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Modern radiotherapy techniques enable delivery of high doses to the target volume without escalating dose to organs at risk, offering the possibility of better local control while preserving good quality of life. Uncertainties in target volume delineation have been demonstrated for most tumour sites, and various studies indicate that inconsistencies in target volume delineation may be larger than errors in all other steps of the treatment planning and delivery process. The aim of this paper is to summarize the degree of delineation uncertainties for different tumour sites reported in the literature and review the effect of strategies to minimize them. Our review confirmed that interobserver variability in target volume contouring represents the largest uncertainty in the process for most tumour sites, potentially resulting in a systematic error in dose delivery, which could influence local control in individual patients. For most tumour sites the optimal combination of imaging modalities for target delineation still needs to be determined. Strict use of delineation guidelines and protocols is advisable both in every day clinical practice and in clinical studies to diminish interobserver variability. Continuing medical education of radiation oncologists cannot be overemphasized, intensive formal training on interpretation of sectional imaging should be included in the program for radiation oncology residents.

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. 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. 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. 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. Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

During radiotherapy of left-sided breast cancer, parts of the heart are irradiated, which may lead to late toxicity. We report on the experience of single institution with cardiac-sparing radiotherapy using voluntary deep inspiration breath hold (V-DIBH) and compare its dosimetric outcome with free breathing (FB) technique. Left-sided breast cancer patients, treated at our department with postoperative radiotherapy of breast/chest wall +/- regional lymph nodes between May 2015 and January 2017, were considered for inclusion. FB-computed tomography (CT) was obtained and dose-planning performed. Cases with cardiac V25Gy ≥ 5% or risk factors for heart disease were coached for V-DIBH. Compliant patients were included. They underwent additional CT in V-DIBH for planning, followed by V-DIBH radiotherapy. Dose volume histogram parameters for heart, lung and optimized planning target volume (OPTV) were compared between FB and BH. Treatment setup shifts and systematic and random errors for V-DIBH technique were compared with FB historic control. Sixty-three patients were considered for V-DIBH. Nine (14.3%) were non-compliant at coaching, leaving 54 cases for analysis. When compared with FB, V-DIBH resulted in a significant reduction of mean cardiac dose from 6.1 +/- 2.5 to 3.2 +/- 1.4 Gy (p < 0.001), maximum cardiac dose from 51.1 +/- 1.4 to 48.5 +/- 6.8 Gy (p = 0.005) and cardiac V25Gy from 8.5 +/- 4.2 to 3.2 +/- 2.5% (p < 0.001). Heart volumes receiving low (10-20 Gy) and high (30-50 Gy) doses were also significantly reduced. Mean dose to the left anterior coronary artery was 23.0 (+/- 6.7) Gy and 14.8 (+/- 7.6) Gy on FB and V-DIBH, respectively (p < 0.001). Differences between FB- and V-DIBH-derived mean lung dose (11.3 +/- 3.2 vs. 10.6 +/- 2.6 Gy), lung V20Gy (20.5 +/- 7 vs. 19.5 +/- 5.1 Gy) and V95% for the OPTV (95.6 +/- 4.1 vs. 95.2 +/- 6.3%) were non-significant. V-DIBH-derived mean shifts for initial patient setup were ≤ 2.7 mm. Random and systematic errors were ≤ 2.1 mm. These results did not differ significantly from historic FB controls. When compared with FB, V-DIBH demonstrated high setup accuracy and enabled significant reduction of cardiac doses without compromising the target volume coverage. Differences in lung doses were non-significant.

