5Gy) and D2 cm3(α/ß=3Gy) for organs at risk. Complications are evaluated using CTCAEv4 scores. The 2- and 5-year survival probability according to stages was estimated (cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS)). STATISTICS: descriptive analysis and the Kaplan-Meier method. RESULTS: 103 patients (stages: I-44, II-14, III-44) were included. Median follow-up: 28 months (7-170). All patients received pelvic ± para-aortic EBRT. Median D90-EQD2(α/ß=4.5) to the CTV:73.3 Gy (44.6-132.7), 69.9 Gy (44.7-87.9 and 75.2 Gy (55.1-97) in stages I, II, and III, respectively. Thirty patients presented relapse (stages: 10-I, 3-II, 17-III): 24 uterine (stages: 7-I, 3-II, 14-III), 15 nodal (stages: 4-I, 1-II, 10-III), and 23 distant (stages: 6-I, 2-II, 15-III). Five year CSS was 71.2% (stages: 82%-I-II and 56%-III) and DFS, LRFS, LRRFS, and DMFS were 55.5%, 59%, 72%, and 67.2%, respectively. Late G3-G4 complications (crude): 1.3% small bowel, 2.5% rectum, and 5% bladder. CONCLUSION: In stages I-III of the IEC, EBRT + IGBT offer good 2- and 5-year CSS of 88.7% and 71.2%, respectively, with the best outcomes in stages I-II. Prospective studies are needed to determine how better outcomes can be achieved.

Overall Severe Morbidity After Chemo-Radiation Therapy and Magnetic Resonance Imaging-Guided Adaptive Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To evaluate overall severe late morbidity (grade ≥3) in patients with locally advanced cervical cancer treated with chemo-radiation therapy and magnetic resonance image guided adaptive brachytherapy within the prospective EMBRACE-I study, and to compare the results with published literature after standard radiograph based brachytherapy (BT). METHODS AND MATERIALS: From 2008 to 2015 the EMBRACE-I study enrolled 1416 patients. Morbidity was assessed (Common Terminology Criteria for Adverse Events version 3.0) every 3 months the 1st year, every 6 months the second and third year, and yearly thereafter and 1251 patients had available follow-up on late morbidity. Morbidity events (grade 3-5) were summarized as the maximum grade during follow-up (crude incidence rates) and actuarial estimates at 3 and 5 years. To compare with the published literature on standard radiograph based BT, Common Terminology Criteria for Adverse Events scores from the EMBRACE-I study were retrospectively converted into a corresponding score in the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer system. RESULTS: In total, 534 severe events occurred in 270 patients; 429 events were grade 3 and 105 were grade 4 events. Actuarial estimates for grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal and fistula events at 5 years were 8.5% (95% confidence interval [CI], 6.9%-10.6%), 6.8% (95% CI, 5.4%-8.6%), 5.7% (95% CI, 4.3%-7.6%), and 3.2% (95% CI, 2.2%-4.5%), respectively. The 5-year actuarial estimate for organ-related events (GI, GU, vaginal, or fistula) was 18.4% (95% CI, 16.0%-21.2%). The 5-year actuarial estimate when aggregating all G≥3 endpoints (GI, GU, vaginal, fistulas, and non-GI/GU/vaginal) was 26.6% (95% CI, 23.8%-29.6%). Thirteen patients had a treatment-related death, 8 of which were associated with GI morbidity. CONCLUSIONS: This report assesses severe morbidity from the largest prospective study on chemo-radiation therapy and image guided adaptive brachytherapy for locally advanced cervical cancer to date. Severe late morbidity was limited per endpoint and organ category, but considerable when aggregated across organs and all endpoints. The late morbidity results in the EMBRACE-I study compare favorably with published literature on standard radiograph based BT for GI morbidity, vaginal morbidity, and fistulas.

Risk Factors for Local Failure Following Chemoradiation and Magnetic Resonance Image-Guided Brachytherapy in Locally Advanced Cervical Cancer: Results From the EMBRACE-I Study.

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study. MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis. RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTVHR), maximum tumor dimension, CTVHR > 45 cm3, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTVHR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology. CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.

Association of persistent morbidity after radiotherapy with quality of life in locally advanced cervical cancer survivors.

