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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.

Radiotherapy with cisplatin (chemoradiation) is the standard treatment for women with locally advanced cervical cancer. Radiotherapy with deep hyperthermia (thermoradiation) is a well established alternative, but is rarely offered as an alternative to chemoradiation, particularly for patients in whom cisplatin is contraindicated. The scope of this review is to provide an overview of the biological rationale of hyperthermia treatment delivery, including patient workflow, and the clinical effectiveness of hyperthermia as a radiosensitizer in the treatment of cervical cancer. Hyperthermia is especially effective in hypoxic and nutrient deprived areas of the tumor where radiotherapy is less effective. Its radiosensitizing effectiveness depends on the temperature level, duration of treatment, and the time interval between radiotherapy and hyperthermia. High quality hyperthermia treatment requires an experienced team, adequate online adaptive treatment planning, and is preferably performed using a phased array radiative locoregional hyperthermia device to achieve the optimal thermal dose effect. Hyperthermia is well tolerated and generally leads to only mild toxicity, such as patient discomfort. Patients in whom cisplatin is contraindicated should therefore be referred to a hyperthermia center for thermoradiation.

Objective: The in-house developed 70 MHz AMC-4 locoregional hyperthermia system has been in clinical use since 1984. This device was recently commercialized as the Alba 4D (Medlogix®, Rome, Italy), with a similar geometrical 4-waveguide design. At the time of this study a hybrid Alba 4D was installed at our center, which incorporated elements of the AMC-4. This study aims to compare clinical performance of both devices. Methods: During one year after clinical acceptance of the hybrid Alba 4D, both devices were used for treatment delivery in patients scheduled for locoregional hyperthermia. Each patient started with the AMC-4, next sessions were allocated to either device. Possible differences between Alba 4D and AMC-4 sessions in power, achieved temperature T0, T10, T50, T90, T100, treatment time and complaints per session, were evaluated using linear mixed models (LMMs) for repeated measures with patient as random effect. Results: From March 2018 to April 2019, eleven patients with cervical, pancreatic, vaginal carcinoma and uterine leiomyosarcoma received 27 locoregional hyperthermia sessions with the Alba 4D and 34 sessions with the AMC-4. Median number of sessions per patient was 5 (range 3–13). Treatment results for both devices were not significantly different: T50 was 40.5 ± 1.0 °C vs. 40.8 ± 0.7 °C, applied power was 500 ± 79 W vs. 526 ± 108 W, for the Alba 4D vs. AMC-4, respectively. Conclusion: Results of the first patients treated with the hybrid Alba 4D demonstrated comparable clinical performance of the Alba 4D and AMC-4 locoregional hyperthermia systems, and both devices are expected to yield similar favorable clinical results.

Purpose: This prospective study evaluates our first clinical experiences with the novel ``BRachytherapy via artificial Intelligent GOMEA-Heuristic based Treatment planning'' (BRIGHT) applied to high-dose-rate prostate brachytherapy. MethodS AND MATERIALs: Between March 2020 and October 2021, 14 prostate cancer patients were treated in our center with a 15Gy HDR-brachytherapy boost. BRIGHT was used for bi-objective treatment plan optimization and selection of the most desirable plans from a coverage-sparing trade-off curve. Selected BRIGHT plans were imported into the commercial treatment planning system Oncentra Brachy. In Oncentra Brachy a dose distribution comparison was performed for clinical plan choice, followed by manual fine-tuning of the preferred BRIGHT plan when deemed necessary. The reasons for plan selection, clinical plan choice, and fine-tuning, as well as process speed were monitored. For each patient, the dose-volume parameters of the (fine-tuned) clinical plan were evaluated. Results: In all patients, BRIGHT provided solutions satisfying all protocol values for coverage and sparing. In four patients not all dose-volume criteria of the clinical plan were satisfied after manual fine-tuning. Detailed information on tumour coverage, dose-distribution, dwell time pattern, and insight provided by the patient-specific trade-off curve, were used for clinical plan choice. Median time spent on treatment planning was 42 min, consisting of 16 min plan optimization and selection, and 26 min undesirable process steps. ConclusionS: BRIGHT is implemented in our clinic and provides automated prostate high-dose-rate brachytherapy planning with trade-off based plan selection. Based on our experience, additional optimization aims need to be implemented to further improve direct clinical applicability of treatment plans and process efficiency.

