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This study evaluates the benefit of weekly delineation and peer review by a multidisciplinary team (MDT) of radiation oncologists (ROs), radiologists (RXs), and nuclear medicine (NM) physicians in defining primary and lymph node tumor volumes (GTVp and GTVn) for head and neck cancer (HNC) radiotherapy.This study includes 30 consecutive HNC patients referred for definitive curative (chemo)-radiotherapy. Imaging data including head and neck MRI, [18F]-FDG-PET and CT scan were evaluated by the MDT. The RO identified the ’undeniable’ tumor as GTVp_core and determined GTVp_max, representing the maximum tumoral volume. The MDT delineation (MDT-D) by RX and NM physicians outlined their respective primary GTVs (GTVp_RX and GTVp_NM). During the MDT meeting (MDT-M), these contours were discussed to reach a consensus on the final primary GTV (GTVp_final). In the comparative analysis of various GTVp delineations, we performed descriptive statistics and assessed two MDT-M factors: 1) the added value of MDT-M, which includes the section of GTVp_final outside GTVp_core but within GTVp_RX or GTVp_NM, and 2) the part of GTVp_final that deviates from GTVp_max, representing the area missed by the RO. For GTVn, discussions evaluated lymph node extent and malignancy, documenting findings and the frequency of disagreements.The average GTVp core and max volumes were 19.5 cc (range: 0.4–90.1) and 22.1 cc (range: 0.8–106.2), respectively. Compared to GTVp_core, MDT-D to GTVp_final added an average of 3.3 cc (range: 0–25.6) and spared an average of 1.3 cc (0–15.6). Compared to GTVp_max, MDT-D and -M added an average of 2.7 cc (range: 0–20.3) and removed 2.3 cc (0–21.3). The most frequent GTVn discussions included morphologically suspicious nodes not fixing on [18F]-FDG-PET and small [18F]-FDG-PET negative retropharyngeal lymph nodes.Multidisciplinary review of target contours in HNC is essential for accurate treatment planning, ensuring precise tumor and lymph node delineation, potentially improving local control and reducing toxicity.

Abstract 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.

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.

Abstract 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/β 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.

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.

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.

Abstract 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

Abstract 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.

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.

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.

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.

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.

Abstract Background Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. Methods The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/− durvalumab +/− oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. Discussion combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. Trial registration trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019.

Purpose/ObjectiveDeep 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 methodsTwo 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.ResultsThe 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.ConclusionDuring 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.

Purpose: To compare the reliability and the required time for two cone-beam CT (CBCT) registration methods for prostate irradiation (PI) and prostate bed irradiation (PBI). Material and methods: Two-hundred treatment fractions (in 10 PI and 10 PBI patients) were reanalyzed, using two CBCT registration methods: (1) a combination of an automated chamfer matching (CM) with manual matching (MM), and (2) the automated XVI dual registration tool (DRT). Bland-Altman 95% Limits of Agreement (LoA) were used to assess agreement with manual registration by Radiation Oncologists. Results: All 95% LoA for CM + MM were ≤ 0.33 cm. For DRT, several 95% LoA were notably larger than the predefined clinical threshold of 0.3 cm: −0.47 to +0.25 cm (PI) and −0.36 to +0.23 cm (PBI) for the superior-inferior direction and −0.52 to +0.24 cm (PI) and −0.38 to +0.31 cm (PBI) for the anterior-posterior direction.For PI, the average time required was 33 s with CM + MM versus only 18 s with DRT (p = 0.002). For PBI, this was 13 versus 19 s, respectively (p = 0.16). Conclusion: For PI, DRT was significantly faster than CM + MM, but the accuracy is insufficient to use without manual verification. Therefore, manual verification is still warranted, but could offset the time benefit. For PBI, the CM + MM method was faster and more accurate.