PURPOSE: To quantify the association of persistent morbidity with different aspects of quality of life (QOL) in locally advanced cervical cancer (LACC) survivors. MATERIAL AND METHODS: Longitudinal outcome from the EMBRACE-I study was evaluated. Patient-reported symptoms and QOL were prospectively scored (EORTC-C30/CX24) at baseline and regular follow-ups. Physician-assessed symptoms were also reported (CTCAEv.3). Persistent symptoms were defined if present in at least half of the follow-ups. QOL items were linearly transformed into a continuous scale. Linear mixed-effects models (LMM) were applied to evaluate and quantify the association of persistent symptoms with QOL. Overall QOL deterioration was evaluated by calculating the integral difference in QOL over time obtained with LMM for patients without and with persistent symptoms. RESULTS: Out of 1416 patients enrolled, 741 with baseline and ≥ 3 late follow-ups were analyzed (median 59 months). Proportions of persistent EORTC symptoms ranged from 21.8 % to 64.9 % (bowel control and tiredness). For CTCAE the range was 11.3-28.6 % (limb edema and fatigue). Presence of any persistent symptom was associated with QOL, although with varying magnitude. Role functioning and Global health/QOL were the most impaired aspects. Fatigue and pain showed large differences, with reductions of around 20 % for most of the QOL aspects. Among organ-related symptoms, abdominal cramps showed the largest effect. CONCLUSION: Persistent symptoms are associated with QOL reductions in LACC survivors. Organ-related symptoms showed smaller differences than general symptoms such as fatigue and pain. In addition to optimizing treatment to minimize organ-related morbidity, effort should be directed towards a more comprehensive and targeted morbidity management.

Prognostic Implications of Uterine Cervical Cancer Regression During Chemoradiation Evaluated by the T-Score in the Multicenter EMBRACE I Study.

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 (TSD) and at BT (TSBT) by the sum of points obtained from the 8 locations at the 2 occasions. RESULTS: Median TSD and TSBT 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 (CTVHR), CTVHR D90 (minimal dose to 90% of the target volume), D2cm3 bladder (minimal dose to the most exposed 2 cm3 of the bladder), and D2cm3 rectum. TS regression (TSBT≤5) was associated with improved local control and survival and with less morbidity compared with patients with TSBT 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.

Exclusive 3D-brachytherapy as a good option for stage-I inoperable endometrial cancer: a retrospective analysis in the gynaecological cancer GEC-ESTRO Working Group.

PURPOSE: Analyse outcomes of stage-I inoperable endometrial cancer (EC) patients from seven European centres treated with 3D-image-guided brachytherapy (IGBT) alone. MATERIALS AND METHODS: From 2004 to 2018, 62 patients (41 stage-IA and 21 IB) were retrospectively studied, analysing anaesthetic procedure, applicator type, BT-planning imaging, clinical target volume (CTV), BT schedule, overall daily-dose equivalent to 2 Gy (EQD2(α/ß=4.5 or 3)) to the CTV(α/ß=4.5) and D2 cm3(α/ß=3) for organs at risk. Complications were evaluated using CTCAEv4 scores. The 2 and 5 year survival was calculated [cancer-specific survival (CSS), disease-free survival (DFS), local relapse-free survival (LRFS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS)]. Descriptive analysis and the Kaplan-Meier method were used for survival analysis. RESULTS: Mean follow-up: 32.8 months (SD 33.7). Spinal anaesthesia (38/62) followed by none (16/62) were the most common. Y-shaped Rotte applicators were used in 74% of patients. High-dose rate brachytherapy was administered in 89%. Median D90 to the CTV was 58.9 Gy (8.66-144 Gy). Eight patients presented relapse: four uterine, four nodal and four distant. The 2 and 5 year CSS was 93.3 and 80.5%, DFS 84.8 and 80.5%, LRFS was 93.1 and 88.7%, LRRFS was 91 and 91% and DMFS was 90.2 and 90.2%, respectively, CSS was better in stage-IA vs. IB (p = 0.043). Late vaginal and bladder G3-complication rates were 2.1%, respectively. CONCLUSION: Inoperable EC patients can be safely treated by BT with 2 and 5 year CSS of 93 and 80.5%, respectively, with even better results for IA cases. Prospective studies on 3D-IGBT are necessary to better analyse EC patient outcomes based on dose and treated volumes.

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future.

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.