Purpose: To compare transarterial chemoembolization delivered with drug eluting beads (TACE-DEB) with stereotactioc body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized trial. Methods and Materials: Patients were included if they were eligible for TACE. They could also be recruited if they required treatment prior to liver transplantation. A maximum of four TACE-DEB procedures and ablation after incomplete TACE-DEB were both allowed. SBRT was delivered in six fractions of 8-9Gy. Primary end point was time to progression (TTP). Secondary endpoints were local control (LC), overall survival (OS), response rate (RR), toxicity, and quality of life (QoL). The calculated sample size was 100 patients. Results: Between May 2015 and April 2020, 30 patients were randomized to the study. Due to slow accrual the trial was closed prematurely. Two patients in the SBRT arm were considered ineligible leaving 16 patients in the TACE-DEB arm and 12 in the SBRT arm. Median follow-up was 28.1 months. Median TTP was 12 months for TACEDEB and 19 months for SBRT (p=0.15). Median LC was 12 months for TACE-DEB and >40 months (not reached) for SBRT (p=0.075). Median OS was 36.8 months for TACEDEB and 44.1 months for SBRT (p=0.36). A post-hoc analysis showed 100% for SBRT 1- and 2-year LC, and 54.4% and 43.6% for TACE-DEB (p=0.019). Both treatments resulted in RR>80%. Three episodes of possibly related toxicity grade ≥3 were observed after TACE-DEB. No episodes were observed after SBRT. QoL remained stable after both treatment arms. Conclusions: In this trial, TTP after TACE-DEB was not significantly improved by SBRT, while SBRT showed higher local antitumoral activity than TACE-DEB, without detrimental effects on OS, toxicity and QoL. To overcome poor accrual in randomized trials that include SBRT, and to generate evidence for including SBRT in treatment guidelines, international cooperation is needed.

Purpose: Deformable Image Registration (DIR) can benefit from additional guidance using corresponding landmarks in the images. However, the benefits thereof are largely understudied, especially due to the lack of automatic landmark detection methods for three-dimensional (3D) medical images. Approach: We present a Deep Convolutional Neural Network (DCNN), called DCNN-Match, that learns to predict landmark correspondences in 3D images in a self-supervised manner. We trained DCNN-Match on pairs of Computed Tomography (CT) scans containing simulated deformations. We explored five variants of DCNN-Match that use different loss functions and assessed their effect on the spatial density of predicted landmarks and the associated matching errors. We also tested DCNN-Match variants in combination with the open-source registration software Elastix to assess the impact of predicted landmarks in providing additional guidance to DIR. Results: We tested our approach on lower-abdominal CT scans from cervical cancer patients: 121 pairs containing simulated deformations and 11 pairs demonstrating clinical deformations. The results showed significant improvement in DIR performance when landmark correspondences predicted by DCNN-Match were used in the case of simulated (p = $0e^0$) as well as clinical deformations (p = 0.030). We also observed that the spatial density of the automatic landmarks with respect to the underlying deformation affect the extent of improvement in DIR. Finally, DCNN-Match was found to generalize to Magnetic Resonance Imaging (MRI) scans without requiring retraining, indicating easy applicability to other datasets. Conclusions: DCNN-Match learns to predict landmark correspondences in 3D medical images in a self-supervised manner, which can improve DIR performance., accepted paper in the Journal of Medical Imaging

Objective. To evaluate feasibility of chemoradiation as alternative for extensive surgery in patients with locally advanced vulvar cancer and to report on locoregional control, toxicity and survival. Methods. In a multicenter, prospective phase II trial patients with locally advanced vulvar cancer were treated with locoregional radiotherapy combined with sensitizing chemotherapy (capecitabine). Treatment feasibility, percentage locoregional control, survival and toxicity were evaluated. Results. 52 patients with mainly T2/T3 disease were treated according to the study protocol in 10 centers in the Netherlands from 2007 to 2019. Full dose radiotherapy (tumor dose of 64.8Gy) was delivered in 92% and full dose capecitabine in 69% of patients. Most prevalent acute >_ grade 3 toxicities were regarding skin/ mucosa and pain (54% and 37%). Late >_grade 3 toxicity was reported for skin/mucosa (10%), fibrosis (4%), GI incontinence (4%) and stress fracture or osteoradionecrosis (4%). Twelve weeks after treatment, local clinical complete response (cCR) and regional control (RC) rates were 62% and 75%, respectively. After 2 years, local cCR persisted in 22 patients (42%) and RC was 58%. Thirty patients (58%) had no evidence of disease at end of follow-up (median 35 months). In 9 patients (17%) extensive surgery with stoma formation was needed. Progression free survival was 58%, 51% and 45% and overall survival was 76%, 66%, 52% at 1,2, and 5 years. Conclusions. Definitive capecitabine-based chemoradiation as alternative for extensive surgery is feasible in locally advanced vulvar cancer and results in considerable locoregional control with acceptable survival rates with manageable acute and late toxicity. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

