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The aim of the study was to test the hypothesis that Intensity Modulated Proton Therapy (IMPT) reduces acute and late radiation toxicity in nasopharyngeal cancer (NPC) patients compared to photon-based radiation techniques including IMRT and VMAT. The study population of this prospective cohort study was composed of 131 NPC patients treated with curative radiotherapy (RT) or chemoradiotherapy. Between July 2007 and December 2017, all patients were treated with IMRT or VMAT. Since January 2018, 97 out of 99 patients (98%) qualified for IMPT according to model-based selection. All patients were included in a prospective data registration program in which acute and late toxicity was prospectively scored weekly during RT and at fixed time points after RT (6 weeks, 6, 12, 18 and 24 months). To determine the overall effect on acute and late toxicity, the Weighted Overall Toxicity Burden (WOTB) was calculated, defined as the sum of all toxicities weighted by toxicity grading. In addition, the WOTB Area Under the Curve (WOTB-AUC) was calculated representing the WOTB from the start of treatment until 24 months after completion of treatment. The two groups were well balanced regarding gender, age, race, T-stage, N-stage, AJCC-stage, and EBV-status. However, there was a significant difference regarding the chemotherapy regimens used between the two groups. In the photon cohort, 33% of patients were treated with conventional RT, 7% with concurrent chemoradiation, 2% with induction chemotherapy + concurrent chemoradiation and 57% with concurrent chemoradiation + adjuvant chemotherapy, while this was 25%, 37%, 36% and 2% in the proton cohort, respectively. The mean dose to all relevant organs at risk (i.e., oral cavity, pharyngeal constrictor muscles, parotid, and submandibular glands) were significantly lower with IMPT compared to photons. This was particularly true for the mean dose to the oral cavity which decreased from 27.2 Gy with IMRT/ VMAT to 10.7 Gy with IMPT (p<0.001). From January 2018, a plan comparison was made in all NPC patients referred for radiotherapy to our centre between IMPT and VMAT. In total, 97 out of 99 patients qualified for protons based on the estimated risk difference on dysphagia and xerostomia resulting from the dose reductions obtained with IMPT. IMPT resulted in significant reductions of various acute and late toxicities (Figure 1), including xerostomia, loss of taste, dysphagia, tube feeding dependence, sore mouth, and mucosal reactions. Only acute dermatitis was significantly worse at the end of IMPT, but completely recovered at 5 weeks after treatment in all patients. [Display omitted] The WOTB was significantly lower after IMPT (Figure 2) at all time points. In the IMPT group, the WOTB-AUC as measure for overall toxicity was 68% lower. The WOTB-AUC reduction was 60% in the acute phase (week 1 to 7), 69% in the recovery phase (from end of treatment to 6 months after RT) and 70% in the late phase (from 6 to 24 months after RT). In this prospective cohort study, patients treated with IMPT had statistically significant and clinically relevant reductions of various acute and late toxicities as compared to modern photon techniques like IMRT and VMAT as a historical control group. [ABSTRACT FROM AUTHOR]

• Optimal timing of re-planning was suggested for a comprehensive set of OARs. • Generic re-planning timing was suggested considering different combinations of OARs. • D mean increase due to anatomical changes were most frequently > 3 Gy in Supraglottic. • The 3rd week is suggested as the optimal timing of re-planning for 10 OARs. • A maximum of 3 re-plannings can guarantee D mean increase below 3 Gy for all OARs. Adaptive radiotherapy (ART) relies on re-planning to correct treatment variations, but the optimal timing of re-planning to account for dose changes in head and neck organs at risk (OARs) is still under investigation. We aimed to find out the optimal timing of re-planning in head and neck ART. A total of 110 head and neck cancer patients were retrospectively enrolled. A semi auto-segmentation method was applied to obtain the weekly mean dose (D mean) to OARs. The K-nearest-neighbour method was used for missing data imputation of weekly D mean. A dose deviation map was built using the planning D mean and weekly D mean values and then used to simulate different ART scenarios consisting of 1 to 6 re-plannings. The difference between accumulated D mean and planning D mean before re-planning (ΔD mean_acc_noART) and after re-planning (ΔD mean_acc_ART) were evaluated and compared. Among all the OARs, supraglottic showed the largest ΔD mean_acc_noART (1.23 ± 3.13 Gy) and most cases of ΔD mean_acc_noART > 3 Gy (26 patients). The 3rd week is suggested in the optimal timing of re-planning for 10 OARs. For all the organs except arytenoid, 2 re-plannings were able to guarantee the ΔD mean_acc_ART below 3 Gy while the average |ΔD mean_acc_ART | was below 1 Gy. ART scenarios of 2_4, 3_4, 3_5 (week of re-planning separated with "_") were able to guarantee ΔD mean_acc_ART of 99 % of patients below 3 Gy simultaneously for 19 OARs. The optimal timing of re-planning was suggested for different organs at risk in head and neck adaptive radiotherapy. Generic scenarios of timing and frequency for re-planning can be applied to guarantee the increase of accumulated mean dose within 3 Gy simultaneously for multiple organs. [ABSTRACT FROM AUTHOR]