Impact of Vaginal Symptoms and Hormonal Replacement Therapy on Sexual Outcomes After Definitive Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: Results from the EMBRACE-I Study.

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.

Risk Factors for Late Persistent Fatigue After Chemoradiotherapy in Patients With Locally Advanced Cervical Cancer: An Analysis From the EMBRACE-I Study.

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.

Risk factors for nodal failure after radiochemotherapy and image guided brachytherapy in locally advanced cervical cancer: An EMBRACE analysis.

OBJECTIVE: To assess risk factors for nodal failure (NF) after definitive (chemo)radiotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) for patients treated in the EMBRACE I study. MATERIALS AND METHODS: Data for pelvic NF and para-aortic (PAO) NF (NFPAO) were analysed. After multiple imputation, univariable and multivariable Cox-regression was performed for clinical and treatment-related variables. For patients with affected pelvic nodes but no PAO nodes at diagnosis, additional analyses were performed for two subgroups: 1. 'small pelvis' nodes in internal and external iliac, obturator, parametrial, presacral and/or common iliac (CI) region and 2. any CI nodes (subgroup of 1). RESULTS: 1338 patients with 152 NF and 104 NFPAO events were analysed with a median follow-up of 34.2 months (IQR 16.4-52.7). For the entire group, larger tumour width, nodal risk groups (in particular any CI nodes without PAO nodes), local failure, and lower Hb-nadir increased the risk of NF. Elective PAO-irradiation was independently associated with a decreased risk of NFPAO (HR 0.53, 95%-CI 0.28-1.00, p = 0.05). For subgroup 1, having 'any CI nodes without PAO nodes' and local failure significantly increased NF risk. Additionally, elective PAO-irradiation was associated with less risk of NFPAO (HR 0.38, 95%-CI 0.17-0.86, p = 0.02). For subgroup 2 only local failure was associated with higher risk of NF. CONCLUSION: In this patient cohort, nodal disease and tumour width at diagnosis, as well as local failure, are risk factors for NF after definitive treatment. Having either 'any PAO nodes' (with or without pelvic nodes) or 'any CI nodes' (without PAO nodes) are stronger risk factors than involvement of nodes in the small pelvis alone. Elective PAO-irradiation was associated with significantly less NFPAO, particularly in patients with nodal disease in the 'small pelvis' and/or CI region at time of diagnosis.

Nomogram Predicting Overall Survival in Patients With Locally Advanced Cervical Cancer Treated With Radiochemotherapy Including Image-Guided Brachytherapy: A Retro-EMBRACE Study.

PURPOSE: To present a nomogram for prediction of overall survival (OS) in patients with locally advanced cervical cancer (LACC) undergoing definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT). METHODS AND MATERIALS: Seven hundred twenty patients with LACC treated with radiochemotherapy including IGABT in 12 institutions (median follow-up 56 months) were analyzed; 248 deaths occurred. Thirteen candidate predictors for OS were a priori chosen on the basis of the literature and expert knowledge. Missing data (7.2%) were imputed using multiple imputation and predictive mean matching. Univariate analysis with a multivariable Cox regression model for OS stratified by center was performed. Stepwise selection of predictive factors with the Akaike Information Criterion was used to obtain a predictive model and construct a nomogram for OS predictions 60 months from diagnosis; this was internally validated by concordance probability as a measure of discrimination and a calibration plot. RESULTS: Thirteen potential predictive factors were evaluated; 10 factors reached statistical significance in univariate analysis (age, Hemoglobin, FIGO Stage2009, tumor width, corpus involvement, lymph node involvement, concurrent chemotherapy, dose to 90% of the high-risk clinical target volume, volume of CTV at the first brachytherapy [CTVHRVolumeBT], overall treatment time [OTT]). Four factors were confirmed significant within the multivariable Cox regression model (FIGO Stage2009, lymph node involvement, concurrent chemotherapy, CTVHRVolumeBT). The predictive model and corresponding nomogram were based on 7 Akaike Information Criterion-selected factors (age, corpus involvement, FIGO Stage2009, lymph node involvement, concurrent chemotherapy, CTVHRVolumeBT, OTT) and showed promising calibration and discrimination (cross-validated concordance probability c = 0.73). CONCLUSIONS: This is the first nomogram to predict OS in patients with LACC treated with IGABT. In addition to previously reported factors (age, FIGO2009 stage, corpus involvement, chemotherapy delivery, OTT, lymph node involvement), status of primary tumor at the time of brachytherapy seems to be an essential outcome predictor. These results can facilitate individualized tailoring of treatment and patient counseling during the treatment.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study.