We aim to investigate the current state of brachytherapy (BT) training among the radiation oncology trainees in Europe. Material and methods: A 22-question online survey based on the one by the American Association of Radiation Oncology Residents (2017) with added queries pertinent to training in Europe was sent to 1450 residents in two iterations. These included site-specific training, volume of experience, barriers to training, institutional support, and preferences for further education. Responses to individual statements were given on a 1 to 5 Likert-type scale. The answers were reported by junior (≤3 years of training) and senior years of training (year of training 4/5/6 and junior staff). Descriptive statistics were used to describe frequencies. Results: Residents from 21 European countries participated, 445 (31%) responded. 205 (47%) were senior residents. 60% residents consider that performing BT independently at the end of residency is very or somewhat important. Confidence in joining a brachytherapy practice at the end of residency was high or somewhat high in 34% of senior residents. They reported as barriers to achieving independence in BT to be lack of appropriate didactic/procedural training from supervisors (47%) and decreased case load (31%). 68% reported their program lacks a formal BT curriculum and standardized training assessment. Conclusions: Residents in Europe, feel independent BT practice is very or somewhat important, but do not feel confident they will achieve this goal. To address this gap, efforts are needed to develop and implement a formal and comprehensive BT curriculum with easy access to trained instructors.

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.

In 2008, the GEC ESTRO Gyn network launched the first multiinstitutional, observational, and prospective international study on MRI-guided brachytherapy in locally advanced cervical cancer patients (EMBRACE-I). EMBRACE-I was followed by EMBRACE-II from 2016 and ongoing. Among the aims of the EMBRACE studies are to benchmark morbidity outcomes and develop dose-volume effects and predictive models for morbidity. The EMBRACE studies collect both physician (CTCAE v.3) and patient (EORTC QLQ-C30/CX24) reported outcomes, including baseline information, in a regular follow-up schedule. The EMBRACE studies feature high numbers of patients (EMBRACE-I N = 1416, EMBRACE-II N = 1500 expected) enrolled from many institutions worldwide (EMBRACE-I n = 23, EMBRACE-II n = 45). This large-scale multiinstitutional approach offers a unique opportunity to investigate and develop new strategies for improving the quality of assessment and reporting of morbidity. This report presents an overview of the challenges and pitfalls regarding the assessment and reporting of morbidity encountered during more than a decade of development and research activities within the EMBRACE consortium. This includes the recognition and evaluation of inconsistencies in the morbidity assessment, and consequently, the provision of assistance and training in the scoring procedure to reduce systematic assessment bias. In parallel, a variety of methodological approaches were tested to comprehensively summarize morbidity outcomes, and a novel approach was developed to refine dose-effect models and risk factor analyses. The purpose of this report is to present an overview of these findings, describe the learning process, and the strategies that have consequently been implemented regarding educational activities, training, and dissemination.

The last 2 decades have witnessed the development and broad adoption of image-guided adaptive brachytherapy (IGABT) combined with radiochemotherapy in patients with locally advanced cervical cancer. A variety of brachytherapy techniques and dose/fractionation schedules have been applied, and until recently, there was no strong evidence available for preferring one approach to another. However, large volumes of data have now provided high level clinical evidence for dose-effect relations for both disease and morbidity endpoints. It is therefore now possible to apply evidence based dose planning aims and dose prescription protocols in IGABT for locally advanced cervical cancer. This review gives an overview of targets/organs-at-risk and disease/morbidity endpoints which are relevant in the context of treatment planning and dose prescription in IGABT. The dosimetric and clinical evidence is summarized to support the implementation of dose prescription protocols which include hard and soft constraints for targets and organs at risk.

Simple Summary Hearing loss (HL) can be a side effect of paediatric cancer treatment and can be caused by chemotherapy but also local therapies such as radiotherapy and/or surgery of the head and neck region. In this study, the frequency and patterns of HL were assessed in survivors of head and neck rhabdomyosarcoma (HNRMS). Our secondary aim was to look into the dose-effect relationship between radiotherapy dose on the cochlea and the presence of HL. Forty-nine survivors of HNRMS were included in this study, forty-two of them underwent audiological evaluation. HL was found in up to 19% of the survivors. Four survivors had low frequencies HL with normal hearing or milder HL in the higher frequencies. In our series, HL (>= Muenster 2b) was significantly associated with the maximum cochlear irradiation dose (p = 0.047). More research is needed on HL patterns in HNRMS survivors and on the radiotherapy dose-effect relationship. Purpose: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. Methods: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster >= 2b, CTCAE >= 2, and SIOP >= 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. Results: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (>= Muenster 2b) (p = 0.047). In our series, HL (>= Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. Conclusion: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.