• Normal tissue radiation tolerance in children is different from adults. • In the abdomen, the pancreas and spleen are the most radiosensitive organs-at-risk. • The gonads should be considered the most radiosensitive pelvic organs in children. • Without quantifiable dose effect data, strive for 'as low as reasonably achievable'. As survival improves in childhood cancer, prevention of late treatment-related toxicity in survivors becomes increasingly relevant. Radiotherapy is an important contributor to late toxicity. Therefore, minimizing radiation exposure to normal tissues is an important step towards improving the long-term therapeutic window of childhood cancer treatment. Since children are growing and developing, they are particularly vulnerable to radiation exposure. This makes the 'as low as reasonably achievable (ALARA)' principle even more important. In order to guide and achieve clinically meaningful dose reductions through advanced and emerging radiation techniques, it is important to investigate age-dependent relationships between radiation exposure to healthy tissues and late radiation-induced toxicity. In this review, we provide an overview of literature on the association between radiotherapy dose and late toxicity after abdominal and pelvic irradiation in childhood cancer. With this information, we aim to aid in decision-making regarding radiotherapy for childhood cancer. [ABSTRACT FROM AUTHOR]

• First time comparison of auto- and human segmentation accuracy using dose and NTCP. • DLC performs better than contour warping by DIR for majority of head and neck OARs. • Human segmentation of parotid glands is needed during adaptive radiotherapy (ART) • Semi auto-segmentation is feasible for accurate dose and NTCP calculation in ART. Accurate segmentation of organs-at-risk (OARs) is crucial but tedious and time-consuming in adaptive radiotherapy (ART). The purpose of this work was to automate head and neck OAR-segmentation on repeat CT (rCT) by an optimal combination of human and auto-segmentation for accurate prediction of Normal Tissue Complication Probability (NTCP). Human segmentation (HS) of 3 observers, deformable image registration (DIR) based contour propagation and deep learning contouring (DLC) were carried out to segment 15 OARs on 15 rCTs. The original treatment plan was re-calculated on rCT to obtain mean dose (D mean) and consequent NTCP-predictions. The average D mean and NTCP-predictions of the three observers were referred to as the gold standard to calculate the absolute difference of D mean and NTCP-predictions (|Δ D mean | and |ΔNTCP|). The average |Δ D mean | of parotid glands in HS was 1.40 Gy, lower than that obtained with DIR and DLC (3.64 Gy, p < 0.001 and 3.72 Gy, p < 0.001, respectively). DLC showed the highest |Δ D mean | in middle Pharyngeal Constrictor Muscle (PCM) (5.13 Gy, p = 0.01). DIR showed second highest |Δ D mean | in the cricopharyngeal inlet (2.85 Gy, p = 0.01). The semi auto-segmentation (SAS) adopted HS, DIR and DLC for segmentation of parotid glands, PCM and all other OARs, respectively. The 90th percentile |ΔNTCP|was 2.19%, 2.24%, 1.10% and 1.50% for DIR, DLC, HS and SAS respectively. Human segmentation of the parotid glands remains necessary for accurate interpretation of mean dose and NTCP during ART. Proposed semi auto-segmentation allows NTCP-predictions within 1.5% accuracy for 90% of the cases. [ABSTRACT FROM AUTHOR]

