C. elegans: A potent model for high-throughput screening experiments investigating the FLASH effect.

This study explores the effects of UHDR irradiation on Caenorhabditis elegans embryos. UHDR proton and electron beams demonstrate a sparing effect, aligning with literature findings. This highlights C. elegans suitability as a screening model for studying the LET impact on the FLASH effect, reinforcing its potential in radiation research.

First-in-human study of SBRT and adenosine pathway blockade to potentiate the benefit of immunochemotherapy in early-stage luminal B breast cancer: results of the safety run-in phase of the Neo-CheckRay trial.

BACKGROUND: Luminal B breast cancer (BC) presents a worse prognosis when compared with luminal A BC and exhibits a lower sensitivity to chemotherapy and a lower immunogenicity in contrast to non-luminal BC subtypes. The Neo-CheckRay clinical trial investigates the use of stereotactic body radiation therapy (SBRT) directed to the primary tumor in combination with the adenosine pathway inhibitor oleclumab to improve the response to neo-adjuvant immuno-chemotherapy in luminal B BC. The trial consists of a safety run-in followed by a randomized phase II trial. Here, we present the results of the first-in-human safety run-in. METHODS: The safety run-in was an open-label, single-arm trial in which six patients with early-stage luminal B BC received the following neo-adjuvant regimen: paclitaxel q1w×12 → doxorubicin/cyclophosphamide q2w×4; durvalumab (anti-programmed cell death receptor ligand 1 (PD-L1)) q4w×5; oleclumab (anti-CD73) q2w×4 → q4w×3 and 3×8 Gy SBRT to the primary tumor at week 5. Surgery must be performed 2-6 weeks after primary systemic treatment and adjuvant therapy was given per local guidelines, RT boost to the tumor bed was not allowed. Key inclusion criteria were: luminal BC, Ki67≥15% or histological grade 3, MammaPrint high risk, tumor size≥1.5 cm. Primary tumor tissue samples were collected at three timepoints: baseline, 1 week after SBRT and at surgery. Tumor-infiltrating lymphocytes, PD-L1 and CD73 were evaluated at each timepoint, and residual cancer burden (RCB) was calculated at surgery. RESULTS: Six patients were included between November 2019 and March 2020. Median age was 53 years, range 37-69. All patients received SBRT and underwent surgery 2-4 weeks after the last treatment. After a median follow-up time of 2 years after surgery, one grade 3 adverse event (AE) was reported: pericarditis with rapid resolution under corticosteroids. No grade 4-5 AE were documented. Overall cosmetical breast evaluation after surgery was 'excellent' in four patients and 'good' in two patients. RCB results were 2/6 RCB 0; 2/6 RCB 1; 1/6 RCB 2 and 1/6 RCB 3. CONCLUSIONS: This novel treatment combination was considered safe and is worth further investigation in a randomized phase II trial. TRIAL REGISTRATION NUMBER: NCT03875573.

Correction: Krayem et al. The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma. Cancers 2019, 11, 1093.

In the original article [...].

A CT-based radiomics classification model for the prediction of histological type and tumour grade in retroperitoneal sarcoma (RADSARC-R): a retrospective multicohort analysis.

