[Protontherapy : principles, advantages, limitations, indications, perspectives...and some Belgian peculiarities]. / La protonthérapie : principes, avantages, limitations, indications, perspectives...et quelques histoires belges.

Most radiotherapy treatments are nowadays delivered with linear accelerators producing photons. This robust radiation technique improved outstandingly during the last three decades, allowing treatments for most tumoural indications with an exquisite accuracy, a formidable effectiveness, a low toxicity, and a very low cost for the society. Therefore, the reasons for using and developing the more expensive hadron therapy and more particularly proton therapy may seem futile. In the current article targeting the general practitioners readership, we look at the principles of this innovative technique, its inherent advantages and limitations, the current and future indications, the challenges and perspectives for the future. We conclude with an overview of the Belgian landscape in terms of installation, operation, access and reimbursement procedures.

L'essentiel des traitements de radiothérapie sont délivrés à l'aide d'accélérateurs linéaires produisant des photons. La technique est robuste et a connu une évolution fulgurante ces trois dernières décennies, apportant une efficacité redoutable et une extrême précision dans de nombreuses indications tumorales, avec les avantages d'un risque de toxicité réduit et d'un coût sociétal extrêmement faible. Dès lors, quel intérêt y aurait-il à utiliser et développer des traitements de radiothérapie par hadrons, et plus particulièrement par protons, sachant que les coûts d'installation et de production sont, au bas mot, décuplés par rapport aux photons ? Dans cet article destiné en première intention aux praticiens de santé généralistes, nous abordons les principes de fonctionnement, les avantages et limitations inhérents à la technique, les indications actuelles et celles qui se profilent, les défis et perspectives à venir. Nous terminons, enfin, par un tour d'horizon du paysage belge en termes d'installation, de fonctionnement, d'accès et de modalités de remboursement.

Stereotactic body radiotherapy for centrally located inoperable early-stage NSCLC: EORTC 22113-08113 LungTech phase II trial results.

BACKGROUND: The international EORTC phase II single-arm LungTech trial 22113-08113 assessed safety and efficacy of stereotactic body radiotherapy (SBRT) in patients with centrally located early-stage non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with inoperable non-metastatic central NSCLC (T1-T3 N0 M0, ≤7cm) were included. After prospective central imaging review and radiation therapy quality assurance (RTQA) for any eligible patient, SBRT (8x7.5 Gy, ICRU 83) was delivered. The primary endpoint was freedom from local progression probability at three years after start of SBRT. RESULTS: The trial was closed earlier due to poor accrual related to repeated safety-related pauses in recruitment. Between 08/2015 and 12/2017, 39 patients from 6 European countries were included and 31 were treated per protocol and analyzed. Patients were mainly male (58%) with a median age of 75 years. Baseline comorbidities were mainly respiratory (68%) and cardiac (48%). Median tumor size was 2.6 cm (range, 1.2-5.5) and most cancers were T1 (51.6%) or T2a (38.7%) N0 M0 and of squamous cell origin (48.4%). Median follow-up was 3.6 years. The 3-year freedom from local progression and overall survival rates were 81.5% (90% CI: 62.7-91.4%) and 61.1% (90%CI: 44.1-74.4%), respectively. Cumulative incidence rates of local, regional and distant progression at 3 years were 6.7% (90% CI: 1.6-17.1%), 3.3% (90% CI: 0.4 - 12.4%) and 29.8% (90% CI: 16.8 - 44.1%), respectively. SBRT-related acute and late AEs ≥ G3 were reported in 6.5% (n=2, including one G5 pneumonitis in a patient with prior interstitial lung disease) and 19.4 % (n=6, including one lethal hemoptysis after a lung biopsy in a patient receiving anticoagulants), respectively. CONCLUSION: The LungTech trial suggests that SBRT with 8×7.5Gy for central lung tumors in inoperable patients is associated with acceptable local control rates. However, late severe adverse events may occur after completion of treatment. This SBRT regimen is a viable treatment option after thorough risk-benefit discussion with patients. To minimize potentially fatal toxicity, careful management of dose constraints and post-SBRT interventions is crucial.