• Radiomic features improve individual lymph node failure prediction. • Clinical parameters, together with radiomic features showed the best performance in predicting nodal failure risk. • Individual nodal failure prediction could lead to treatment individualization in HNC patients. To develop and validate a pre-treatment radiomics-based prediction model to identify pathological lymph nodes (pLNs) at risk of failures after definitive radiotherapy in head and neck squamous cell carcinoma patients. Training and validation cohorts consisted of 165 patients with 558 pLNs and 112 patients with 467 pLNs, respectively. All patients were primarily treated with definitive radiotherapy, with or without systemic treatment. The endpoint was the cumulative incidence of nodal failure. For each pLN, 82 pre-treatment CT radiomic features and 7 clinical features were included in the Cox proportional-hazard analysis. There were 68 and 23 nodal failures in the training and validation cohorts, respectively. Multivariable analysis revealed three clinical features (T-stage, gender and WHO Performance-status) and two radiomic features (Least-axis-length representing nodal size and gray level co-occurrence matrix based - Correlation representing nodal heterogeneity) as independent prognostic factors. The model showed good discrimination with a c-index of 0.80 (0.69–0.91) in the validation cohort, significantly better than models based on clinical features (p < 0.001) or radiomics (p = 0.003) alone. High- and low-risk groups were defined by using thresholds of estimated nodal failure risks at 2-year of 60% and 10%, resulting in positive and negative predictive values of 94.4% and 98.7%, respectively. A pre-treatment prediction model was developed and validated, integrating the quantitative radiomic features of individual lymph nodes with generally used clinical features. Using this prediction model, lymph nodes with a high failure risk can be identified prior to treatment, which might be used to select patients for intensified treatment strategies targeted on individual lymph nodes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to investigate whether quantitative CT image-biomarkers (IBMs) can improve the prediction models with only classical prognostic factors for local-control (LC), regional-control (RC), distant metastasis-free survival (DMFS) and disease-free survival (DFS) for head and neck cancer (HNC) patients.Materials and Methods: The cohort included 240 and 204 HNC patients in the training and validation analysis, respectively. Clinical variables were scored prospectively and IBMs of the primary tumor and lymph nodes were extracted from planning CT-images. Clinical, IBM and combined models were created from multivariable Cox proportional-hazard analyses based on clinical features, IBMs, and both for LC, RC, DMFS and DFS.Results: Clinical variables identified in the multivariable analysis included tumor-site, WHO performance-score, tumor-stage and age. Bounding-box-volume describing the tumor volume and irregular shape, IBM correlation representing radiological heterogeneity, and LN_major-axis-length showing the distance between lymph nodes were included in the IBM models. The performance of IBM LC, RC, DMFS and DFS models (c-index(validated):0.62, 0.80, 0.68 and 0.65) were comparable to that of the clinical models (0.62, 0.76, 0.70 and 0.66). The combined DFS model (0.70) including clinical features and IBMs performed significantly better than the clinical model. Patients stratified with the combined models revealed larger differences between risk groups in the validation cohort than with clinical models for LC, RC and DFS. For DMFS, the differences were similar to the clinical model.Conclusion: For prediction of HNC treatment outcomes, image-biomarkers performed as good as or slightly better than clinical variables. [ABSTRACT FROM AUTHOR]

Background: Deep learning has shown promising results to generate MRI‐based synthetic CTs and to enable accurate proton dose calculations on MRIs. For clinical implementation of synthetic CTs, quality assurance tools that verify their quality and reliability are required but still lacking. Purpose: This study aims to evaluate the predictive value of uncertainty maps generated with Monte Carlo dropout (MCD) for verifying proton dose calculations on deep‐learning‐based synthetic CTs (sCTs) derived from MRIs in online adaptive proton therapy. Methods: Two deep‐learning models (DCNN and cycleGAN) were trained for CT image synthesis using 101 paired CT‐MR images. sCT images were generated using MCD for each model by performing 10 inferences with activated dropout layers. The final sCT was obtained by averaging the inferred sCTs, while the uncertainty map was obtained from the HU variance corresponding to each voxel of 10 sCTs. The resulting uncertainty maps were compared to the observed HU‐, range‐, WET‐, and dose‐error maps between the sCT and planning CT. For range and WET errors, the generated uncertainty maps were projected along the 90‐degree angle. To evaluate the dose distribution, a mask based on the 5%‐isodose curve was applied to only include voxels along the beam paths. Pearson's correlation coefficients were calculated to determine the correlation between the uncertainty maps and HUs, range, WET, and dose errors. To evaluate the dosimetric accuracy of synthetic CTs, clinical proton treatment plans were recalculated and compared to the pCTs Results: Evaluation of the correlation showed an average of r = 0.92 ± 0.03 and r = 0.92 ± 0.03 for errors between uncertainty‐HU, r = 0.66 ± 0.09 and r = 0.62 ± 0.06 between uncertainty‐range, r = 0.64 ± 0.06 and r = 0.58 ± 0.07 between uncertainty‐WET, and r = 0.65 ± 0.09 and r = 0.67 ± 0.07 between uncertainty and dose difference for DCNN and cycleGAN model, respectively. Dosimetric comparison for target volumes showed an average 3%/3 mm gamma pass rate of 99.76 ± 0.43 (DCNN) and 99.10 ± 1.27 (cycleGAN). Conclusion: The observed correlations between uncertainty maps and the various metrics (HU, range, WET, and dose errors) demonstrated the potential of MCD‐based uncertainty maps as a reliable QA tool to evaluate the accuracy of deep learning‐based sCTs. [ABSTRACT FROM AUTHOR]