Abstract Background Nutritional complications in patients with locally advanced head and neck cancer (LA-HNC) treated by concurrent chemoradiotherapy (CCRT) often lead to placement of a prophylactic gastrostomy (PG) tube, while indication lacks harmonization. Our aim was to explore the current PG tube utilization among Belgian radiation oncology centers. Methods A survey was distributed to all 24 Belgian Radiation oncology departments, with questions about the number of patient treated per year, whether the PG indication is discussed at the multidisciplinary board, placement technique, time of starting nutrition and removal, its impact on swallowing function and importance of clinical factors. For the latter Relative Importance and Discordance Indexes were calculated to describe the ranking and agreement. Results All 24 centers submitted the questionnaire. Twenty three treat more than 20 head and neck (HNC) patients per year, while four (1 in 21–50; 3 in 51–100) are not discussing the gastrostomy tube indication at the multidisciplinary board. For the latter, endoscopic placement (68%) is the dominant technique, followed by the radiologic (16%) and laparoscopic (16%) methods. Seventy-five percent start the enteral nutrition when clinically indicated, 17% immediately and 8% from the start of radiotherapy. Majority of specialists (19/24) keep the gastrostomy tube until the patient assume an adequate oral feeding. Fifteen centres are considering PG decrease swallowing function. Regarding factors and their importance in the decision for the PG, foreseen irradiated volume reached highest importance, followed by ‘anatomical site’, ‘patients’ choice’ and ‘postoperative versus definitive’ and ‘local expertise’, with decreasing importance respectively. Disagreement indexes showed moderate variation. Conclusions The use of a PG tube for LAHNC patients treated by CCRT shows disparity at national level. Prospective studies are needed to ensure proper indication of this supportive measure.

Abstract Background While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors. Methods/design Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study’s primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. Discussion: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. Trial registration Clinicaltrials.gov identifier: NCT03511391 . Registered 17 April 2018.

Abstract Background To improve split-VMAT technique by optimizing treatment delivery time for deep-inspiration breath hold (DIBH) radiotherapy in left-sided breast cancer patients, when automatic beam-interruption devices are not available. Methods Ten consecutive patients were treated with an eight partial arcs (8paVMAT) plan, standard of care in our center. A four partial arcs (4paVMAT) plan was also created and actual LINAC outputs were measured, to evaluate whether there was a dosimetric difference between both techniques and potential impact on the delivered dose. Subsequently, ten other patients were consecutively treated with a 4paVMAT plan to compare the actual treatment delivery time between both techniques. The prescribed dose was 40.05 Gy/15 fractions on the PTV breast (breast or thoracic wall), lymph nodes (LN) and intramammary lymph node chain (IMN). Treatment delivery time, PTVs coverage, conformity index (CI), organs at risk (OAR) dose, monitor units (MU), and gamma index were compared. Results Both split-VMAT techniques resulted in similar dose coverage for the PTV Breast and LN, and similar CI. For PTV IMN we observed a 5% increased coverage for the volume receiving ≥ 36 Gy with 4paVMAT, with an identical volume receiving ≥ 32 Gy. There was no difference for the OAR sparing, with the exception of the contralateral organs: there was a 0.6 Gy decrease for contralateral breast mean (p ≤ 0.01) and 1% decrease for the volume of right lung receiving ≥ 5 Gy (p = 0.024). Overall, these results indicate a modest clinical benefit of using 4paVMAT in comparison to 8paVMAT. An increase in the number of MU per arc was observed for the 4paVMAT technique, as expected, while the total number of MU remained comparable for both techniques. All the plans were measured with the Delta4 phantom and passed the gamma index criteria with no significant differences. Finally, the main difference was seen for the treatment delivery time: there was a significant decrease from 8.9 to 5.4 min for the 4paVMAT plans (p

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.

Abstract Aims Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults. Glioma stem cells (GSCs) are implicated in this poor prognosis and in radio(chemo‐)resistance. We have previously demonstrated that among potentially highly specific GSC markers oligodendrocyte lineage transcription factor 2 (OLIG2) appears to be the most specific and cyclin D2 (CCND2) the only one related to cell cycle regulation. The purpose of this work was to investigate the clinical significance and the evolution of OLIG2 and CCND2 protein expression in GBM. Methods and results Immunohistochemical expression analysis of Olig2 and Ccnd2 was carried out on a cohort of human paired GBM samples comparing initial resections with local recurrent tumors after radiation therapy (RT) alone or radio‐chemotherapy with temozolomide (RT‐TMZ). Uni‐ and multivariate logistic regression analysis revealed that significant risk factors predicting early mortality (

TP53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes p53 an attractive target to improve HNSCC therapy by restoring the tumor suppressor activity of this protein. Therapeutic strategies targeting p53 in HNSCC can be divided into three categories related to three subtypes encompassing WT p53, mutated p53 and HPV-positive HNSCC. First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV+ cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection.