Markerless liver online adaptive stereotactic radiotherapy: feasibility analysisCervantes.

Objective. Radio-opaque markers are recommended for image-guided radiotherapy in liver stereotactic ablative radiotherapy (SABR), but their implantation is invasive. We evaluate in thisin-silicostudy the feasibility of cone-beam computed tomography-guided stereotactic online-adaptive radiotherapy (CBCT-STAR) to propagate the target volumes without implanting radio-opaque markers and assess its consequence on the margin that should be used in that context.Approach. An emulator of a CBCT-STAR-dedicated treatment planning system was used to generate plans for 32 liver SABR patients. Three target volume propagation strategies were compared, analysing the volume difference between the GTVPropagatedand the GTVConventional, the vector lengths between their centres of mass (lCoM), and the 95th percentile of the Hausdorff distance between these two volumes (HD95). These propagation strategies were: (1) structure-guided deformable registration with deformable GTV propagation; (2) rigid registration with rigid GTV propagation; and (3) image-guided deformable registration with rigid GTV propagation. Adaptive margin calculation integrated propagation errors, while interfraction position errors were removed. Scheduled plans (PlanNon-adaptive) and daily-adapted plans (PlanAdaptive) were compared for each treatment fraction.Main results.The image-guided deformable registration with rigid GTV propagation was the best propagation strategy regarding tolCoM(mean: 4.3 +/- 2.1 mm), HD95 (mean 4.8 +/- 3.2 mm) and volume preservation between GTVPropagatedand GTVConventional. This resulted in a planning target volume (PTV) margin increase (+69.1% in volume on average). Online adaptation (PlanAdaptive) reduced the violation rate of the most important dose constraints ('priority 1 constraints', 4.2 versus 0.9%, respectively;p< 0.001) and even improved target volume coverage compared to non-adaptive plans (PlanNon-adaptive).Significance. Markerless CBCT-STAR for liver tumours is feasible using Image-guided deformable registration with rigid GTV propagation. Despite the cost in terms of PTV volumes, daily adaptation reduces constraints violation and restores target volumes coverage.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study.

BACKGROUND AND INTRODUCTION: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. MATERIALS AND METHODS: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/ß of 10 Gy for all primaries, and cancer-specific α/ß of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). RESULTS: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. CONCLUSION: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

Cardiac structure, function, and coronary anatomy 10 years after isolated contemporary adjuvant radiotherapy in breast cancer patients with low cardiovascular baseline risk.

AIMS: The effects of isolated contemporary low-dose breast cancer (BC) radiotherapy (RT) on the heart remain poorly understood. This study aims to assess the long-term impacts of BC-RT on cardiac structure and function. METHODS AND RESULTS: Seventy-six women (62 ± 7 years) without history of prior heart disease, who had undergone RT for either first left (n = 36) or right (n = 40) BC, without additional medical oncology therapy apart from hormonal treatment 11 ± 1 years earlier, underwent transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), computed tomography coronary angiography (CTCA), NT-proBNP, and a 6-min walk test (6MWT). They were compared with 54 age-matched healthy female controls. By CTCA, 68% of BC patients exhibited no or very mild coronary disease, while only 11% had moderate stenosis (50-69%) and 3% had significant stenosis (>70%). Despite slightly reduced regional echocardiographic midventricular strains, BC patients exhibited similar global left and right ventricular volumes, ejection fractions, and global strains by echocardiography and CMR as controls. Mitral E/e' ratios were slightly higher, and mitral deceleration times were slightly lower, but NT-proBNP was similar to controls. Also, 6MWT was normal. None had late gadolinium enhancement, and extracellular volume fraction was similar in BC (28 ± 3 vs. 29 ± 3, P = 0.15) and controls. No differences were observed relative to dose or side of RT. CONCLUSION: Aside from minor alterations of regional strains and diastolic parameters, women who received isolated RT for BC had low prevalence of coronary disease, normal global systolic function, NT-proBNP, and exercise capacity and showed no structural changes by CMR, refuting significant long-term cardiotoxicity in such low-risk patients.