• Head & neck cancer patients can be selected for ART in the first treatment week. • Mean dose change to OARs in week 1 and 2 is predictive for overall BIOΔNTCP. • Comprehensive evaluation of planned vs. actual NTCP in 110 patients. • The proposed strategy could classify all true candidates regarding late toxicity. • The strategy could correctly spare 88.2% patients from ART regarding late toxicity. Adaptive radiotherapy (ART) is workload intensive but only benefits a subgroup of patients. We aimed to develop an efficient strategy to select candidates for ART in the first two weeks of head and neck cancer (HNC) radiotherapy. This study retrospectively enrolled 110 HNC patients who underwent modern photon radiotherapy with at least 5 weekly in-treatment re-scan CTs. A semi auto-segmentation method was applied to obtain the weekly mean dose (D mean) to OARs. A comprehensive NTCP-profile was applied to obtain NTCP's. The difference between planning and actual values of D mean (ΔD mean) and dichotomized difference of clinical relevance (BIOΔNTCP) were used for modelling to determine the cut-off maximum ΔD mean of OARs in week 1 and 2 (maxΔD mean_1 and maxΔD mean_2). Four strategies to select candidates for ART, using cut-off maxΔD mean were compared. The Spearman's rank correlation test showed significant positive correlation between maxΔD mean and BIOΔNTCP (p -value <0.001). For major BIOΔNTCP (>5%) of acute and late toxicity, 10.9% and 4.5% of the patients were true candidates for ART. Strategy C using both cut-off maxΔD mean_1 (3.01 and 5.14 Gy) and cut-off maxΔD mean_2 (3.41 and 5.30 Gy) showed the best sensitivity, specificity, positive and negative predictive values (0.92, 0.82, 0.38, 0.99 for acute toxicity and 1.00, 0.92, 0.38, 1.00 for late toxicity, respectively). We propose an efficient selection strategy for ART that is able to classify the subgroup of patients with >5% BIOΔNTCP for late toxicity using imaging in the first two treatment weeks. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to generate normal tissue complication probability (NTCP) models in patients treated with either proton beam therapy (PBT) or intensity-modulated radiation therapy (IMRT) for oropharynx cancer and to use a model-based approach to investigate the added value of PBT in preventing treatment complications.Methods and Materials: For patients with advanced-stage oropharynx cancer treated with curative intent (PBT, n = 30; IMRT, n = 175), NTCP models were developed using multivariable logistic regression analysis with backward selection. For PBT-treated patients, an equivalent IMRT plan was generated to serve as a reference to determine the benefit of PBT in terms of NTCP. The models were then applied to the PBT-treated patients to compare predicted and observed clinical outcomes (calibration-in-the-large). Five binary endpoints were analyzed at 6 months after treatment: dysphagia ≥ grade 2, dysphagia ≥ grade 3, xerostomia ≥ grade 2, salivary duct inflammation ≥ grade 2, and feeding tube dependence. Corresponding toxicity grading was based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Paired t tests and Wilcoxon rank tests were used to compare mean NTCP results for endpoints between PBT and IMRT.Results: NTCP models developed based on outcomes from all patients were applied to those receiving PBT. NTCP values were calculated for the equivalent IMRT plans for all PBT-treated patients, revealing significantly higher NTCP values with IMRT. PBT was associated with statistically significant reductions in the mean NTCP values for each endpoint at 6 months after treatment, with the largest absolute differences in rates of ≥grade 2 dysphagia and ≥grade 2 xerostomia.Conclusions: NTCP models predict significant improvements in the probability of short-term, treatment-related toxicity with PBT compared with IMRT for oropharyngeal cancer. This study demonstrates an NTCP model-based approach to compare predicted patient outcomes when randomized data are not available. [ABSTRACT FROM AUTHOR]

The overarching aim of work package 1 of the European Proton Therapy Network (EPTN) is to create a firm basis for evidence-based particle therapy at the European level. To achieve this, this work package will set up a worldwide unique prospective data registration programme for nine different tumour sites. Such programme will provide more insights into the current practice across all European particle therapy centres and into the results of particle therapy with regard to radiation-induced toxicity and efficacy in terms of local control and survival. More importantly, prospective data registration provides major opportunities to continuously improve the quality of particle therapy, by defining bench marks, to identify best practices that may learn others to improve quality of particle therapy, to synchronize selection criteria and to create more homogeneous patient cohorts to evaluate results, which is particularly important in rare tumours. This will be supported by EORTC through existing and new IT-infrastructure for data collection in different formats next to QA-platforms. In addition, work package 1 will define the requirements for high quality clinical trials in order to enhance high quality clinical trial proposals and determine alternative methods for RCT, such as the model-based approach. [ABSTRACT FROM AUTHOR]