BACKGROUND: Retroperitoneal sarcomas are tumours with a poor prognosis. Upfront characterisation of the tumour is difficult, and under-grading is common. Radiomics has the potential to non-invasively characterise the so-called radiological phenotype of tumours. We aimed to develop and independently validate a CT-based radiomics classification model for the prediction of histological type and grade in retroperitoneal leiomyosarcoma and liposarcoma. METHODS: A retrospective discovery cohort was collated at our centre (Royal Marsden Hospital, London, UK) and an independent validation cohort comprising patients recruited in the phase 3 STRASS study of neoadjuvant radiotherapy in retroperitoneal sarcoma. Patients aged older than 18 years with confirmed primary leiomyosarcoma or liposarcoma proceeding to surgical resection with available contrast-enhanced CT scans were included. Using the discovery dataset, a CT-based radiomics workflow was developed, including manual delineation, sub-segmentation, feature extraction, and predictive model building. Separate probabilistic classifiers for the prediction of histological type and low versus intermediate or high grade tumour types were built and tested. Independent validation was then performed. The primary objective of the study was to develop radiomic classification models for the prediction of retroperitoneal leiomyosarcoma and liposarcoma type and histological grade. FINDINGS: 170 patients recruited between Oct 30, 2016, and Dec 23, 2020, were eligible in the discovery cohort and 89 patients recruited between Jan 18, 2012, and April 10, 2017, were eligible in the validation cohort. In the discovery cohort, the median age was 63 years (range 27-89), with 83 (49%) female and 87 (51%) male patients. In the validation cohort, median age was 59 years (range 33-77), with 46 (52%) female and 43 (48%) male patients. The highest performing model for the prediction of histological type had an area under the receiver operator curve (AUROC) of 0·928 on validation, based on a feature set of radiomics and approximate radiomic volume fraction. The highest performing model for the prediction of histological grade had an AUROC of 0·882 on validation, based on a radiomics feature set. INTERPRETATION: Our validated radiomics model can predict the histological type and grade of retroperitoneal sarcomas with excellent performance. This could have important implications for improving diagnosis and risk stratification in retroperitoneal sarcomas. FUNDING: Wellcome Trust, European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group, the National Institutes for Health, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

Assessment of radio(chemo)therapy-related dysphagia in head and neck cancer patients based on cough-related acoustic features: a prospective phase II national clinical trial (ACCOUGH-P/A trial).

BACKGROUND: Radiation-associated dysphagia is defined as impaired swallowing efficiency/safety following (chemo)radiotherapy in head and neck cancer patients. In a dysphagia framework, impaired coughing may lead to lung aspiration and fatal lung infection. Although cough efficacy is a predictor of the risk of aspiration, cough investigation is minimal in patients with radiation-associated dysphagia. Because cough is a transient signal, existing software for speech analysis are not appropriate. The goal of our project is to develop an assessment method using acoustic features related to voluntary and reflexive coughs as biomarkers of the risk of penetration/aspiration in patients with radiation-associated dysphagia. METHODS: Healthy subjects and head and neck cancer patients with and without dysphagia will produce voluntary coughs, throat clearings and reflexive coughs. Recordings will be made using an acoustic microphone and a throat microphone. The recorded signals will be manually segmented and subsequently analysed with a software under development. Automatic final segmentation enables to measure cough duration. The first method of analysis includes temporal features: the amplitude contour, the sample entropy and the kurtosis. These features report respectively the strength, the unpredictability (turbulence noise due to the air jet) and the impulsive quality (burst) of the signal. The second method of analysis consists of a spectral decomposition of the relative cough signal energy into several frequency bands (0-400 Hz, 400-800 Hz, 800-1600 Hz, 1600-3200 Hz, > 3200 Hz). The primary outcome of this exploratory research project is the identification of a set of descriptive acoustic cough features in healthy subjects as reference data (ACCOUGH). The secondary outcome of this research in head and neck cancer patients with radiation-associated dysphagia includes the identification of (1) a set of descriptive acoustic cough features as biomarkers of penetration-aspiration (ACCOUGH-P/A), (2) swallowing scores, (3) voice features and (4) aerodynamic cough features. DISCUSSION: This study is expected to develop methods of acoustic cough analysis to enhance the assessment of radiation-associated dysphagia in head and neck cancer patients following (chemo)radiation. TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN) registry ISRCTN16540497. Accepted on 23 June 2023.

Results of a multicenter 4D computed tomography quality assurance audit: Evaluating image accuracy and consistency.