Purpose: Magnetic resonance imaging (MRI) is increasingly used in radiation oncology for target delineation and radiotherapy treatment planning, for example, in patients with gynecological cancers. As a consequence of pelvic radiotherapy, a part of the bowel is irradiated, yielding risk of bowel toxicity. Existing dose-effect models predicting bowel toxicity are inconclusive and bowel motion might be an important confounding factor. The exact motion of the bowel and dosimetric effects of its motion are yet uncharted territories in radiotherapy. In diagnostic radiology methods on the acquisition of dynamic MRI sequences were developed for bowel motility visualization and quantification. Our study aim was to develop an imaging technique based on three-dimensional (3D) cine-MRI to visualize and quantify bowel motion and demonstrate it in a cohort of gynecological cancer patients. Methods: We developed an MRI acquisition suitable for 3D bowel motion quantification, namely a balanced turbo field echo sequence (TE = 1.39 ms, TR = 2.8 ms), acquiring images in 3.7 s (dynamic) with a 1.25 × 1.25 × 2.5 mm3 resolution, yielding a field of view of 200 × 200 × 125 mm3. These MRI bowel motion sequences were acquired in 22 gynecological patients. During a 10-min scan, 160 dynamics were acquired. Subsequent dynamics were deformably registered using a B-spline transformation model, resulting in 159 3D deformation vector fields (DVFs) per MRI set. From the 159 DVFs, the average vector length was calculated per voxel to generate bowel motion maps. Quality assurance was performed on all 159 DVFs per MRI, using the Jacobian Determinant and the Harmonic Energy as deformable image registration error metrics. In order to quantify bowel motion, we introduced the concept of cumulative motion–volume histogram (MVH) of the bowel bag volume. Finally, interpatient variation of bowel motion was analyzed using the MVH parameters M10%, M50%, and M90%. The M10%/M50%/M90% represents the minimum bowel motion per frame of 10%/50%/90% of the bowel bag volume. Results: The motion maps resulted in a visualization of areas with small and large movements within the bowel bag. After applying quality assurance, the M10%, M50%, and M90% were 4.4 (range 2.2–7.6) mm, 2.2 (range 0.9–4.1) mm, and 0.5 (range 0.2–1.4) mm per frame, on average over all patients, respectively. Conclusion: We have developed a method to visualize and quantify 3D bowel motion with the use of bowel motion specific MRI sequences in 22 gynecological cancer patients. This 3D cine-MRI-based quantification tool and the concept of MVHs can be used in further studies to determine the effect of radiotherapy on bowel motion and to find the relation with dose effects to the small bowel. In addition, the developed technique can be a very interesting application for bowel motility assessment in diagnostic radiology.

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.

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.

Purpose: This study assessed outcomes following the nowadays standing treatment for primary vaginal cancer with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT) in a multicenter patient cohort. Methods: Patients treated with computer tomography (CT)–MRI-assisted-based IGABT were included. Retrospective data collection included patient, tumor and treatment characteristics. Late morbidity was assessed by using the CTCAE 3.0 scale. Results: Five European centers included 148 consecutive patients, with a median age of 63 years. At a median follow-up of 29 months (IQR 25–57), two- and five-year local control were 86% and 83%, disease-free survival (DFS) was 73% and 66%, and overall survival (OS) was 79% and 68%, respectively. Crude incidences of ≥ grade-three urogenital, gastro-intestinal and vaginal morbidity was 8%, 3% and 8%, respectively. Lymph node metastasis was an independent prognostic factor for disease-free survival (DFS). Univariate analysis showed improved local control in patients with T2–T4 tumors if &gt, 80 Gy EQD2α/β10 was delivered to the clinical target volume (CTV) at the time of brachytherapy. Conclusions: In this large retrospective multicenter study, IGABT for primary vaginal cancer resulted in a high local control with acceptable morbidity. These results compared favorably with two-dimensional (2D) radiograph-based brachytherapy and illustrate that IGABT plays an important role in the treatment of vaginal cancer.

Contains fulltext : 232797.pdf (Publisher’s version ) (Open Access) PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Primary vaginal cancer is a rare cancer and clinical evidence to support recommendations on its optimal management is insufficient. Because primary vaginal cancer resembles cervical cancer in many aspects, treatment strategies are mainly adopted from evidence in locally advanced cervical cancer. To date, the organ-sparing treatment of choice is definitive radiotherapy, consisting of external beam radiotherapy and brachytherapy, combined with concurrent chemotherapy. Brachytherapy is an important component of the treatment and its steep dose gradient enables the delivery of high doses of radiation to the primary tumour, while simultaneously sparing the surrounding organs at risk. The introduction of volumetric CT or MRI image-guided adaptive brachytherapy in cervical cancer has led to better pelvic control and survival, with decreased morbidity, than brachytherapy based on x-ray radiographs. MRI-based image-guided adaptive brachytherapy with superior soft-tissue contrast has also been adopted sporadically for primary vaginal cancer. This therapy has had promising results and is considered to be the state-of-the-art treatment for primary vaginal cancer in standard practice.

The aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy (IGART) and improved dose conformity based on intensity-modulated proton therapy (IMPT). The study included planning CTs from 11 previously treated patients with cervical cancer with a >4-cm tumour-free part of the proximal uterus on diagnostic magnetic resonance imaging (MRI). IGART and robustly optimised IMPT plans were generated for both conventional target volumes and for MRI-based target tailoring (where the non-invaded proximal part of the uterus was excluded), yielding four treatment plans per patient. For each plan, the V15Gy, V30Gy, V45Gy and Dmean for bladder, sigmoid, rectum and bowel bag were compared, and the normal tissue complication probability (NTCP) for ≥grade 2 acute small bowel toxicity was calculated. Both IMPT and MRI-based target tailoring resulted in significant reductions in V15Gy, V30Gy, V45Gy and Dmean for bladder and small bowel. IMPT reduced the NTCP for small bowel toxicity from 25% to 18%; this was further reduced to 9% when combined with MRI-based target tailoring. In four of the 11 patients (36%), NTCP reductions of >10% were estimated by IMPT, and in six of the 11 patients (55%) when combined with MRI-based target tailoring. This >10% NTCP reduction was expected if the V45Gy for bowel bag was >275 cm3 and >200 cm3, respectively, during standard IGART alone. In patients with cervical cancer, both proton therapy and MRI-based target tailoring lead to a significant reduction in the dose to surrounding organs at risk and small bowel toxicity.

Introduction Management regarding completing hysterectomy in case of intraoperative finding of positive lymph nodes in early-stage cervical cancer differs between institutions. The aim of this study was to compare survival and toxicity after completed hysterectomy followed by adjuvant (chemo-)radiotherapy versus abandoned hysterectomy and primary treatment with chemoradiotherapy (CRT). Methods A retrospective multicenter cohort study was performed. All patients were scheduled for radical hysterectomy with pelvic lymphadenectomy (RHL). In the RHL group, hysterectomy was completed followed by adjuvant (chemo-)radiotherapy. In the second group, hysterectomy was abandoned, and CRT was conducted. Primary outcomes were disease-free survival (DFS) and overall survival. A multivariable analysis on DFS was performed. Toxicity was scored according to the National Cancer Institute CTCAE (Common Terminology Criteria for Adverse Events) v4.03. Results A total of 121 patients were included (RHL, n = 89; CRT, n = 32). There was no difference in overall survival (84% vs 77%). Five-year DFS was in favor of completing RHL (81% vs 67%). Multivariable analysis showed that, corrected for lymph node variables, treatment regimen was not associated with DFS. After RHL, pelvic recurrence rate was significantly lower compared with CRT (2% vs 16%). CTCAE grade 3–4 toxicity rates were higher in the CRT compared with the RHL group (59% vs 30%), mainly because of differences in chemotherapy-related hematologic toxicity. Conclusions In patients with clinically N0 early-stage cervical cancer with intraoperative detection of positive nodes, completing RHL followed by adjuvant (chemo-)radiotherapy may result in a better pelvic control compared with abandoning hysterectomy and treatment with chemoradiotherapy. However, if corrected for lymph node variables, treatment (RHL or CRT) was not associated with DFS.

ObjectiveTo compare long-term morbidity and quality of life after primary surgery or primary radiotherapy for stage IB/II cervical cancer.MethodsA cross-sectional study was performed. Patients treated for stage IB/II cervical cancer between 2000 and 2010 were approached to participate. Primary treatment consisted of radical hysterectomy with pelvic lymphadenectomy (RHL), for selected cases followed by adjuvant (chemo-)radiotherapy, or primary (chemo)radiotherapy (PRT). European Organization for Research and Treatment of Cancer-C30 and European Organization for Research and Treatment of Cancer-CX24 questionnaires were administered. A multivariable analysis was performed to identify factors associated with morbidity/quality of life. In a subgroup analysis, we compared patients with RHL + adjuvant radiotherapy with those after PRT.ResultsThree hundred twenty-three cervical cancer survivors were included (263 RHL/60 PRT). In the PRT group, International Federation of Gynecology and Obstetrics stage was higher and women were older. In the RHL group, more women had a partner. Women treated with PRT reported lower physical (β, −6.01) and social functioning (β, −15.2), more financial problems (β, 10.9), diarrhea (β, 9.98), symptom experience (β, 6.13), sexual worry (β, 11.3), and worse sexual/vaginal functioning (β, 11.4). Women treated with RHL reported significantly more lymphedema (β, −16.1). No differences in global health were found. In the subgroup analysis, women after PRT (n = 60) reported poorer social functioning, less sexual enjoyment, and higher symptoms experience than women after RHL and adjuvant radiotherapy (n = 60). The latter reported more lymphedema.ConclusionsAlthough global health scores are not significantly different, women after PRT report more physical, social, and sexual symptoms. These results can be well used by physicians to inform their patients about treatment-related morbidity.

Background and purpose: The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported.Materials and methods: Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans.Results: For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R-2 Conclusions: Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected. (c) 2017 Elsevier B.V. All rights reserved.