Background:Considerable controversy exists about the safety and efficacy of second re-irradiations (three courses of radiotherapy to overlapping volumes). Therefore, all published clinical studies were reviewed. Material and methods:Contemporary and historical articles were identified. Outcomes such as survival, local control, symptom improvement and side effects were extracted. Contemporary results were grouped by anatomical location of the re-irradiated region in the body. Results:Most data were derived from central nervous system tumors, pelvic tumors and bone metastases. We could include nine contemporary, retrospective studies with 2–25 patients each. Nearly, all patients were treated with palliative intent. Most of the prescribed re-irradiation regimens were highly individualized and thus difficult to compare. Symptomatic responses were recorded in most patients. In palliatively treated patients with pelvic and bony target volumes, high-grade toxicity was uncommon. Conclusions:Despite of issues related to study size, length of follow-up and calculation of lifetime cumulative equivalent dose, the available data provide an initial framework for future studies and discussion of dose constraints. Selected dose-fractionation regimens may result in a satisfactory therapeutic ratio even after two previous courses of radiotherapy, if these were well tolerated. [ABSTRACT FROM AUTHOR]

Background/purpose To report on health-related quality-of-life (HRQoL) of patients with laryngeal cancer, treated in a randomized trial comparing accelerated radiotherapy with carbogen and nicotinamide (ARCON) against accelerated radiotherapy alone (AR). Material/methods HRQoL was assessed using the HRQoL Questionnaire-C30 (QLQ-C30) and the Head & Neck cancer module (QLQ-H&N35) at baseline, at completion of radiotherapy and at 6, 12, and 24 months post-baseline. Results From 269/345 patients (AR: 136/174; ARCON: 133/171) data on HRQoL were available for analysis. Moderate to severe clinical impact of the treatment was observed for nearly all items of the QLQ-C30 and QLQ-H&N35 between baseline and end-of-treatment. At 6 months, scores returned to baseline level with exception of dry mouth, sticky saliva, and taste/smell. No difference between AR and ARCON was observed. At 2 years from baseline, the percentage of patients reporting moderate to severe complaints of dry mouth, sticky saliva, or changes in taste/smell was 30%, 22% and 18%, respectively, while the majority of patients had no or few complaints of swallowing (79%) or speech (64%). Conclusions With accelerated radiotherapy, high local tumor control was obtained while maintaining good speech and swallowing function. Long-term dry mouth, sticky saliva and changes in taste/smell are limited to one quarter of patients. (ClinicalTrials.gov number, NCT00147732). [ABSTRACT FROM AUTHOR]

Purpose: The phase III 22071–26071 trial was designed to evaluate the addition of panitumumab to adjuvant chemotherapy plus intensity modulated radiotherapy (IMRT) in locally advanced resected squamous cell head and neck cancer. We report the results of the dummy run (DR) performed to detect deviations from protocol guidelines. Methods and Materials: DR datasets consisting of target volumes, organs at risk (OAR) and treatment plans were digitally uploaded, then compared with reference contours and protocol guidelines by six central reviewers. Summary statistics and analyses of potential correlations between delineations and plan characteristics were performed. Results: Of 23 datasets, 20 (87.0%) GTVs were evaluated as acceptable/borderline, along with 13 (56.5%) CTVs and 10 (43.5%) PTVs. All PTV dose requirements were met by 73.9% of cases. Dose constraints were met for 65.2-100% of mandatory OARs. Statistically significant correlations were observed between the subjective acceptability of contours and the ability to meet dose constraints for all OARs (p ≤ 0.01) except for the parotids and spinal cord. Ipsilateral parotid doses correlated significantly with CTV and PTV volumes (p ≤ 0.05). Conclusions: The observed wide variations in treatment planning, despite strict guidelines, confirms the complexity of development and quality assurance of IMRT-based multicentre studies for head and neck cancer. [ABSTRACT FROM AUTHOR]

Abstract: Most new radiation techniques, have been introduced primarily to reduce the dose to normal tissues in order to prevent radiation-induced side effects. Radiotherapy with protons is such a radiation technique that due to its superior beam properties compared to photons enables better sparing of normal tissues. This paper describes a stepwise methodology to select patients for proton therapy when the primary aim is to reduce side effects. This method has been accepted by the Dutch health authorities to select patients for proton therapy. In addition, an alternative method is described in case randomised controlled trials are considered not appropriate. [Copyright &y& Elsevier]