Purpose: For most disease sites, level 1 evidence is lacking for proton beam therapy (PBT). By identifying target populations that would benefit most from PBT, prospective registries could overcome many of the challenges in clinical trial enrollment. Herein, we report clinical outcomes of patients treated with PBT for locally advanced non-small cell lung cancer (LA-NSCLC). Methods and Materials: Data were obtained from the multi-institutional prospective database of the Proton Collaborative Group (PCG). Inclusion criteria of our study were stage III de novo or recurrent LA-NSCLC, use of PBT, and availability of follow-up data. Overall survival (OS) time was calculated from the start of treatment until death or last follow-up. Kaplan-Meier curves were generated for groups of interest and compared with log-rank tests. Cox regression modeling was used to evaluate the multivariate association between selected covariates and OS. Results: A total of 195 patients were included in the analysis. PBT was given with a median equivalent dose in 2 Gy fractions (EQD2) of 63.8 Gy (relative biological effectiveness). Pencil beam scanning was used in 20% of treatments. Treatment-related grade 3 adverse events were rare: 1 pneumonitis, 2 dermatitis, and 3 esophagitis. No grade 4 events were reported. Two cardiac-related grade 5 events occurred in patients with multiple risk factors. The median follow-up time for living patients was 37.1 months and the median OS was 19.0 months. On multivariate analysis, good performance status (hazard ratio, 0.27; [95% confidence interval, 0.15-0.46]; P < .0001), pencil beam scanning use (0.55; [0.31-0.97]; P = .04), and increased EQD2 (0.80; [0.71-0.90] - per 10 Gy increase; P = .0002) were associated with decreased mortality. Conclusions: PBT appears to yield low rates of adverse events with an OS similar to other retrospective studies on PBT for LA-NSCLC. PBS use and increased EQD2 can potentially improve OS.

Immunotherapy with checkpoint inhibitors opened new horizons in cancer treatment. Clinical trials for novel immunotherapies or unexplored combination regimens either need years of development or are simply impossible to perform like is the case in cancer patients with limited life expectancy. Thus, the need for preclinical models that rapidly and safely allow for a better understanding of underlying mechanisms, drug kinetics and toxicity leading to the selection of the best regimen to be translated into the clinic, is of high importance. Humanized mice that can bear both human immune system and human tumors, are increasingly used in recent preclinical immunotherapy studies and represent a remarkably unprecedented tool in this field. In this review, we describe, summarize, and discuss the recent advances of humanized mouse models used for cancer immunotherapy research and the challenges faced during their establishment. We also highlight the lack of preclinical studies using this model for radiotherapy-based research and argue that it can be a great asset to understand and answer many open questions around radiation therapy such as its presumed associated “abscopal effect”.

Background: Our aim was to evaluate the feasibility and safety of isotoxic high-dose (iHD) stereotactic body radiation therapy (SBRT) in a total neoadjuvant sequence for the treatment of localized pancreatic adenocarcinoma. Materials and methods: Biopsy-proven borderline resectable/locally advanced pancreatic cancer (BR/LAPC) patients were included in this observational prospective analysis from August 2017 to April 2020 without excluding tumours showing a radiological direct gastrointestinal (GI) invasion. An induction chemotherapy by modified fluorouracil, irinotecan and oxaliplatin was performed for a median of six cycles. In case of non-progression, an isotoxic high-dose stereotactic body radiotherapy (iHD-SBRT) was delivered in 5 fractions followed by a surgical exploration. The primary endpoint was acute/late gastrointestinal grade ⩾3 toxicity. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and local control (LC). Results: A total of 39 consecutive patients (21 BR and 18 LAPC) were included: 34 patients (87.2%, 18 BR and 16 LAPC) completed the planned neoadjuvant sequence. After iHD-SBRT, 19 patients [55.9% overall, 13/18 BR (72.2%) and 6/16 LAPC (37.5%)] underwent an oncological resection among the 25 patients surgically explored (73.5%). The median follow up was 18.2 months. The rates of acute and late GI grade 3 toxicity were, respectively, 2.9% and 4.2%. The median OS and PFS from diagnosis were, respectively, 24.5 and 15.6 months. The resected patients had improved median OS and PFS in comparison with the non-resected patients (OS: 32.3 versus 18.2 months, p = 0.02; PFS: 24.1 versus 7.1 months, p