Introduction/Background Limited data are available on the preferred policy in patients with vulvar cancer and bulky lymph nodes in the groin. Debulking of the nodes followed by radiotherapy resulted in less morbidity and similar groin control and survival compared with a complete inguino femoral groin dissection (IFL) in studies with limited patient numbers. The aim of this study was to gather more data and confirm the ‘safety’ of debulking compared to IFL followed by radiotherapy. Historically, patients with bulky lymph nodes were treated by a complete IFL. From 2007 onwards the policy changed into nodal debulking. Groin recurrence-free survival and survival were evaluated in both groups. Methodology Between 1982 and 2016, 217 patients were identified with positive groin lymph nodes. Clinically suspicious bulky lymph nodes and histologically confirmed as tumor positive were found in 71 patients. Before 2007, 36 patients with bulky nodes were treated by a complete IFL. After 2007, 35 patients were treated by nodal debulking. All patients received radiotherapy to both groins and pelvis. Clinical (age, tumor diameter) and pathologic (number of positive nodes, extracapsular growth) variables among the two groups were compared. Disease specific survival and groin recurrence-free survival were calculated. Results No difference was seen in clinical and pathological parameters between the debulking and IFL groups. Per groin analysis showed no difference in groin recurrence rate (12.3% versus 14.3%, p=0,41). The 2 year groin recurrence free survival for debulking versus IFL was 81,3% versus 73,5%, respectively (p=0.31, figure 1). Two years disease specific survival was better for patients after nodal debulking (62.5% versus 31.9%, p=0.04, figure 2). Conclusion Because of the limited number of patients analyzed it is difficult to draw firm conclusions, but it is suggested that nodal debulking instead of formal IFL followed by radiotherapy does not compromise groin control and survival. Disclosure Nothing to disclose.

BackgroundThe efficacy of adjuvant radiotherapy in patients with intermediate risk early cervical cancer after radical hysterectomy is still under debate. Most guidelines recommend adjuvant radiotherapy, whereas others consider observation a viable option.ObjectiveTo investigate if patients with intermediate risk factors for cervical cancer who underwent radical hysterectomy may benefit from adjuvant radiotherapy.MethodsConsecutive patients with tumor confined to the cervix and intermediate risk factors (according to Sedlis), treated between January 1982 and December 2014 who were observed after a type C2 radical hysterectomy formed the basis for this study. The frequency of recurrences, specifically isolated loco-regional recurrences, and the risk of death from recurrences, were analyzed. Data were analyzed using SPSS, version 23.0 for WindowsResultsA total of 161 patients were included in the analysis. Median age was 40 (range 20–76). Stages IB1 and IB2 were seen in 87 (54%) and 74 patients (46%), respectively. Squamous cell and non-squamous histology was seen in 114 (70.8%) and 47 patients (29.2%), respectively. Of the 161 patients, 25 (15.5%) had recurrent disease, of whom nine had an isolated loco-regional recurrence (5.6%). Median time to recurrence for isolated loco-regional recurrences was 28 months (range 9–151). Treatment for an isolated loco-regional recurrence was radiotherapy (n = 4) and chemoradiotherapy (n = 5). Four patients (2.5%) died from disease as a result of an isolated loco-regional recurrence. Actuarial disease- specific survival was 93.0% for the total group. No variables were found that predicted an isolated loco-regional recurrence.DiscussionThe mortality from isolated loco-regional recurrence in patients with intermediate risk factors for cervical cancer who underwent only radical hysterectomy type C2 was 2.5%. Further studies should compare outcomes between patients who undergo a type C2 radical hysterectomy without adjuvant radiotherapy with those undergoing a less radical hysterectomy but with adjuvant radiotherapy.

Purpose: Bi-objective treatment planning for high-dose-rate prostate brachytherapy is a novel treatment planning method with two separate objectives that represent target coverage and organ-at-risk sparing. In this study, we investigated the feasibility and plan quality of this method by means of a retrospective observer study.Methods and Materials: Current planning sessions were recorded to configure a bi-objective optimization model and to assess its applicability to our clinical practice. Optimization software, GOMEA, was then used to automatically generate a large set of plans with different trade-offs in the two objectives for each of 18 patients treated with high-dose-rate prostate brachytherapy. From this set, five plans per patient were selected for comparison to the clinical plan in terms of satisfaction of planning criteria and in a retrospective observer study. Three brachytherapists were asked to evaluate the blinded plans and select the preferred one.Results: Recordings demonstrated applicability of the bi-objective optimization model to our clinical practice. For 14/18 patients, GOMEA plans satisfied all planning criteria, compared with 4/18 clinical plans. In the observer study, in 53/54 cases, a GOMEA plan was preferred over the clinical plan. When asked for consensus among observers, this ratio was 17/18 patients. Observers highly appreciated the insight gained from comparing multiple plans with different trade-offs simultaneously.Conclusions: The bi-objective optimization model adapted well to our clinical practice. GOMEA plans were considered equal or superior to the clinical plans. In addition, presenting multiple high-quality plans provided novel insight into patient-specific trade-offs.