Comparison of Ethos template-based planning and AI-based dose prediction: General performance, patient optimality, and limitations.

PURPOSE: Ethos proposes a template-based automatic dose planning (Etb) for online adaptive radiotherapy. This study evaluates the general performance of Etb for prostate cancer, as well as the ability to generate patient-optimal plans, by comparing it with another state-of-the-art automatic planning method, i.e., deep learning dose prediction followed by dose mimicking (DP + DM). MATERIALS: General performances and capability to produce patient-optimal plan were investigated through two studies: Study-S1 generated plans for 45 patients using our initial Ethos clinical goals template (EG_init), and compared them to manually generated plans (MG). For study-S2, 10 patients which showed poor performances at study-S1 were selected. S2 compared the quality of plans generated with four different methods: 1) Ethos initial template (EG_init_selected), 2) Ethos updated template-based on S1 results (EG_upd_selected), 3) DP + DM, and 4) MG plans. RESULTS: EG_init plans showed satisfactory performance for dose level above 50 Gy: reported mean metrics differences (EG_init minus MG) never exceeded 0.6 %. However, lower dose levels showed loosely optimized metrics, mean differences for V30Gy to rectum and V20Gy to anal canal were of 6.6 % and 13.0 %. EG_init_selected showed amplified differences in V30Gy to rectum and V20Gy to anal canal: 8.5 % and 16.9 %, respectively. These dropped to 5.7 % and 11.5 % for EG_upd_selected plans but strongly increased V60Gy to rectum for 2 patients. DP + DM plans achieved differences of 3.4 % and 4.6 % without compromising any V60Gy. CONCLUSION: General performances of Etb were satisfactory. However, optimizing with template of goals might be limiting for some complex cases. Over our test patients, DP + DM outperformed the Etb approach.

Dosimetrically triggered adaptive radiotherapy for head and neck cancer: Considerations for the implementation of clinical protocols.

PURPOSE: Defining dosimetric rules to automatically detect patients requiring adaptive radiotherapy (ART) is not straightforward, and most centres perform ad-hoc ART with no specific protocol. This study aims to propose and analyse different steps to design a protocol for dosimetrically triggered ART of head and neck (H&N) cancer. As a proof-of-concept, the designed protocol was applied to patients treated in TomoTherapy units, using their available software for daily MVCT image and dose accumulation. METHODS: An initial protocol was designed by a multidisciplinary team, with a set of flagging criteria based only on dose-volume metrics, including two action levels: (1) surveillance (orange flag), and (2) immediate verification (red flag). This protocol was adapted to the clinical needs following an iterative process. First, the protocol was applied to 38 H&N patients with daily imaging. Automatic software generated the daily contours, recomputed the daily dose and flagged the dosimetric differences with respect to the planning dose. Second, these results were compared, by a sensitivity/specificity test, to the answers of a physician. Third, the physician, supported by the multidisciplinary team, performed a self-analysis of the provided answers and translated them into mathematical rules in order to upgrade the protocol. The upgraded protocol was applied to different definitions of the target volume (i.e. deformed CTV + 0, 2 and 4 mm), in order to quantify how the number of flags decreases when reducing the CTV-to-PTV margin. RESULTS: The sensitivity of the initial protocol was very low, specifically for the orange flags. The best values were 0.84 for red and 0.15 for orange flags. After the review and upgrade process, the sensitivity of the upgraded protocol increased to 0.96 for red and 0.84 for orange flags. The number of patients flagged per week with the final (upgraded) protocol decreased in median by 26% and 18% for red and orange flags, respectively, when reducing the CTV-to-PTV margin from 4 to 2 mm. This resulted in only one patient flagged at the last fraction for both red and orange flags. CONCLUSION: Our results demonstrate the value of iterative protocol design with retrospective data, and shows the feasibility of automatically-triggered ART using simple dosimetric rules to mimic the physician's decisions. Using a proper target volume definition is important and influences the flagging rate, particularly when decreasing the CTV-to-PTV margin.