Abstract Background This literature review explores the terminology, the neurophysiology, and the assessment of cough in general, in the framework of dysphagia and regarding head and neck cancer patients at risk for dysphagia. In the dysphagic population, cough is currently assessed perceptually during a clinical swallowing evaluation or aerodynamically. Recent findings Recent findings have shown intra and inter‐rater disagreements regarding perceptual scoring of cough. Also, aerodynamic measurements are impractical in a routine bedside assessment. Coughing, however, is considered to be a clinically relevant sign of aspiration and dysphagia in head and cancer patients treated with concurrent chemoradiotherapy. Conclusion This article surveys the literature regarding the established cough assessment and stresses the need to implement innovative methods for assessing cough in head and neck cancer patients treated with concurrent chemoradiotherapy at risk for dysphagia.

Purpose: COVID-19 reached Belgium in February and quickly became a major public health challenge. It is of importance to evaluate the actual impact of COVID-19 on patients and staff in Belgian radiotherapy departments (RTDs). This was evaluated through a weekly national survey sent to departments measuring key factors that were affected by the pandemic.Materials and Methods: The Belgian SocieTy for Radiation Oncology (BeSTRO) together with the Belgian College for physicians in Radiation Oncology invited all 26 RTD to participate in a survey that started on March 2nd and was re- submitted weekly for 4 months to assess variations in time. The survey focused on: (1) the COVID-19 status of patients and staff; (2) the management of clinically suspected COVID patients and COVID positive patients; (3) the impact of COVID-19 on RTD activities; (4) its impact in radiotherapy indications and fractionation schemes.Results: Seventy-three percent of 26 RTDs completed the first survey and 57% responded to all weekly surveys. In the RTD staff, 24 members were COVID-positive of whom 67% were RTTs. Over the study period, the number of patients treated dropped by a maximum of 18.8% when compared to March 2nd. In 32.3% of COVID-positive and 54% of COVID suspected patients, treatment was continued without any interruptions. Radiotherapy indications were adapted within the 1st weeks of the survey in 47.4% of RTD, especially for urological and breast tumors. Fractionation schemes were changed in 68.4% of RTD, mainly for urological, breast, gastro-intestinal, and lung tumors.Conclusions: Between March and June 2020, the COVID-19 pandemic resulted in an important decrease in treatment activity in RTD in Belgium (18.8%). The COVID-19 infection status of patients influenced the continuity of the radiotherapy schedule. Changes in indications and fractionation schedules of radiotherapy were rapidly incorporated in the different RTD.