Background and purpose Survival after relapse of head and neck rhabdomyosarcoma (HNRMS) after prior external beam radiotherapy (EBRT) is poor, since options for adequate local treatment are often lacking. In this study we describe our experience with salvage AMORE in patients with relapsed HNRMS after prior EBRT. Materials and methods Patients with relapsed HNRMS after prior EBRT in which salvage AMORE treatment was considered feasible were analysed; this includes patients with parameningeal, head and neck non-parameningeal and orbital localization. AMORE treatment consisted of Ablative surgery, MOuld technique brachytherapy and surgical REconstruction. Results In total 18 patients received salvage AMORE treatment; nine patients had relapsed parameningeal (PM) RMS, two patients had relapsed head and neck non-parameningeal RMS (HN-nonPM) and seven patients had relapsed orbital RMS. Local control rate was 67% and 5-year overall survival was 54% (95% confidence interval: 31–78%); 3/9 patients with PM RMS, 0/2 patients with HN-nonPM RMS and 6/7 patients with orbital RMS were alive after a median follow-up of 8.6 years. One patient with PM RMS survived more than 5 years after which he died from a secondary cancer. Six patients developed a local relapse (of which one patient also developed a distant metastasis) and two patients developed distant metastases. Conclusions Salvage AMORE treatment is a feasible and effective local therapy approach even after prior EBRT. Since salvage AMORE treatment is sometimes the only curative option in patient with relapsed HNRMS, we encourage physicians to consider salvage AMORE treatment for patients with relapsed HNRMS after prior EBRT.

Purpose/Objective: It is unknown whether the historically found dosimetric advantages of treating gynecologic cancer with the patient in a prone position with use of a small-bowel displacement device (belly-board) remain when volumetric arc therapy (VMAT) is used and whether these advantages depend on the necessary margin between clinical target volume (CTV) and planning target volume (PTV). The aim of this study is to determine the best patient position (prone or supine) in terms of sparing organs at risk (OAR) for various CTV-to-PTV margins and VMAT dose delivery. Methods and Materials: In an institutional review boarddapproved study, 26 patients with gynecologic cancer scheduled for primary (9) or postoperative (17) radiation therapy were scanned in a prone position on a belly-board and in a supine position on the same day. The primary tumor CTV, nodal CTV, bladder, bowel, and rectum were delineated on both scans. The PTVs were created each with a different margin for the primary tumor and nodal CTV. The VMAT plans were generated with our in-house system for automated treatment planning. For all margin combinations, the supine and prone plans were compared with consideration of all OAR dose-volume parameters but with highest priority given to bowel cavity V-45Gy (cm(3)). Results: For both groups, the prone position reduced the bowel cavity V-45Gy, in particular for nodal margins >= 10 mm (Delta V-45Gy = 23.9 +/- 10.6 cm(3)). However, for smaller margins, the advantage was much less pronounced (Delta V-45Gy = 6.5 +/- 3.0 cm(3)) and did not reach statistical significance. The rectum mean dose (D-mean) was significantly lower (Delta D-mean = 2.5 +/- 0.3 Gy) in the prone position for both patient groups and for all margins, and the bladder Dmean was significantly lower in the supine position (Delta D-mean = 2.6 +/- 0.4 Gy) only for the postoperative group. The advantage of the prone position was not present if it needed a larger margin than the supine position. Conclusion: For patients with gynecologic cancer, the historically found dosimetric advantages for the prone position remain for modern dose delivery techniques if large margins are needed. However, the advantage is lost for small margins and if the prone position needs a larger margin than the supine position. (C) 2016 Elsevier Inc. All rights reserved.

Introduction The reliability of hyperthermia treatment planning (HTP) is strongly dependent on the accuracy of the electric properties of each tissue. The values currently used are mostly based on ex vivo measurements. In this study, in vivo conductivity of human muscle, bladder content and cervical tumours, acquired with magnetic resonance-based electric properties tomography (MR-EPT), are exploited to investigate the effect on HTP for cervical cancer patients. Methods Temperature-based optimisation of five different patients was performed using literature-based conductivity values yielding certain antenna settings, which are then used to compute the temperature distribution of the patient models with EPT-based conductivity values. Furthermore, the effects of altered bladder and muscle conductivity were studied separately. Finally, the temperature-based optimisation was performed with patient models based on EPT conductivity values. Results The tumour temperatures for all EPT-based dielectric patient models were lower compared to the optimal tumour temperatures based on literature values. The largest deviation was observed for patient 1 with ΔT90 = -1.37 °C. A negative impact was also observed when the treatment was optimised based on the EPT values. For four patients ΔT90 was less than 0.6 °C; for one patient it was 1.5 °C. Conclusions Electric conductivity values acquired by EPT are higher than commonly used from literature. This difference has a substantial impact on cervical tumour temperatures achieved during hyperthermia. A higher conductivity in the bladder and in the muscle tissue surrounding the tumour leads to higher power dissipation in the bladder and muscle, and therefore to lower tumour temperatures.