Machine learning-based automatic proton therapy planning: Impact of post-processing and dose-mimicking in plan robustness.

PURPOSE: Automated treatment planning strategies are being widely implemented in clinical routines to reduce inter-planner variability, speed up the optimization process, and improve plan quality. This study aims to evaluate the feasibility and quality of intensity-modulated proton therapy (IMPT) plans generated with four different knowledge-based planning (KBP) pipelines fully integrated into a commercial treatment planning system (TPS). MATERIALS/METHODS: A data set containing 60 oropharyngeal cancer patients was split into 11 folds, each containing 47 patients for training, five patients for validation, and five patients for testing. A dose prediction model was trained on each of the folds, resulting in a total of 11 models. Three patients were left out in order to assess if the differences introduced between models were significant. From voxel-based dose predictions, we analyze the two steps that follow the dose prediction: post-processing of the predicted dose and dose mimicking (DM). We focused on the effect of post-processing (PP) or no post-processing (NPP) combined with two different DM algorithms for optimization: the one available in the commercial TPS RayStation (RSM) and a simpler isodose-based mimicking (IBM). Using 55 test patients (five test patients for each model), we evaluated the quality and robustness of the plans generated by the four proposed KBP pipelines (PP-RSM, PP-IBM, NPP-RSM, NPP-IBM). After robust evaluation, dose-volume histogram (DVH) metrics in nominal and worst-case scenarios were compared to those of the manually generated plans. RESULTS: Nominal doses from the four KBP pipelines showed promising results achieving comparable target coverage and improved dose to organs at risk (OARs) compared to the manual plans. However, too optimistic post-processing applied to the dose prediction (i.e. important decrease of the dose to the organs) compromised the robustness of the plans. Even though RSM seemed to partially compensate for the lack of robustness in the PP plans, still 65% of the patients did not achieve the expected robustness levels. NPP-RSM plans seemed to achieve the best trade-off between robustness and OAR sparing. DISCUSSION/CONCLUSIONS: PP and DM strategies are crucial steps to generate acceptable robust and deliverable IMPT plans from ML-predicted doses. Before the clinical implementation of any KBP pipeline, the PP and DM parameters predefined by the commercial TPS need to be modified accordingly with a comprehensive feedback loop in which the robustness of the final dose calculations is evaluated. With the right choice of PP and DM parameters, KBP strategies have the potential to generate IMPT plans within clinically acceptable levels comparable to plans manually generated by dosimetrists.

Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials.

Voluntary versus mechanically-induced deep inspiration breath-hold for left breast cancer: A randomized controlled trial.