Abstract: Background and purpose: Radiotherapy, alone or combined with chemotherapy, is a treatment modality used frequently in head and neck cancer. In order to report, compare and interpret the sequelae of radiation treatment adequately, it is important to delineate organs at risk (OARs) according to well-defined and uniform guidelines. The aim of this paper was to present our institutional Computed Tomography (CT)-based delineation guidelines for organs in the head and neck at risk for radiation-induced swallowing dysfunction (SWOARs). Material and methods: After analyses of the human anatomy of the head and neck area and literature review, CT-based guidelines for delineation of the most relevant SWOARs were described by a panel of experts. Results and conclusions: This paper described institutional guidelines for the delineation of potential SWOARs, accompanied by CT-based illustrations presenting examples of the delineated structures and their corresponding anatomic borders. This paper is essential to ensure adequate interpretation of future reports on the relationship between dose distribution in these SWOARs and different aspects of post-treatment swallowing dysfunction. [Copyright &y& Elsevier]

Summary: Treatment choice in elderly pharyngeal cancer patient is disputed. This study was aimed to asses association of co-morbidity, complications and survival in different treatment modalities of pharyngeal cancer patients. Retrospective analysis of pharyngeal cancer patients, diagnosed between 1997 and 2007 in a tertiary referral hospital was performed. Patients 75years and older (n =42), were matched with two control patients 64years and younger (n =84). Co-morbidity (ACE-27), treatment related complications and survival data were assessed and analyzed. Frequency of co-morbidity was similar in both age groups, although discarding alcohol abuse resulted in higher incidence of co-morbidity in the elderly group. Complication rate was not significantly different. In a multivariate analysis only stage found to be a significant predictor of complications. Survival estimates adjusted to sex, age and birth cohort revealed co-morbidity to be a significant predictor for survival in elderly and young patients. No evidence has been found to treat elderly pharyngeal cancer patients differently than younger ones. Treatment related complications are not predicted by co-morbidities in young and elderly patients; however survival is predicted by comorbidity. Therefore thorough pre-treatment evaluation and care necessary in the elderly population. [Copyright &y& Elsevier]

Summary: This review discusses the role of adjuvant treatment after curative surgery for patients with head and neck squamous cell carcinoma (HNSCC). In general, patients with unfavourable prognostic factors have a high-risk of loco-regional recurrence and subsequent worse survival after surgery alone and are therefore considered proper candidates for adjuvant treatment by either postoperative radiotherapy alone or postoperative chemoradiation. Selection of the most optimal adjuvant treatment strategy should be based on the most important prognostic factors. In this review, the different treatment strategies will be discussed in general. More specifically, we will discuss the role of the interval between surgery and radiotherapy, the overall treatment time of radiation, the selection of target volumes for radiation and the value of adding concomitant chemotherapy to postoperative radiation. [Copyright &y& Elsevier]