Background and purpose The need for radiation oncologists and other radiation oncology (RO) professionals to lead quality improvement activities and contribute to shaping the future of our specialty is self-evident. Leadership knowledge, skills and behaviours, like other competencies, can be learned (Blumenthal et al., 2012). The objective of this study was to define a globally applicable competency set specific to radiation oncology for the CanMEDS Leader Role (Frank et al., 2015). Methods A modified Delphi consensus process delivering two rounds of on-line surveys was used. Participants included trainees, radiation/clinical oncologists and other RO team members (radiation therapists, physicists, and nurses), professional educators and patients. Results 72 of 95 (76%) invitees from nine countries completed the Round 1 (R1) survey. Of the 72 respondents to RI, 70 completed Round 2 (R2) (97%). In R1, 35 items were deemed for ‘inclusion' and 21 for ‘exclusion', leaving 41 ‘undetermined'. After review of items, informed by participant comments, 14 competencies from the ‘inclusion' group went into the final curriculum; 12 from the ‘undetermined' group went to R2. In R2, 6 items reached consensus for inclusion. Conclusion This process resulted in 20 RO Leader Role competencies with apparent global applicability. This is the first step towards developing learning, teaching and assessment tools for this important area of training.

Background and purpose Traditionally, vaginal dose points have been defined at the vaginal source level, thus not providing dose information for the entire vagina. Since reliable vaginal dose volume/surface histograms are unavailable, a strategy for comprehensive vaginal dose reporting for combined EBRT and BT was established and investigated. Material and methods An anatomical vaginal reference point was defined at the level of the Posterior–Inferior Border of Symphysis (PIBS), plus two points ±2cm (mid/introitus vagina). For BT extra points were selected for the upper vagina at 12/3/6/9o'clock, at the vaginal surface and 5mm depth. A vaginal reference length (VRL) was defined from ring centre to PIBS. Fifty-nine patients treated for cervical cancer were included in this retrospective feasibility study. Results The method was applicable to all patients. Total EQD2 doses at PIBS and ±2cm were 36.7Gy (3.1–68.2), 49.6Gy (32.1–89.6) and 4.3Gy (1.0–46.6). At the vaginal surface at ring level doses were respectively 266.1Gy (67.6–814.5)/225.9Gy (61.5–610.5) at 3/9o'clock, and 85.1Gy (55.4–140.3)/72.0Gy (49.1–108.9) at 12/6o'clock. Mean VRL on MRI was 5.6cm (2.0–9.4). Conclusions With this novel system, a comprehensive reporting of vaginal doses is feasible. The present study has demonstrated large dose variations between patients observed in all parts of the vagina, resulting from different contributions from EBRT and BT.

Background and purposeRecently, a vaginal dose reporting method for combined EBRT and BT in cervical cancer patients was proposed. The current study was to evaluate vaginal doses with this method in a multicentre setting, wherein different applicators, dose rates and protocols were used.Material and methodsIn a subset of patients from the EMBRACE study, vaginal doses were evaluated. Doses at the applicator surface left/right and anterior/posterior and at 5 mm depth were measured. In addition, the dose at the Posterior–Inferior Border of Symphysis (PIBS) vaginal dose point and PIBS±2 cm, corresponding to the mid and lower vagina, was measured.Results153 patients from seven institutions were included. Large dose variations expressed in EQD2 with α/β = 3 Gy were seen between patients, in particular at the top left and right vaginal wall (median 195 (range 61–947) Gy/178 (61–980) Gy, respectively). At 5 mm depth, doses were 98 (55–212) Gy/91 (54–227) Gy left/right, and 71 (51–145) Gy/67 (49–189) Gy anterior/posterior, respectively. The dose at PIBS and PIBS±2 cm was 41 (3–81) Gy, 54 (32–109) Gy and 5 (1–51) Gy, respectively. At PIBS+2 cm (mid vagina) dose variation was coming from BT. The variation at PIBS−2 cm (lower vagina) was mainly dependent on EBRT field border location.ConclusionsThis novel method for reporting vaginal doses coming from EBRT and BT through well-defined dose points gives a robust representation of the dose along the vaginal axis. In addition, it allows comparison of vaginal dose between patients from different centres. The doses at the PIBS points represent the doses at the mid and lower parts of the vagina. Large variations in dose throughout the vagina were observed between patients and centres.

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.

Dosimetric intra-fraction uncertainties in MRI-guided brachytherapy were analysed for HR-CTV and OARs. While dose differences were generally small, individual outliers occurred. In contrast to HDR, patients treated with PDR show increased mean rectal dose over time. Re-imaging prior to dose delivery helps to detect unfavorable anatomical changes, and allows for intervention.

Mutation screening of the BOULE gene in 156 men with azoospermia or severe oligozoospermia revealed no relevant mutations; thus, mutations in BOULE can be eliminated as a major cause of impaired spemiatogenesis. (C)2005 by American Society for Reproductive Medicine