Background: Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma (STS), usually of adults, displaying skeletal muscle differentiation. STS principally metastasize to the lungs with more than 50% of metastatic patients presenting with isolated pulmonary metastasis. Paradoxically, the majority of drugs prescribed to treat RMS are associated with multidrug resistance. Case report: We report the case of a 53 year-old patient who developed three synchronous chemoresistant lung metastasis from pleomorphic RMS. Considering the poor prognosis, the patient's preference and the chemoresistance of her lung metastasis, we decided to perform two consecutive stereotactic body radiotherapy (SBRT) on two of these three lesions. Discussion: Initially, the patient was referred to our institute with a painful mass in the anterior part of the left thigh increasing in volume for 3 months. Biopsy revealed a high-grade pleomorphic RMS. The cancer being staged IB, she had neoadjuvant radiotherapy. After complete surgical excision, pathology examination revealed a 6 cm Grade II pleomorphic RMS, with clear margins. Six months later, she developed three synchronous lung metastases. She got 4 courses of doxorubicin-ifosfamide which were poorly supported. After two courses, a heterogeneous (morphological and metabolic) response was observed, hence SBRT was delivered with a Biologically Equivalent Dose (α/β10)> 100 Gray on the two more chemoresistant lesions. This SBRT was very well tolerated, no side effects were reported. The patient remained alive and achieved a complete response of these three metastases, which sustains after more than 3 years. Conclusion: Early recognition and proper management of these oligometastatic patients may lead to motivating results in a poor prognosis disease.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive solid tumours with an estimated 5-year overall survival rate of 7% for all stages combined. In this highly resistant disease that is located in the vicinity of many radiosensitive organs, the role of radiotherapy (RT) and indications for its use in this setting have been debated for a long time and are still under investigation. Although a survival benefit has yet to be clearly demonstrated for RT, it is the only technique, other than surgery, that has been demonstrated to lead to local control improvement. The adjuvant approach is now strongly challenged by neoadjuvant treatments that could spare patients with rapidly progressive systemic disease from unnecessary surgery and may increase free margin (R0) resection rates for those eligible for surgery. Recently developed dose-escalated RT treatments, designed either to maintain full-dose chemotherapy or to deliver a high biologically effective dose, particularly to areas of contact between the tumour and blood vessels, such as hypofractionated ablative RT (HFA-RT) or stereotactic body RT (SBRT), are progressively changing the treatment landscape. These modern strategies are currently being tested in prospective clinical trials with encouraging preliminary results, paving the way for more effective treatment combinations using novel targeted therapies. This review summarizes the current literature regarding the use of RT for the treatment of primary PDAC, describes the limitations of conventional RT, and discusses the emerging role of dose-escalated RT and heavy-particle RT.

The traditional concept of post-treatment surveillance in head and neck cancer patients relies on examinations directed at early detection of disease recurrence and/or second primary tumors. They are usually provided by ear, nose and throat specialists with complementary input from radiation oncologists and medical oncologists. Emerging evidence underscores the importance of monitoring and effective management of late adverse events. One of the major drawbacks is a lack of prospective controlled data. As a result, local institutional policies differ, and practice recommendations are subject to continuing debate. Due to the economic burden and impact on emotional comfort of patients, intensity and content of follow-up visits are a particularly conflicting topic. According to the current evidence-based medicine, follow-up of head and neck cancer patients does not prolong survival but can improve quality of life. Therefore, an approach giving priority to a multidisciplinary care involving a speech and swallowing expert, dietician, dentist, and psychologist may indeed be more relevant. Moreover, on a case-by-case basis, some patients need more frequent consultations supplemented by imaging modalities. Human papillomavirus positive oropharyngeal cancer tends to develop late failures at distant sites, and asymptomatic oligometastatic disease, especially in the lungs, can be successfully salvaged by local ablation, either surgically or by radiation. The deep structures of the skull base related to the nasopharynx are inaccessible to routine clinical examination, advocating periodic imaging supplemented by nasofibroscopy as indicated. Anamnesis of heavy smoking justifies annual low-dose computed tomography screening of the thorax and intensive smoking cessation counseling. Finally, some cancer survivors feel more comfortable with regular imaging, and their voice should be taken into consideration. Future development of surveillance strategies will depend on several variables including identification of reliable predictive factors to select those who could derive the most benefit from follow-up visits, the availability of long-term follow-up data, the results of the first randomized trials, resource allocation patterns, infrastructure density, and the therapeutic landscape of locally advanced and recurrent and/or metastatic disease, which is rapidly changing with the advent of immune checkpoint inhibitors and better utilization of local approaches.

The impact of radiotherapy (RT) quality assurance (QA) has been demonstrated by numerous studies and is particularly important for head and neck cancer (HNC) treatment due to the complexity of RT target volumes in this region and the multiple adjacent organs at risk. The RT planning process includes many critical steps including interpretation of diagnostic imaging, image fusion, target volume delineation (tumor, lymph nodes, and organs at risk), and planning. Each step has become highly complex, and precise and rigorous QA throughout the planning process is essential. The ultimate aim is to precisely deliver radiation dose to the target, maximizing the tumor dose and minimizing the dose to surrounding organs at risk, in order to improve the therapeutic index. It is imperative that RT QA programs should systematically control all aspects of the RT planning pathway and include regular end-to-end tests and external audits. However, comprehensive QA should not be limited to RT and should, where possible, also be implemented for surgery, systemic therapy, pathology, as well as other aspects involved in the interdisciplinary treatment of HNC.