Abstract: Introduction: Recently, we found that swallowing dysfunction after curative (chemo) radiation (CH) RT has a strong negative impact on health-related quality of life (HRQoL), even more than xerostomia. The purpose of this study was to design a predictive model for swallowing dysfunction after curative radiotherapy or chemoradiation. Materials and methods: A prospective study was performed including 529 patients with head and neck squamous cell carcinoma (HNSCC) treated with curative (CH) RT. In all patients, acute and late radiation-induced morbidity (RTOG Acute and Late Morbidity Scoring System) was scored prospectively. To design the model univariate and multivariate logistic regression analyses were carried out with grade 2 or higher RTOG swallowing dysfunction at 6 months as the primary (SWALL6months) endpoint. The model was validated by comparing the predicted and observed complication rates and by testing if the model also predicted acute dysphagia and late dysphagia at later time points (12, 18 and 24 months). Results: After univariate and multivariate logistic regression analyses, the following factors turned out to be independent prognostic factors for SWALL6months: T3–T4, bilateral neck irradiation, weight loss prior to radiation, oropharyngeal and nasopharyngeal tumours, accelerated radiotherapy and concomitant chemoradiation. By summation of the regression coefficients derived from the multivariate model, the Total Dysphagia Risk Score (TDRS) could be calculated. In the logistic regression model, the TDRS was significantly associated with SWALL6months ((p <0.001). Subsequently, we defined three risk groups based on the TDRS. The rate of SWALL6months was 5%, 24% and 46% in case of low-, intermediate- and high-risk patients, respectively. These observed percentages were within the 95% confidence intervals of the predicted values. The TDRS risk group classification was also significantly associated with acute dysphagia (P <0.001 at all time points) and with late swallowing dysfunction at 12, 18 and 24 months (p <0.001 at all time points). Conclusion: The TDRS is a simple and validated measure to predict swallowing dysfunction after curative (CH) RT for HNC. This classification system enables identification of patients who may benefit from strategies aiming at prevention of swallowing dysfunction after curative (CH) RT such as preventive swallowing exercises during treatment and/or emerging IMRT techniques aiming at sparing anatomical structures that are involved in swallowing. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate retrospectively the prognostic significance of lymph node parameters assessed on pretreatment magnetic resonance (MR) images for development of distant metastases in patients with head and neck squamous cell carcinomas. Materials and methods: Pretreatment MR images of 311 patients were retrospectively reviewed for the presence of lymph nodes at specific neck node levels as well as the size and the presence of a number of lymph node characteristics including extranodal spread, central necrosis and number and volume of ipsi- and contralateral nodes. Of these patients, 174 (56%) had MRI-positive nodes (defined as nodes with minimum axial diameter >8 and >4mm for paratracheal level and retropharyngeal nodes). Results: The 2-year distant-metastasis free survival rate (DMFSR) for patients without MRI-positive nodes was 94% compared to 75% for those patients with MRI-positive nodes. In patients with MRI-positive nodes, results of multivariate analysis with the Cox regression model yielded statistical significance for presence of extranodal spread (ENS), detected on MRI, as the only independent prognostic factor associated with the 2-year DMFSR (p =0.002). Based on the analysis, three risk groups regarding the DMFSR could be identified. Low-risk group (DMFSR:94%) consisted of patients without MRI-positive nodes. Intermediate-risk group (DMFSR:81%) consisted of patients with MRI-positive nodes without ENS. High-risk group (DMFSR:59%) consisted of patients with MRI-positive nodes and ENS as shown on MRI (p <0.0001). Statistical separation for different tumor locations showed MRI-determined ENS (larynx: p =0.05; oropharynx: p =0.04; oral cavity: p <0.001), lowjugular/posterior triangle nodes (oropharynx: p =0.02), paratracheal nodes (larynx: p =0.03), and contralateral node volume >5cm3 (larynx: p =0.03; oral cavity: p =0.02) to be significant predictors with regard to DMFSR. Conclusion: Especially patients with on MRI demonstrating extranodal spread and with suspicious nodes at lowjugular/posterior triangle (oropharyngeal cancer) or paratracheal level (laryngeal cancer), or with contralateral enlarged nodes (laryngeal and oral cavity cancer) are at high risk for developing distant metastases and this subset of patients might benefit from supplementary imaging screening (CT-chest, PET-scan). [Copyright &y& Elsevier]

Abstract: Background and purpose: In this prospective study, the effect of a second course of primary radiotherapy on locoregional control, survival and toxicity was investigated, in patients who underwent a second course of high dose irradiation for second primary or locoregional recurrent squamous cell head and neck carcinoma (HNSCC) in a previously irradiated area. Patients and methods: A total of 34 patients with second primary (n=26) or locoregional recurrent (n=8) tumours were treated with a second course of high dose radiotherapy. Patients were selected for re-irradiation in case of inoperable and/or unresectable tumours. In most cases, the target volume for re-irradiation was confined to the gross tumour volume (GTV). No elective radiotherapy was applied in the former high-dose area. A total dose of 46Gy was applied to elective areas with a boost up to 60Gy with conventional fractionation. The median follow-up period was 32 months. Results: The locoregional control rate after 2 years was 27%. The 3-year overall survival was 22%. The most frequently reported acute side-effect was acute mucositis resulting in swallowing complaints. Pharyngeal and oesophageal late morbidity was also the most important late side-effect. In general, acute and late radiation-induced morbidity remained within acceptable limits. Conclusions: In conclusion, primary re-irradiation appears to be feasible in terms of acute and late radiation-induced toxicity. To improve outcome in terms locoregional control and survival, future studies should be focussed on optimising radiation schedules and the addition of concomitant chemotherapy. [Copyright &y& Elsevier]

Purpose: To evaluate the results of primary radiotherapy (RT) for squamous cell carcinoma of the nasal vestibule.Methods and materials: A total of 56 patients with Stage T1 and T2 tumors (Wang classification) were treated with external beam RT (EBRT) with or without a boost using endocavitary brachytherapy. Of these, 32 were treated with EBRT and an additional boost with intermediate-dose-rate brachytherapy, 15 with EBRT and a boost with high-dose-rate brachytherapy, and 9 with EBRT alone.Results: The local control rate at 2 years was 80%. Most cases could be successfully salvaged with surgery, resulting in an ultimate local control rate of 95%. No statistically significant differences were noted among the different treatment approaches. Of the 56 patients, 12% developed lymph node metastases.Conclusion: Primary RT is an adequate treatment for Stage T1 and T2 squamous cell carcinoma of the nasal vestibule with excellent cosmetic results. The radiation technique used depends on the primary tumor extension and the experience of the treating radiation oncologist. In the case of N0 disease, elective treatment of the regional lymph nodes is not recommended. [Copyright &y& Elsevier]