BACKGROUND: The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. METHODS: EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m2, 5-6 cycles, 1 day per cycle, plus 45-50 Gy external-beam radiotherapy delivered in 1·8-2 Gy fractions) followed by MRI-based IGABT. The MRI-based IGABT target volume definition and dose reporting was according to Groupe Européen de Curiethérapie European Society for Radiation Oncology recommendations. IGABT dose prescription was open according to institutional practice. Local control and late morbidity were selected as primary endpoints in all patients available for analysis. The study was registered with ClinicalTrials.gov, NCT00920920. FINDINGS: Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm3 (IQR 20-40) and median minimal dose to 90% of the clinical target volume (D90%) was 90 Gy (IQR 85-94) equi-effective dose in 2 Gy per fraction. At a median follow-up of 51 months (IQR 20-64), actuarial overall 5-year local control was 92% (95% CI 90-93). Actuarial cumulative 5-year incidence of grade 3-5 morbidity was 6·8% (95% CI 5·4-8·6) for genitourinary events, 8·5% (6·9-10·6) for gastrointestinal events, 5·7% (4·3-7·6) for vaginal events, and 3·2% (2·2-4·5) for fistulae. INTERPRETATION: Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. FUNDING: Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis.

PURPOSE: 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). MATERIAL AND METHODS: 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. RESULTS: 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 D2cm3 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 D2cm3 resulted in an increase from 8% to 13% for 4-year actuarial estimate of G ≥ 2 cystitis. CONCLUSION: 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 D2cm3, reinforcing the importance of continued optimization during individualized IGABT planning.

Results of image guided brachytherapy for stage IB cervical cancer in the RetroEMBRACE study.

OBJECTIVE: Multiple treatment options are used in early local-stage cervical cancer, including combinations of surgery with neoadjuvant/adjuvant radiotherapy and chemotherapy. Our aim was to determine the outcome for definitive chemoradiation with image guided brachytherapy (IGBT). METHODS: FIGO1994 staging system was used in our study. We included 123 patients with stage IB cervical cancer, treated at 12 centers with external beam radiotherapy (EBRT) ± Chemotherapy and IGBT. Three- and 5-year actuarial local control (LC), pelvic control (PC), overall survival (OS), cancer-specific survival (CSS) and late morbidity (CTCAE v 3.0) were computed. RESULTS: Median age was 48 (23-82) years. FIGO1994 stage distribution was: IB1 68% and IB2 32%; 41% of the entire cohort had nodal metastases and 73% squamous-cell carcinoma. MRI-based tumor size was >40 mm in 63%. Median EBRT dose was 45 (40-50) Gy; 84% received chemotherapy. At IGBT, mean CTV-HR D90 was 93 ± 17 Gy (EQD210). D2cc for bladder was 76 ± 14 Gy, rectum 66 ± 11 Gy, sigmoid 66 ± 10 Gy, bowel 67 ± 7 Gy (EQD23). At 43-months median follow-up, 9% of patients had systemic, 6% paraaortic, 3% pelvic-nodal and 2% local failure. Five-year LC was 98%, PC 96%, CSS 90%, OS 83%. Intestinal G3--4 morbidity was 8%, urinary 7% and vaginal 0%. CONCLUSIONS: Chemoradiation with IGBT for FIGO1994 stage IB cervical cancer leads to excellent loco-regional control with limited morbidity. In IB node-negative disease, it can be regarded equivalent to surgery in terms of oncologic outcome. In tumors with unfavorable pre-treatment characteristics, chemoradiation is the first choice to avoid combining surgery with adjuvant therapy.

Dose-Volume Effects and Risk Factors for Late Diarrhea in Cervix Cancer Patients After Radiochemotherapy With Image Guided Adaptive Brachytherapy in the EMBRACE I Study.

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.

Importance of the ICRU bladder point dose on incidence and persistence of urinary frequency and incontinence in locally advanced cervical cancer: An EMBRACE analysis.

PURPOSE: 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). MATERIAL AND METHODS: 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. RESULTS: 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 D2cm3. 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. CONCLUSION: 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.

Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study.

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.