Standard applicators for cervical cancer Brachytherapy (BT) do not always achieve acceptable balance between target volume and normal tissue irradiation. We aimed to develop an innovative method of Target-volume Density Mapping (TDM) for modelling of novel applicator prototypes with optimal coverage characteristics. Patients and methods. Development of Contour-Analysis Tool 2 (CAT-2) software for TDM generation was the core priority of our task group. Main requests regarding software functionalities were formulated and guided the coding process. Software validation and accuracy check was performed using phantom objects. Concepts and terms for standardized workflow of TDM post-processing and applicator development were introduced. CAT-2 enables applicator-based co-registration of Digital Imaging and Communications in Medicine (DICOM) structures from a sample of cases, generating a TDM with pooled contours in applicator-eye-view. Each TDM voxel is assigned a value, corresponding to the number of target contours encompassing that voxel. Values are converted to grey levels and transformed to DICOM image, which is transported to the treatment planning system. Iso-density contours (IDC) are generated as lines, connecting voxels with same grey levels. Residual Volume at Risk (RVR) is created for each IDC as potential volume that could contain organs at risk. Finally, standard and prototype applicators are applied on the TDM and virtual dose planning is performed. Dose volume histogram (DVH) parameters are recorded for individual IDC and RVR delineations and characteristic curves generated. Optimal applicator configuration is determined in an iterative manner based on comparison of characteristic curves, virtual implant complexities and isodose distributions. Using the TDM approach, virtual applicator prototypes capable of conformal coverage of any target volume, can be modelled. Further systematic assessment, including studies on clinical feasibility, safety and effectiveness are needed before routine use of novel prototypes can be considered.

Omitting the placement of clips inside tumour bed during breast cancer surgery poses a challenge for delineation of lumpectomy cavity clinical target volume (CTV ). We aimed to quantify inter-observer variation and accuracy for CT- and MRI-based segmentation of CTV in patients without clips. CT- and MRI-simulator images of 12 breast cancer patients, treated by breast conserving surgery and radiotherapy, were included in this study. Five radiation oncologists recorded the cavity visualization score (CVS) and delineated CTV on both modalities. Expert-consensus (EC) contours were delineated by a senior radiation oncologist, respecting opinions of all observers. Inter-observer volumetric variation and generalized conformity index (CI ) were calculated. Deviations from EC contour were quantified by the accuracy index (AI) and inter-delineation distances (IDD). Mean CVS was 3.88 +/- 0.99 and 3.05 +/- 1.07 for MRI and CT, respectively (p = 0.001). Mean volumes of CTV were similar: 154 +/- 26 cm on CT and 152 +/- 19 cm on MRI. Mean CI and AI were superior for MRI when compared with CT (CI : 0.74 +/- 0.07 vs. 0.67 +/- 0.12, p = 0.007; AI: 0.81 +/- 0.04 vs. 0.76 +/- 0.07; p = 0.004). CI and AI increased with increasing CVS. Mean IDD was 3 mm +/- 1.5 mm and 3.6 mm +/- 2.3 mm for MRI and CT, respectively (p = 0.017). When compared with CT, MRI improved visualization of post-lumpectomy changes, reduced interobserver variation and improved the accuracy of CTV contouring in patients without clips in the tumour bed. Further studies with bigger sample sizes are needed to confirm our findings.

There are no reports on pre-insertion identification of cervix cancer patients at risk for uterine perforation during brachytherapy (BT). Our aim was to assess the incidence of risk factors in our patient cohort, and assess feasibility of a novel technique of magnetic resonance imaging (MRI)-guided navigation for applicator insertion (NAI) in high-risk cases. All patients with locally advanced cervical cancer, treated with image guided adaptive BT at our department between October 2013 and June 2017 were considered for analysis. Tumor characteristics on initial MRI (MRI ), pre-BT MRI (MRI ), and BT MRI (MRI ) were assessed. Frequency of risk factors (age above 60 years, retroverted/retroflected uterus, tumor necrosis, non-visible cervical orifice, distorted cervical canal) was recorded. Patients with two or more factors underwent MRI guided NAI. Time needed for NAI was estimated and procedure feasibility score assigned using a three-tiered scoring system. Twenty-seven patients (98 insertions) were included. Mean tumor volume was 70.2 (± 47.9), 17.8 (± 18.9), and 10.3 (± 9.1) cm on MRI , MRI , and MRI , respectively ( < 0.05). In 16 (59%) cases, ≥ 1 perforation risk factor was found on MRI : distorted canal in 12 (44%), necrosis in 9 (33%), retroverted/retroflected uterus in 8 (30%) cases. Nine (33%) patients had ≥ 2 risk factors and underwent MRI guided NAI. Additional time to perform NAI was estimated at 105 minutes, and feasibility score was 1 in all cases. There were no cases of uterine perforation. Using pre-insertion MRI, we found ≥ 2 risk factors for uterine perforation in 1/3 of patients. Off-line MRI navigation was feasible and enabled non-complicated insertion in all cases. Further studies with larger sample size are warranted to assess its clinical efficacy.