Background and purpose: 4D Computed Tomography (4DCT) technology captures the location and movement of tumors and nearby organs at risk over time. In this study, a multi-institutional multi-vendor 4DCT audit was initiated to assess the accuracy of current imaging protocols. Materials and methods: Twelve centers, including thirteen scanners performed a 4DCT acquisition of a dynamic thorax phantom using the institution's own protocol with the in-house breathing monitoring system. Five regular and three irregular breathing patterns were used. Image acquisition and reconstruction were followed by automated image analysis with our in-house developed 4DCT QA program (QAMotion). CT number accuracy, volume deviation, amplitude deviation, and spatial integrity were assessed per pattern using both the segmented volumes and line profiles. Results: Regular breathing curves showed relatively accurate results across all institutions, with mean volume and CT number deviations and median amplitude deviation below 2%, 5 HU and 2 mm, respectively. Results obtained for irregular patterns showed more variation across the institutions. Volume and CT number deviations co-occurred with a blurring of the sphere, interpolation, or double-structure artifacts that were confirmed through the line profiles. For some of the irregular patterns, amplitude deviations up to 6 mm were observed. Maximum Intensity Projection (MaxIP) correctly captured the applied motion amplitude with deviations across all institutions within 2 mm except for double amplitude pattern. Conclusions: All centers invited to participate in the audit responded positively, highlighting the need for a comprehensive yet easy-to-execute 4DCT quality assurance program. The largest variances between the results from one institution to another confirmed that a standardized 4DCT audit is warranted.

Checkpoint Inhibitors in Combination With Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors: The CHEERS Phase 2 Randomized Clinical Trial.

Importance: Although immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and PD-1 ligand 1 have improved the outcome for many cancer types, the majority of patients fails to respond to ICI monotherapy. Hypofractionated radiotherapy has the potential to improve the therapeutic ratio of ICIs. Objective: To assess the addition of radiotherapy to ICIs compared with ICI monotherapy in patients with advanced solid tumors. Design, Setting, and Participants: This open-label, multicenter, randomized phase 2 trial was conducted in 5 Belgian hospitals and enrolled participants between March 2018 and October 2020. Patients 18 years or older with locally advanced or metastatic melanoma, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, or non-small cell lung carcinoma were eligible. A total of 99 patients were randomly assigned to either the control arm (n = 52) or the experimental arm (n = 47). Of those, 3 patients (1 in the control arm vs 2 in the experimental arm) withdrew consent and thus were not included in the analysis. Data analyses were performed between April 2022 and March 2023. Interventions: Patients were randomized (1:1) to receive anti-PD-1/PD-1 ligand 1 ICIs alone as per standard of care (control arm) or combined with stereotactic body radiotherapy 3 × 8 gray to a maximum of 3 lesions prior to the second or third ICI cycle, depending on the frequency of administration (experimental arm). Randomization was stratified according to tumor histologic findings and disease burden (3 and fewer or more than 3 cancer lesions). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as per immune Response Evaluation Criteria in Solid Tumors. Key secondary end points included overall survival (OS), objective response rate, local control rate, and toxic effects. Efficacy was assessed in the intention-to-treat population, while safety was evaluated in the as-treated population. Results: Among 96 patients included in the analysis (mean age, 66 years; 76 [79%] female), 72 (75%) had more than 3 tumor lesions and 65 (68%) had received at least 1 previous line of systemic treatment at time of inclusion. Seven patients allocated to the experimental arm did not complete the study-prescribed radiotherapy course due to early disease progression (n = 5) or intercurrent illness (n = 2). With a median (range) follow-up of 12.5 (0.7-46.2) months, median PFS was 2.8 months in the control arm compared with 4.4 months in the experimental arm (hazard ratio, 0.95; 95% CI, 0.58-1.53; P = .82). Between the control and experimental arms, no improvement in median OS was observed (11.0 vs 14.3 months; hazard ratio, 0.82; 95% CI, 0.48-1.41; P = .47), and objective response rate was not statistically significantly different (22% vs 27%; P = .56), despite a local control rate of 75% in irradiated patients. Acute treatment-related toxic effects of any grade and grade 3 or higher occurred in 79% and 18% of patients in the control arm vs 78% and 18% in the experimental arm, respectively. No grade 5 adverse events occurred. Conclusions and Relevance: This phase 2 randomized clinical trial demonstrated that while safe, adding subablative stereotactic radiotherapy of a limited number of metastatic lesions to ICI monotherapy failed to show improvement in PFS or OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03511391.

Boost modalities in cervical cancer: dosimetric comparison between intracavitary BT vs. intracavitary + interstitial BT vs. SBRT.