BACKGROUND AND PURPOSE: Deep inspiration breath-hold (DIBH) protects critical organs-at-risk (OARs) for adjuvant breast radiotherapy. Guidance systems e.g. surface guided radiation therapy (SGRT) improve the positional breast reproducibility and stability during DIBH. In parallel, OARs sparing with DIBH is enhanced through different techniques e.g. prone position, continuous positive airway pressure (CPAP). By inducing repeated DIBH with the same level of positive pressure, mechanically-assisted and non-invasive ventilation (MANIV) could potentially combine these DIBH optimizations. MATERIALS AND METHODS: We conducted a randomized, open-label, multicenter and single-institution non-inferiority trial. Sixty-six patients eligible for adjuvant left whole-breast radiotherapy in supine position were equally assigned between mechanically-induced DIBH (MANIV-DIBH) and voluntary DIBH guided by SGRT (sDIBH). The co-primary endpoints were positional breast stability and reproducibility with a non-inferiority margin of 1 mm. Secondary endpoints were tolerance assessed daily via validated scales, treatment time, dose to OARs and their inter-fraction positional reproducibility. RESULTS: Differences between both arms for positional breast reproducibility and stability occurred at a sub-millimetric level (p < 0.001 for non-inferiority). The left anterior descending artery near-max dose (14,6 ± 12,0 Gy vs. 7,7 ± 7,1 Gy, p = 0,018) and mean dose (5,0 ± 3,5 Gy vs. 3,0 ± 2,0 Gy, p = 0,009) were improved with MANIV-DIBH. The same applied for the V5Gy of the left ventricle (2,4 ± 4,1 % vs. 0,8 ± 1,6 %, p = 0,001) as well as for the left lung V20Gy (11,4 ± 2,8 % vs. 9,7 ± 2,7 %, p = 0,019) and V30Gy (8,0 ± 2,6 % vs. 6,5 ± 2,3 %, p = 0,0018). Better heart's inter-fraction positional reproducibility was observed with MANIV-DIBH. Tolerance and treatment time were similar. CONCLUSION: Mechanical ventilation provides the same target irradiation accuracy as with SGRT while better protecting and repositioning OARs.

High-intensity aerobic interval training and resistance training are feasible in rectal cancer patients undergoing chemoradiotherapy: a feasibility randomized controlled study.

Background: There has been growing evidence of the benefits of high-intensity aerobic interval training (HIIT) and resistance training (RES) for populations with cancer. However, these two modalities have not yet been performed alone in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (NACR T). Therefore, this study aimed to determine the feasibility of HIIT and RES in rectal cancer patients undergoing NACR T. Materials and methods: Rectal cancer patients set to undergo NACRT were randomly assigned to HIIT intervention, RES intervention, or the usual care. Feasibility of HIIT and RES was assessed by measuring recruitment rate, adherence (retention rate, attendance rate, and exercise sessions duration and intensity), and adverse events. Endpoints (changes in fatigue, health-related quality of life, depression, daytime sleepiness, insomnia, sleep quality, functional exercise capacity, and executive function) were assessed at baseline and at week 5. Results: Among the 20 eligible patients, 18 subjects were enrolled and completed the study, yielding a 90% recruitment rate and 100% retention rate. Attendance at exercise sessions was excellent, with 92% in HIIT and 88% in RES. No exercise-related adverse events occurred. Conclusion: This study demonstrated that HIIT and RES are feasible in rectal cancer patients undergoing NACR T. Trial registration: www.clinicaltrials.gov, NCT03252821 (date of registration: March 30, 2017).

Low-dose CT allows for accurate proton therapy dose calculation and plan optimization.

Objective.Protons offer a more conformal dose delivery compared to photons, yet they are sensitive to anatomical changes over the course of treatment. To minimize range uncertainties due to anatomical variations, a new CT acquisition at every treatment session would be paramount to enable daily dose calculation and subsequent plan adaptation. However, the series of CT scans results in an additional accumulated patient dose. Reducing CT radiation dose and thereby decreasing the potential risk of radiation exposure to patients is desirable, however, lowering the CT dose results in a lower signal-to-noise ratio and therefore in a reduced quality image. We hypothesized that the signal-to-noise ratio provided by conventional CT protocols is higher than needed for proton dose distribution estimation. In this study, we aim to investigate the effect of CT imaging dose reduction on proton therapy dose calculations and plan optimization.Approach.To verify our hypothesis, a CT dose reduction simulation tool has been developed and validated to simulate lower-dose CT scans from an existing standard-dose scan. The simulated lower-dose CTs were then used for proton dose calculation and plan optimization and the results were compared with those of the standard-dose scan. The same strategy was adopted to investigate the effect of CT dose reduction on water equivalent thickness (WET) calculation to quantify CT noise accumulation during integration along the beam.Main results.The similarity between the dose distributions acquired from the low-dose and standard-dose CTs was evaluated by the dose-volume histogram and the 3D Gamma analysis. The results on an anthropomorphic head phantom and three patient cases indicate that CT imaging dose reduction up to 90% does not have a significant effect on proton dose calculation and plan optimization. The relative error was employed to evaluate the similarity between WET maps and was found to be less than 1% after reducing the CT imaging dose by 90%.Significance.The results suggest the possibility of using low-dose CT for proton therapy dose estimation, since the dose distributions acquired from the standard-dose and low-dose CTs are clinically equivalent.