Background. Optimal applicator insertion is a precondition for the success of cervix cancer brachytherapy (BT). We aimed to assess feasibility and efficacy of MRI-assisted pre-planning, based on applicator insertion in para-cervical anaesthesia (PCA). Patients and methods. Five days prior to BT, the pre-planning procedure was performed in 18 cervix cancer patients: tandem-ring applicator was inserted under PCA, pelvic MRI obtained and applicator removed. Procedure tolerability was assessed. High risk clinical target volume (HR CTV) and organs at risk were delineated on the pre-planning MRI, virtual needles placed at optimal positions, and dose planning performed. At BT, insertion was carried out in subarachnoidal anaesthesia according to pre-planned geometry. Pre-planned and actual treatment parameters were compared. Results. Pre-planning procedure was well tolerated. Median difference between the pre-planned and actual needle insertion depth and position were 2 (0―10) mm and 4 (0―30) degrees, respectively. The differences between the pre-planned and actual geometric and dosimetric parameters were statistically non-significant. All actual needles were positioned inside the HR CTV and outside the organs at risk (OAR). Conclusions. Our pre-planning approach is well tolerated and effective. Pre-planned geometry and dose distribution can be reproduced at BT.

Major improvements in radiotherapy over the past two decades in the definitive treatment of locally advanced cervical cancer have significantly improved loco-regional control and survival, whereas little progress has been made with chemotherapy since the implementation of concomitant cisplatin 25 years ago. However, the randomized study INTERLACE (A phase III multicenter trial of weekly induction chemotherapy followed by standard chemoradiation versus standard chemoradiation alone in patients with locally advanced cervical cancer) of neoadjuvant chemotherapy presented recently, has shown significant improvement in survival with the use of six cycles of weekly carboplatin and paclitaxel. Although INTERLACE is yet to be published, neoadjuvant chemotherapy is already being advocated as the new standard, and studies are being designed with neoadjuvant chemotherapy followed by chemoradiation and brachytherapy as the standard arm. It is noteworthy that INTERLACE was initiated before the improvements in radiotherapy mentioned above were broadly implemented. The survival rate in the standard arm of INTERLACE was therefore inferior to the results obtained with the latest state-of-the-art external beam radiotherapy and image guided adaptive brachytherapy (EMBRACE, Magnetic Resonance Imaging (MRI)-Guided Brachytherapy in Locally Advanced Cervical Cancer). Moreover, patient selection impedes the comparison of INTERLACE with other studies as the patients included in INTERLACE were younger, had better performance status, and had less advanced disease than in other studies. Notably patients with involved para-aortic nodes were excluded. In this review, we discuss neoadjuvant chemotherapy in the frame of the EMBRACE studies and show how the impact of modern radiotherapy and patient selection affects the interpretation of the results of INTERLACE. This has led us to conclude that neoadjuvant chemotherapy is not needed for the majority of patients with cervical cancer treated with definitive modern radiotherapy, and may cause harm. However, it is possible that short course neoadjuvant chemotherapy may benefit a minor subgroup of patients who need to be identified. Comprehensive understanding, including cost utility analyses, are needed to draw conclusions regarding the potential benefit of neoadjuvant chemotherapy in low and middle income countries with limited access to modern radiotherapy.