PURPOSE / OBJECTIVE: This study compares the dosimetric plans of three distinct boost modalities in cervical cancer (CC): intracavitary (IC) with tandem/ovoids brachytherapy (BT), IC + interstitial (IS) BT, and Stereotactic-Body-Radiotherapy (SBRT). The aim is to determine the dosimetric impact in terms of target coverage and organ at risk (OAR) doses. MATERIALS AND METHODS: 24 consecutive IC + IS BT boost treatment plans were retrospectively identified. For each plan included, two additional plans were created: IC-BT and SBRT. Importantly, no planning target volume (PTV) or planning (organ at) risk volume (PRV) margins were generated, therefore all structures were identical for any boost modality. Two different normalizations were performed: (1) Normalization to the target: prescription of 7.1 Gy to the D90% (defined as the minimum dose covering 90%) of the high-risk clinical target volume (HR-CTV); (2) Normalization to the OARs. HR-CTV coverage and OARs sparing were compared. The equivalent doses in 2 Gy fractions (EQD2) of EBRT and BT for CTV-HR and OARs were calculated using the linear-quadratic model with α/ß of 10 (EQD210) and 3 (EQD23), respectively RESULTS: A total of 72 plans were investigated. In the first normalization, the mean EQD23-D2cc (defined as the minimal dose of the 2 cc) of OAR was significantly higher in the IC-BT plans, and the bladder D2cc hard constraint could not be reached. IC + IS BT leads to a 1 Gy mean absolute decrease of bladder EQD23-D2cc (relative dose: -19%), allowing to reach the hard constraint. SBRT (without PTV) delivers the lowest EQD23-D2cc to the OAR. In the second normalization, IC-BT provides a significantly lower dose to the EQD210-D90% (6.62 Gy) and cannot achieve the coverage goal. SBRT (without PTV) yields the highest dose to the D90% of HR-CTV and a significantly lower EQD210-D50% and D30%. CONCLUSION: The key dosimetric benefit of BT over SBRT without PTV is a significantly higher D50% and D30% in the HR-CTV, which increases the local and conformal dose to the target. IC + IS BT vs. IC-BT provides significantly better target coverage and a lower dose to the OARs, making it the preferred boost modality in CC.

Acoustic Analysis of Voluntary Coughs, Throat Clearings, and Induced Reflexive Coughs in a Healthy Population.

Cough efficacy is considered a reliable predictor of the aspiration risk in head and neck cancer patients with radiation-associated dysphagia. Currently, coughing is assessed perceptually or aerodynamically. The goal of our research is to develop methods of acoustic cough analysis. In this study, we examined in a healthy population the acoustical differences between three protective maneuvers: voluntary cough, voluntary throat clearing, and induced reflexive cough. Forty healthy participants were included in this study. Voluntary cough, voluntary throat clearing, and reflexive cough samples were recorded and analyzed acoustically. Temporal acoustic features were the following: the slope and curvature of the amplitude contour, as well as the average, slope, and curvature of the sample entropy and kurtosis contours of the recorded signal. Spectral features were the relative energy in the frequency bands (0-400 Hz, 400-800 Hz, 800-1600 Hz, 1600 Hz-3200 Hz, > 3200 Hz) as well as the weighted spectral energy. Results showed that, compared to a voluntary cough, a throat clearing starts with a weaker onset pulse and involves oscillations from the onset to the offset (concave curvature of the amplitude contour, p < 0.05), lower average (p < 0.05), and slope (p < 0.05) as well as lower convex curvature (p < 0.05) of the kurtosis contour. An induced reflexive cough starts with a higher and briefer onset burst and includes higher frication noise (larger convexity of the curvature of the amplitude and kurtosis contours (p < 0.05)) compared to a voluntary cough. The conclusion is that voluntary coughs are acoustically significantly different from voluntary throat clearings and induced reflexive coughs.

The benefit of co-targeting PARP-1 and c-Met on the efficacy of radiotherapy in wild type BRAF melanoma.