Automated detection and segmentation of non-small cell lung cancer computed tomography images.

Detection and segmentation of abnormalities on medical images is highly important for patient management including diagnosis, radiotherapy, response evaluation, as well as for quantitative image research. We present a fully automated pipeline for the detection and volumetric segmentation of non-small cell lung cancer (NSCLC) developed and validated on 1328 thoracic CT scans from 8 institutions. Along with quantitative performance detailed by image slice thickness, tumor size, image interpretation difficulty, and tumor location, we report an in-silico prospective clinical trial, where we show that the proposed method is faster and more reproducible compared to the experts. Moreover, we demonstrate that on average, radiologists & radiation oncologists preferred automatic segmentations in 56% of the cases. Additionally, we evaluate the prognostic power of the automatic contours by applying RECIST criteria and measuring the tumor volumes. Segmentations by our method stratified patients into low and high survival groups with higher significance compared to those methods based on manual contours.

Is there a place for definitive radiotherapy in the treatment of unresectable soft-tissue sarcoma? A systematic review.

BACKGROUND: Definitive external beam radiotherapy (EBRT) is an unusual treatment of unresectable soft-tissue sarcomas (STS). Recent technical innovations and physical advantages of particle therapies may improve results of this therapeutic option. The role of this review was to report the clinical results of photon- and particle-based EBRT in unresectable STS. MATERIAL AND METHODS: We performed a systematic review of the literature on Pubmed database to identify studies investigating the efficacy and safety of EBRT. The primary endpoint was local control (LC) and secondary endpoints were progression-free survival (PFS), overall survival (OS) and adverse events in a subset of patients with gross disease STS. RESULTS: We identified 29 studies involving 1409 patients (pts) evaluating photon (n = 18; 956 pts), proton (n = 1; 21 pts), carbon ion (n = 2; 152 pts), neutron (n = 7; 259 pts) or pion (n = 1; 21 pts) therapy. Definitive EBRT achieves valuable 5-year LC rates of 28-73% with photon and 52-69% with particle therapies. Most local failures (66-100%) occurred within 3 years. Long-term disease control can be achieved in a fraction of patients, with 5-year PFS and OS of 0-39% and 24.7-63%, respectively. The rate of severe adverse events was highly variable with photons, <15% in proton and carbon ion therapy, whereas 25 to 50% of patients treated with neutrons and pions presented severe AE. While a dose higher or equal 64 Gy seem to improve the prognosis, delivering a dose higher or equal 68 Gy dramatically increases severe adverse events. CONCLUSION: Definitive EBRT with dose 64-66 Gy seems to be a safe and efficient treatment for unresectable STS. Future clinical trials should assess the potential of biomarkers of response, thus identifying patients that could benefit from local treatment.

Long-term outcomes after definitive radiotherapy with modern techniques for unresectable soft tissue sarcoma.