Abstract Background The development of a second primary tumor is a potential late side effect of radiotherapy. Particularly, an increased risk of secondary cancers, mostly of digestive or breast origin, has been observed in patients treated with high-dose radiotherapy for Wilms tumor (WT) in childhood. However, hepatocellular carcinoma (HCC) has been very rarely described as a potentially radiotherapy-induced tumor. We describe the case of a patient with an aggressive HCC 50 years after the treatment of a WT. Case presentation A 49-year old man, treated at the age of 6 weeks for a right WT by a right nephrectomy and adjuvant radiotherapy, presented with a right abdominal mass. Imaging demonstrated a 100-mm tumor invading the inferior segment of the right liver, the right colon and the right psoas muscle. The patient had no previous history of liver disease, nor of alcohol consumption, and hepatitis serologies were negatives. Biopsy demonstrated a poorly differentiated tumor of unknown origin. A panel of tumor markers was negative. Explorative surgery has been performed allowing en bloc R0 tumor resection, including resection of segments VI and VII of the liver, right hemicolectomy and resection of the anterior sheet of the right psoas muscle. Pathological examination revealed a poorly differentiated HCC. No signs of cirrhosis or chronic liver disease were observed in the non-tumor liver. Twenty weeks after surgery, the patient developed a multifocal tumor recurrence that was treated with intra-arterial 90Yttrium radioembolization. Conclusion In this case, the absence of risk factors for HCC, such as cirrhosis, viral hepatitis and chronic liver disease, highly suggests the development of HCC to be related to previous high-dose radiation therapy given for a right WT to a field involving the inferior part of the liver. This observation shows radiotherapy to/near the liver, particularly in childhood, to be a potential risk factor for HCC, stressing the need for a long-term specific follow-up in patients irradiated in childhood.

In locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN), concurrent chemoradiotherapy is an integral part of multimodality management both in the adjuvant and in the definitive settings. Although de-intensification strategies have been propelled to the forefront of clinical research in human papillomavirus (HPV) positive oropharyngeal cancer, three cycles of 100 mg/m2 cisplatin given every 3 weeks concurrently with conventionally fractionated external beam radiotherapy represent a cost-effective and globally accessible treatment option for the majority of LA-SCCHN cases. Based on four large randomized trials, this regimen has become the non-surgical standard of care for cisplatin-eligible patients. Nevertheless, the outcomes in terms of efficacy, toxicity, and compliance have been rather disappointing. Therefore, there is an unmet need to find a better alternative. With limited support from randomized trials, weekly low-dose cisplatin regimens have replaced the standard high-dose schedule at some institutions. Four prospective trials exploring radiotherapy with and without weekly low-dose cisplatin have been published. Two of them were conducted in the 1980s, one of which had a negative outcome, the third study provided insufficient information on toxicity, and the fourth trial had to be prematurely terminated due to poor accrual. Moreover, the findings of two phase III trials comparing the two concurrent cisplatin regimens favored the high-dose protocol. We performed a composite meta-analysis of 59 prospective trials enrolling a total of 5,582 patients. The primary endpoint was overall survival. Reflecting different radiotherapy fractionation schemes and treatment intents, three meta-analyses were carried out, one for postoperative conventional chemoradiotherapy, one for definitive conventional chemoradiotherapy, and one for definitive altered fractionation chemoradiotherapy. In the former two settings, both high- and low-dose regimens yielded similar survival outcomes, thus, the primary objective was not met. When given concurrently with altered fractionation radiotherapy, patients treated with high-dose cisplatin had significantly longer overall survival than those who received low-dose cisplatin. In this article we provide a synthetic view of the results, discuss the issue of cumulative dose, compare two vs. three cycles of high-dose cisplatin, and present our three-step recommendations for use of the current standard of care, high-dose cisplatin, in clinical practice.