Melanoma is known to be a radioresistant cancer. Melanoma radioresistance can be due to several factors such as pigmentation, antioxidant defenses and high Deoxyribonucleic acid (DNA) repair efficacy. However, irradiation induces intracellular translocation of RTKs, including cMet, which regulates response to DNA damage activating proteins and promotes DNA repair. Accordingly, we hypothesized that co-targeting DNA repair (PARP-1) and relevant activated RTKs, c-Met in particular, may radiosensitize wild-type B-Raf Proto-Oncogene, Serine/Threonine Kinase (WTBRAF) melanomas where RTKs are often upregulated. Firstly, we found that PARP-1 is highly expressed in melanoma cell lines. PARP-1 inhibition by Olaparib or its KO mediates melanoma cell sensitivity to radiotherapy (RT). Similarly, specific inhibition of c-Met by Crizotinib or its KO radiosensitizes the melanoma cell lines. Mechanistically, we show that RT causes c-Met nuclear translocation to interact with PARP-1 promoting its activity. This can be reversed by c-Met inhibition. Accordingly, RT associated with the inhibition of both c-Met and PARP-1 resulted in a synergistic effect not only on tumor growth inhibition but also on tumor regrowth control in all animals following the stop of the treatment. We thus show that combining PARP and c-Met inhibition with RT appears a promising therapeutic approach in WTBRAF melanoma.

The current understanding of the immune landscape relative to radiotherapy across tumor types.

Radiotherapy is part of the standard of care treatment for a great majority of cancer patients. As a result of radiation, both tumor cells and the environment around them are affected directly by radiation, which mainly primes but also might limit the immune response. Multiple immune factors play a role in cancer progression and response to radiotherapy, including the immune tumor microenvironment and systemic immunity referred to as the immune landscape. A heterogeneous tumor microenvironment and the varying patient characteristics complicate the dynamic relationship between radiotherapy and this immune landscape. In this review, we will present the current overview of the immunological landscape in relation to radiotherapy in order to provide insight and encourage research to further improve cancer treatment. An investigation into the impact of radiation therapy on the immune landscape showed in several cancers a common pattern of immunological responses after radiation. Radiation leads to an upsurge in infiltrating T lymphocytes and the expression of programmed death ligand 1 (PD-L1) which can hint at a benefit for the patient when combined with immunotherapy. In spite of this, lymphopenia in the tumor microenvironment of 'cold' tumors or caused by radiation is considered to be an important obstacle to the patient's survival. In several cancers, a rise in the immunosuppressive populations is seen after radiation, mainly pro-tumoral M2 macrophages and myeloid-derived suppressor cells (MDSCs). As a final point, we will highlight how the radiation parameters themselves can influence the immune system and, therefore, be exploited to the advantage of the patient.

Combination, Modulation and Interplay of Modern Radiotherapy with the Tumor Microenvironment and Targeted Therapies in Pancreatic Cancer: Which Candidates to Boost Radiotherapy?

Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly diverse disease with low tumor immunogenicity. PDAC is also one of the deadliest solid tumor and will remain a common cause of cancer death in the future. Treatment options are limited, and tumors frequently develop resistance to current treatment modalities. Since PDAC patients do not respond well to immune checkpoint inhibitors (ICIs), novel methods for overcoming resistance are being explored. Compared to other solid tumors, the PDAC's tumor microenvironment (TME) is unique and complex and prevents systemic agents from effectively penetrating and killing tumor cells. Radiotherapy (RT) has the potential to modulate the TME (e.g., by exposing tumor-specific antigens, recruiting, and infiltrating immune cells) and, therefore, enhance the effectiveness of targeted systemic therapies. Interestingly, combining ICI with RT and/or chemotherapy has yielded promising preclinical results which were not successful when translated into clinical trials. In this context, current standards of care need to be challenged and transformed with modern treatment techniques and novel therapeutic combinations. One way to reconcile these findings is to abandon the concept that the TME is a well-compartmented population with spatial, temporal, physical, and chemical elements acting independently. This review will focus on the most interesting advancements of RT and describe the main components of the TME and their known modulation after RT in PDAC. Furthermore, we will provide a summary of current clinical data for combinations of RT/targeted therapy (tRT) and give an overview of the most promising future directions.