Salvage Mastectomy Versus Second Conservative Treatment for Second Ipsilateral Breast Tumor Event: A Propensity Score-Matched Cohort Analysis of the GEC-ESTRO Breast Cancer Working Group Database.

PURPOSE: Second conservative treatment has emerged as an option for patients with a second ipsilateral breast tumor event after conserving surgery and breast irradiation. We aimed to address the lack of evidence regarding second breast event treatment by comparing oncologic outcomes after conservative treatment or mastectomy. METHODS AND MATERIALS: Oncologic outcomes were analyzed using a propensity score-matched cohort analysis study on patients who received a diagnosis of a second breast event between January 1995 and June 2017. Patient data were collected from 15 hospitals/cancer centers in 7 European countries. Patients were offered mastectomy or lumpectomy plus brachytherapy. Propensity scores were calculated with logistic regression and multiple imputations. Matching (1:1) was achieved using the nearest neighbor method, including 10 clinical/pathologic data related to the second breast event. The primary endpoint was 5-year overall survival from the salvage surgery date. Secondary endpoints were 5-year cumulative incidence of third breast event, regional relapse and distant metastasis, and disease-free and specific survival. Complications and 5-year incidence of mastectomy were investigated in the conservative treatment cohort. RESULTS: Among the 1327 analyzed patients (mastectomy, 945; conservative treatment, 382), 754 were matched by propensity score (mastectomy, 377; conservative treatment, 377). The median follow-up was 75.4 months (95% confidence interval [CI], 65.4-83.3) and 73.8 months (95% CI, 67.5-80.8) for mastectomy and conservative treatment, respectively (P = .9). In the matched analyses, no differences in 5-year overall survival and cumulative incidence of third breast event were noted between mastectomy and conservative treatment (88% [95% CI, 83.0-90.8] vs 87% [95% CI, 82.1-90.2], P = .6 and 2.3% [95% CI, 0.7-3.9] vs 2.8% [95% CI, 0.8-4.7], P = .4, respectively). Similarly, no differences were observed for all secondary endpoints. Five-year cumulative incidence of mastectomy was 3.1% (95% CI, 1.0-5.1). CONCLUSIONS: To our knowledge, this is the largest matched analysis of mastectomy and conservative treatment combining lumpectomy with brachytherapy for second breast events. Compared with mastectomy, conservative treatment does not appear to be associated with any differences in terms of oncologic outcome. Consequently, conservative treatment could be considered a viable option for salvage treatment.

Dose volume histogram constraints in patients with head and neck cancer treated with surgery and adjuvant HDR brachytherapy: A proposal of the head and neck and skin GEC ESTRO Working group.

BACKGROUND: The Head and Neck and Skin (HNS) Working group of the GEC-ESTRO acknowledges the lack of widely accepted Dose Volume Histogram (DVH) constraints in adjuvant head and neck brachytherapy and issues recommendations to minimize mandibular Osteoradionecrosis (ORN) and Soft Tissue Necrosis (STN). METHODS: A total of 227 patients with the diagnosis of head and neck cancer treated with surgery and adjuvant HDR brachytherapy alone or combined with other treatment modalities during the period 2000-2018 were analyzed. RESULTS: STN was observed in 28 out of 227 cases (12.3%) with an average time to appearance of 4.0 months. In previously unirradiated cases, there was a positive correlation between CTV size and STN (p = 0.017) and a trend towards significance between Total EQD2-DVH TV100 dose and STN (p = 0.06). The risk of STN in the absence of both factors (i.e, CTV < 15 cm3 and Total EQD2-DVH TV100 dose < 87 Gy) was 2%, with one factor present 15.7% and with both factors 66.7% (p = 0.001). ORN was observed in 13 out of 227 cases (5.7%) with an average time to appearance of 26.2 months. In unirradiated cases, ORN correlated with Total Physical Dose to Mandible2cm3 (p = 0.027). Patients receiving Total Physical Doses greater than 61 Gy had a 20-fold increased risk of ORN. CONCLUSIONS: In Unirradiated patients the panel recommends to avoid implantation of postoperative CTVs exceeding 15 cm3 at Total EQD2-DVH TV100 doses in excess of 87 Gy as well as to limit the irradiation of the Mandible2cm3 to 61 Gy. In previously irradiated patients the panel cannot make a recommendation based on the available results.