INTRODUCTION: The use of definitive radiotherapy (dRT) in unresectable soft-tissue sarcomas (STS) is still controversial and recent data are scarce. We report clinical results of this therapeutic option. METHODS: We retrospectively included STS patients treated between 2009 and 2020, with dRT for unresectable or with a measurable residual disease after R2 surgery. Response rate, local failure (LF), progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: 116 patients with localized/locally advanced STS were treated from 2009 to 2020, with a median age of 71 years (range 18-92). Most tumors were deep-seated (96.6%), grade 2-3 (85.1%), located in the trunk or extremities (74.2%). Helical tomotherapy, volumetric modulated arc therapy, or stereotactic radiotherapy was performed in 39.7%, 19% and 8.6% of patients, respectively. The median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR 52-65). At first follow-up, 66 (58.9%) and 25 (22%) patients had stable disease and partial response. After a median follow-up of 54.8 months (IQR 40.3-95.4), 3-year LF, PFS and OS were 43.2%, 16.6% and 34%, respectively. Median OS was 21.4 months (95%CI 14-26). The multivariate analysis identified grade 3 and AJCC T3-T4 stage to be associated with both shorter PFS and OS (all p < 0.001). Macroscopically incomplete resection and EQD2 ≥ 64 Gy were associated with better OS (p = 0.016 and p = 0.007). Acute and late severe adverse events occurred in 24 (19.7%) and 5 (4.3%) patients. CONCLUSION: In unresectable STS patients, definitive modern radiotherapy is a safe and effective treatment yielding long term control in selected patients.

ProCaLung - Peer review in stage III, mediastinal node-positive, non-small-cell lung cancer: How to benchmark clinical practice of nodal target volume definition and delineation in Belgium☆.

BACKGROUND AND PURPOSE: The Quality Assurance project for stage III non-small cell lung cancer radiotherapy ProCaLung performed a multicentric two-step exercise evaluating mediastinal nodal Target Volume Definition and Delineation (TVD) variability and the opportunity for standardization. The TVD variability before and after providing detailed guidelines and the value of qualitative contour reviewing before applying quantitative measures were investigated. MATERIALS AND METHODS: The case of a patient with stage III NSCLC and involved mediastinal lymph nodes was used as a basis for this study. Twenty-two radiation oncologists from nineteen centers in Belgium and Luxembourg participated in at least one of two phases of the project (before and after introduction of ProCaLung contouring guidelines). The resulting thirty-three mediastinal nodal GTV and CTV contours were then evaluated using a qualitative-before-quantitative (QBQ) approach. First, a qualitative analysis was performed, evaluating adherence to most recent guidelines. From this, a list of observed deviations was created and these were used to evaluate contour conformity. The second analysis was quantitative, using overlap and surface distance measures to compare contours within qualitative groups and between phases. A 'most robust' reference volume for these analyses was created using the STAPLE-algorithm and an averaging method. RESULTS: Five GTV and seven CTV qualitative groups were identified. Second step contours were more often in higher-conformity groups (p = 0.012 for GTV and p = 0.024 for CTV). Median Residual Mean Square Distances improved from 2.34 mm to 1.36 mm for GTV (p = 0.01) and from 4.53 mm to 1.58 mm for CTV (p < 0.0001). Median Dice coefficients increased from 0.81 to 0.84 for GTV (p = 0.07) and from 0.82 to 0.89 for CTV (p ≤ 0.001). Using HC-contours only to generate references translated in more robust quantitative evaluations. CONCLUSION: Variability of mediastinal nodal TVD was reduced after providing the ProCaLung consensus guidelines. A qualitative review was essential for providing meaningful quantitative measures.

Incorporation of tumor motion directionality in margin recipe: The directional MidP strategy.

PURPOSE: Planning target volume (PTV) definition based on Mid-Position (Mid-P) strategy typically integrates breathing motion from tumor positions variances along the conventional axes of the DICOM coordinate system. Tumor motion directionality is thus neglected even though it is one of its stable characteristics in time. We therefore propose the directional MidP approach (MidP dir), which allows motion directionality to be incorporated into PTV margins. A second objective consists in assessing the ability of the proposed method to better take care of respiratory motion uncertainty. METHODS: 11 lung tumors from 10 patients with supra-centimetric motion were included. PTV were generated according to the MidP and MidP dir strategies starting from planning 4D CT. RESULTS: PTVMidP dir volume didn't differ from the PTVMidP volume: 31351 mm3 IC95% [17242-45459] vs. 31003 mm3 IC95% [ 17347-44659], p = 0.477 respectively. PTVMidP dir morphology was different and appeared more oblong along the main motion axis. The relative difference between 3D and 4D doses was on average 1.09%, p = 0.011 and 0.74%, p = 0.032 improved with directional MidP for D99% and D95%. D2% was not significantly different between both approaches. The improvement in dosimetric coverage fluctuated substantially from one lesion to another and was all the more important as motion showed a large amplitude, some obliquity with respect to conventional axes and small hysteresis. CONCLUSIONS: Directional MidP method allows tumor motion to be taken into account more tightly as a geometrical uncertainty without increasing the irradiation volume.