Patient-reported outcomes in terms of swallowing and quality of life after prophylactic versus reactive percutaneous endoscopic gastrostomy tube placement in advanced oropharyngeal cancer patients treated with definitive chemo-radiotherapy: Swall PEG study.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is often used to provide nutritional support in locally advanced head and neck cancer patients undergoing multimodality treatment. However, there is little published data on the impact of prophylactic versus reactive PEG. PEG placement may affect swallowing-related physiology, function, and quality of life. The Swall PEG study is a randomized controlled phase III trial testing the impact of prophylactic versus reactive PEG on patient-reported outcomes in terms of swallowing and quality of life in oropharyngeal cancer patients. METHODS: Patients with locally advanced oropharyngeal cancer receiving chemo-radiotherapy will be randomized to either the prophylactic or reactive PEG tube group. Randomization will be stratified by human papillomavirus (HPV) status and unilateral versus bilateral positive neck lymph nodes. The primary objective of the study is the patient's reported outcome in terms of swallowing (MD Anderson Dysphagia Inventory (MDADI)) at 6 months. Secondary objectives include health-related quality of life, dosimetric parameters associated with patient-reported outcomes, chemo-radiation toxicities, PEG tube placement complications, the impact of nutritional status on survival and toxicity outcomes, loco-regional control, overall survival, the impact of HPV and tobacco smoking on survival outcomes and toxicities, and the cost-effectiveness of each treatment strategy. DISCUSSION: Findings from this study will enhance clinical evidence regarding nutritional management in oropharyngeal cancer patients treated by concurrent chemo-radiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04019548, study protocol version 2.0_08/08/2019. Registered on 15 July 2019.

Isotoxic High-Dose Stereotactic Body Radiotherapy (iHD-SBRT) Versus Conventional Chemoradiotherapy for Localized Pancreatic Cancer: A Single Cancer Center Evaluation.

Given the lack of direct comparative evidence, we aimed to compare the oncological outcomes of localized pancreatic ductal adenocarcinoma (PDAC) treated in the same tertiary cancer center with isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) or conventional chemoradiotherapy (CRT). Biopsy-proven borderline/locally advanced patients treated with iHD-SBRT (35 Gy in 5 fractions with a simultaneous integrated boost up to 53 Gy) or CRT (45−60 Gy in 25−30 fractions) were retrospectively included from January 2006 to January 2021. The median overall survival (mOS) was evaluated trough uni- and multivariate analyses. The progression free survival (PFS) and the 1-year local control (1-yLC) were also reported. Eighty-two patients were included. The median follow-up was 19.7 months. The mOS was in favour of the iHD-SBRT group (22.5 vs. 15.9 months, p < 0.001), including after multivariate analysis (HR 0.39 [CI95% 0.18−0.83], p = 0.014). The median PFS and the 1-yLC were also significantly better for iHD-SBRT (median PFS: 16.7 vs. 11.5 months, p = 0.011; 1-yLC: 75.8 vs. 39.3%, p = 0.004). In conclusion, iHD-SBRT is a promising RT option and may offer an improvement in OS in comparison to CRT for localized PDAC. Further validation is required to confirm the exact role of iHD-SBRT and the optimal therapeutic sequence for the treatment of localized PDAC.

Intraoperative electron radiotherapy in early invasive ductal breast cancer: 6-year median follow-up results of a prospective monocentric registry.

BACKGROUND: Intraoperative electron radiotherapy (IOERT) can be used to treat early breast cancer during the conservative surgery thus enabling shorter overall treatment times and reduced irradiation of organs at risk. We report on our first 996 patients enrolled prospectively in a registry trial. METHODS: At Jules Bordet Institute, from February 2010 onwards, patients underwent partial IOERT of the breast. Women with unifocal invasive ductal carcinoma, aged 40 years or older, with a clinical tumour size ≤ 20 mm and tumour-free sentinel lymph node (on frozen section and immunohistochemical analysis). A 21 Gy dose was prescribed on the 90% isodose line in the tumour bed with the energy of 6 to 12 MeV (Mobetron®-IntraOp Medical). RESULTS: Thirty-seven ipsilateral tumour relapses occurred. Sixteen of those were in the same breast quadrant. Sixty patients died, and among those, 12 deaths were due to breast cancer. With 71.9 months of median follow-up, the 5-year Kaplan-Meier estimate of local recurrence was 2.7%. CONCLUSIONS: The rate of breast cancer local recurrence after IOERT is low and comparable to published results for IORT and APBI. IOERT is highly operator-dependent, and appropriate applicator sizing according to tumour size is critical. When used in a selected patient population, IOERT achieves a good balance between tumour control and late radiotherapy-mediated toxicity morbidity and mortality thanks to insignificant irradiation of organs at risk.

Inter-fraction heart displacement during voluntary deep inspiration breath hold radiation therapy without visual feedback measured by daily CBCT.

Purpose/Objective: Deep Inspiration Breath Hold (DIBH) is now considered as the standard of care for many breast cancer patients. However, there are still uncertainties about the dose given to the heart, and it is unknown if patients may improve voluntary DIBH depth by gaining experience during treatment. In this study, we will examine the interfractional three-dimensional (3D) heart displacement throughout voluntary DIBH (vDIBH) radiotherapy by means of daily cone-beam computed tomography (CBCT). Material and methods: Two hundred twenty-five unique CBCTs from 15 patients treated in 15 fractions were analyzed. During CBCT, a vDIBH was conducted without any visual feedback. Patients performed their DIBH freely after receiving explanations and training. After daily CBCT matching to the chest wall (CW), surface-guided radiation therapy (SGRT) tracked DIBH depth to ensure that the CW position was the same as the daily acquired CBCT. The CBCTs were retrospectively registered to the DIBH planning-CT to calculate daily changes in heart displacement relative to the CW. Results: The mean displacement of the heart during DIBH treatment relative to the DIBH planning-CT was as follows: 1.1 mm to the right, interquartile range (IQR) 8.0; 0.5 mm superiorly, IQR 4.8; and 0 mm posteriorly, IQR 6.4. The Spearman correlation coefficients (rs) were -0.15 (p=0.025), 0.04 (p=0.549), and 0.03 (p=0.612) for the X, Y, and Z directions, respectively. The differences in median heart displacement were significant: Friedmann rank sum test p=0.031 and pairwise comparison using the Wilcoxon rank-sum test were p=0.008 for X and Y; p=0.33 for X and Z; and p=0.07 for Y and Z. The total median heart motion was δtot median= 7.26 mm, IQR= 6.86 mm. Conclusion: During DIBH, clinicians must be aware of the wide range of intra- and inter-individual heart position variations. The inter-individual heterogeneity shown in our study should be investigated further in order to avoid unexpected cardiac overexposure and to develop a more accurate heart dose-volume model.

Lymphocyte-sparing pelvic radiotherapy for prostate cancer: An in-silico study.

Background and Purpose: Evidence regarding radiation-induced lymphopenia and its negative impact on oncological outcome is incrementing. Therefore, the aim of this study is to evaluate the feasibility of lymphocyte-rich organs at risk (LOAR) sparing in pelvic irradiation for localized prostate cancer and to estimate its impact on the effective dose to circulating immune cells (EDIC). Materials and Methods: Twenty patients with pelvic nodal and prostate or prostate bed irradiation were included. The following bone marrow (BM) structures were delineated as LOARs using semi-automatic segmentation: lumbosacral spine (Ls-BM), ilium (Il-BM), lower pelvis (Lp-BM), and the combined whole-pelvis (Wp-BM). Twenty new lymphocyte sparing treatment plans (LS plans) were calculated, optimizing doses to LOARs while maintaining strict coverage of the targets and respecting standard OARs dose constraints. Finally, we elaborated an EDIC calculation model for pelvic irradiation. Results: LS plans showed a statistically significant dose decrease for LOAR compared to standard of care plans without compromising target coverage nor classic OAR dose constraints: in prostate plans, the V40Gy for Ls-BM, Il-BM, and Lp-BM was decreased by 23 %, 36 %, 52 % respectively. For prostate bed plans, the V40Gy for Ls-BM, Il-BM, and Lp-BM was decreased by 25 %, 59 %, 56 %, respectively. For Wp-BM, the V10Gy, V20Gy, and Dmean have been decreased by 3 %, 14 %, 15 %, and by 5 %, 15 %, 17 %, respectively for prostate and prostate bed plans. A statistically significant decrease in EDIC was seen for LS plans in both groups. Conclusions: We successfully demonstrated the feasability of lympocyte-sparing treatment planning in pelvic irradiation, also proposing a model for EDIC calculation.