Role of Postoperative Radiotherapy in the Management for Resected NSCLC - Decision Criteria in Clinical Routine Pre- and Post-LungART.

BACKGROUND: The role of postoperative radiation therapy (PORT) in stage III N2 NSCLC is controversial. We analyzed decision-making for PORT among European radiation oncology experts in lung cancer. METHODS: Twenty-two experts were asked before and after presentation of the results of the LungART trial to describe their decision criteria for PORT in the management of pN+ NSCLC patients. Treatment strategies were subsequently converted into decision trees and analyzed. RESULTS: Following decision criteria were identified: extracapsular nodal extension, incomplete lymph node resection, multistation lymph nodes, high nodal tumor load, poor response to induction chemotherapy, ineligibility to receive adjuvant chemotherapy, performance status, resection margin, lung function and cardiopulmonary comorbidities. The LungART results had impact on decision-making and reduced the number of recommendations for PORT. The only clear indication for PORT was a R1/2 resection. Six experts out of ten who initially recommended PORT for all R0 resected pN2 patients no longer used PORT routinely for these patients, while four still recommended PORT for all patients with pN2. Fourteen experts used PORT only for patients with risk factors, compared to eleven before the presentation of the LungART trial. Four experts stated that PORT was never recommended in R0 resected pN2 patients regardless of risk factors. CONCLUSION: After presentation of the LungART trial results at ESMO 2020, 82% of our experts still used PORT for stage III pN2 NSCLC patients with risk factors. The recommendation for PORT decreased, especially for patients without risk factors. Cardiopulmonary comorbidities became more relevant in the decision-making for PORT.

Feasibility of a TPS-integrated method to incorporate tumor motion in the margin recipe.

BACKGROUND AND PURPOSE: There are several alternatives to the widespread ITV strategy in order to account for breathing-induced motion in PTV margins. The most sophisticated one includes the generation of a motion-compensated CT scan with the CTV placed in its average position - the mid-position approach (MidP). In such configuration, PTV margins integrate breathing as another random error. Despite overall irradiated volume reduction, such approach is barely used in clinical practice because of its dependence to deformable registration and its unavailability in commercial treatment planning systems. As an alternative, the mid-ventilation approach (MidV) selects the phase in the 4D-CT scan that is the closest to the MidP, with a residual error accounted for in the PTV margin. We propose a treatment planning system-integrated strategy, aiming at better approximating the MidP approach without its drawbacks: Hybrid MidV-MidP approach, i.e., the delineation on the MidV-CT and translation at the mid-position coordinates using treatment planning system built-in capabilities. MATERIAL AND METHODS: Forty-five lung lesions treated with stereotactic radiotherapy were selected. PTV was defined using MidP, MidV, Hybrid MidV-MidP and ITV strategies. Margin definitions were adapted and resulting PTVs were compared. RESULTS: Hybrid MidV-MidP showed similar target volume and location than the MidP and confirmed that margin-incorporated tumor motion strategies lead to significantly smaller PTVs than the ITV with mean reduction of 26 ± 7%. CONCLUSION: We report on the successful implementation of a pseudo-MidP solution without its inherent drawbacks. It answers the need for TPS-embedded tumor motion range identification and related margin's component calculation.