The State of the Art of Radiotherapy for Non-melanoma Skin Cancer: A Review of the Literature.

Due to the general aging population and the fashion trend of sun exposure, non-melanoma skin cancer (NMSC) is rising. The management of NMSC is difficult and necessitates a multidisciplinary team (i.e., pathologists, dermatologists, medical oncologists, surgeons, and radiation oncologists). When surgery is not an option or will cause unacceptably functional morbidity, radiation therapy (RT) may be a preferable tissue-preserving option. Whether used alone or in conjunction with other treatments, RT has been shown to be quite effective in terms of cosmetic results and local control. Contact hypofractionated RT, brachytherapy, and electronic brachytherapy are all promising new treatments. However, rigorous, randomized trials are missing, explaining the disparity in dose, fractionation, and technique recommendations. Therefore, it is essential that interdisciplinary teams better understand RT modalities, benefits, and drawbacks. Our review will provide the role and indications for RT in patients with NMSC.

The Road to Dissemination: The Concept of Oligometastases and the Barriers for Widespread Disease.

Over the last years, the oligometastatic disease state has gained more and more interest, and randomized trials are now suggesting an added value of stereotactic radiotherapy on all macroscopic disease in oligometastatic patients; but what barriers could impede widespread disease in some patients? In this review, we first discuss the concept of oligometastatic disease and some examples of clinical evidence. We then explore the route to dissemination: the hurdles a tumoral clone has to overtake before it can produce efficient and widespread dissemination. The spectrum theory argues that the range of metastatic patterns encountered in the clinic is the consequence of gradually obtained metastatic abilities of the tumor cells. Tumor clones can obtain these capabilities by Darwinian evolution, hence early in their genetic progression tumors might produce only a limited number of metastases. We illustrate selective dissemination by discussing organ tropism, the preference of different cancer (sub)types to metastasize to certain organs. Finally we discuss biomarkers that may help to distinguish the oligometastatic state.

Qualitative evaluation of the role of RTTs IGRT specialists and their influence on treatment delivery.

Purpose: The study aims to investigate qualitatively how Radiation Therapist IGRT specialists (RTT spIGRTs) experience their role and whether they have an impact on the treatment delivery. Methods: Eleven RTTs, i.e. six RTT spIGRTs and five RTTs not specialised in IGRT (RTTs noIGRT) were interviewed during October and November 2020. RTTs noIGRT having knowledge of the daily practice before and after the creation of this RTT spIGRT role, served as control group capable of weighing its impact on the work environment. A qualitative method using face-to-face semi-structured questionnaires was used. Interviews lasted approximately 10-20 min, and were after coded and analysed for thematic content. Results: Five themes and twelve sub-themes were drawn from the analysis. RTT spIGRTs experience their role positively, despite the limited role perception and different work experiences. The implemented role increased autonomy and facilitated decision-making and Radiotherapy (RT) treatment delivery.Interviewees considered the new role useful to very useful. The raised concerns are related to a bigger role involvement and improvement, with focus on visibility, regular meetings and training. Interviewees considered the RTT spIGRT role to have an influence on the treatment delivery when properly carried out. Conclusion: RTT spIGRTs experience their role positively. Their knowledge confidence seems to rely on the training received. The RTT spIGRT role is perceived to have a positive influence on the treatment delivery. Continuous follow up and training were amongst the suggested solutions to improve the RTT spIGRT's role. This study stresses the urgent need for a legal framework to provide formal RTT training and continuous education in order to increase RT treatment quality.