Purpose: The aim of this study was to investigate changes in quality of life (QOL) among medically inoperable Stage I non-small-cell lung cancer (NSCLC) patients treated with curative radiotherapy.Patients and Methods: The study sample was composed of 46 patients irradiated for Stage I NSCLC. Quality of life was assessed before, during, and after radiotherapy using the European Organization for the Research and Treatment of Cancer QLQ-C30 and QLQ-LC13. Changes in symptom and QOL scores over time were evaluated with a repeated measurement analysis of variance using the mixed effect modeling procedure, SAS Proc Mixed. Twenty-seven patients were treated only at the primary site, whereas for 19 patients, the regional lymph nodes were included in the target volume as well.Results: The median follow-up time of patients alive was 34 months. The median survival was 19.0 months. None of the locally treated patients developed regional recurrence. A significant, gradual increase over time was observed for dyspnea, fatigue, and appetite loss. A significant, gradual deterioration was observed also for role functioning. No significant changes were noted for the other symptoms or the functioning scales. Significantly higher levels of dysphagia, which persisted up to 12 months, were observed in those in which the regional lymph nodes were treated, as compared to the locally treated patients. Radiation-induced pulmonary changes assessed with chest radiograph were more pronounced in the group treated with locoregional radiotherapy.Conclusions: After curative radiotherapy for Stage I medically inoperable NSCLC, a gradual increase in dyspnea, fatigue, and appetite loss, together with a significant deterioration of role functioning, was observed, possibly because of pre-existing, slowly progressive chronic obstructive pulmonary disease and radiation-induced pulmonary changes. Taking into account the low incidence of regional recurrences after local irradiation, the higher incidence and severity of radiation-induced changes, and the higher levels of dysphagia persisting up to 12 months, local irradiation of the primary tumor without elective irradiation of the regional lymph nodes may be the most appropriate treatment for patients with small, peripherally located tumors. [Copyright &y& Elsevier]

This study examined the association between the most important prognostic factors in non-small cell lung carcinoma (NSCLC) and self-reported pretreatment quality of life (QoL) and the impact of the presence, severity and changes in respiratory symptoms on general symptoms and QoL. The study included 262 patients. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-LC13 were used to assess symptoms and QoL before radiotherapy. Patients with inoperable NSCLC showed major differences in self-reported QoL as a function of clinical prognostic factors. A significant association was found between World Health Organization (WHO) performance status and QoL but not other prognostic factors. Dyspnoea was the only respiratory symptom associated significantly with general symptoms, physical and psychosocial functioning and QoL. Furthermore, changes in dyspnoea were associated significantly with changes in physical and role functioning, global QoL and fatigue as assessed 6 weeks after radiotherapy. These results indicate that palliation of dyspnoea may have a significant beneficial effect on QoL and that palliation of other respiratory symptoms is not necessarily associated with improvement of general symptoms, physical and psychological functioning or global QoL. [ABSTRACT FROM AUTHOR]

This study aimed to describe the local recurrence (LR) pattern in post-prostatectomy prostate cancer patients using PSMA PET/CT scans. We retrospectively collected 103 PSMA PET/CT scans from patients with suspected LR across nine medical centres. Anonymized scans underwent review by an expert nuclear medicine physician. After review, on 83 PSMA PET/CT scans, 93 lesions were identified as a LR. The predominant LR location (56%) was found within 2 cm cranial to the penile bulb. Additionally, 24 LR (26%) were observed > 2 cm cranial to the penile bulb and caudal to the top of the pubic bone. Only 17 LR (18%) occurred cranial to the symphysis pubis. These findings contribute to the understanding of LR pattern post-prostatectomy, potentially optimizing accurate salvage radiotherapy to the prostate bed. [ABSTRACT FROM AUTHOR]

Objectives: To identify associations between frailty and non-response to follow-up questionnaires, in a longitudinal head and neck cancer (HNC) study with patient-reported outcome measures (PROMs). Materials and methods: Patients referred with HNC were included in OncoLifeS, a prospective data-biobank, underwent Geriatric Assessment (GA) and frailty screening ahead of treatment, and were followed up at 3, 6, 12 and 24 months after treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Head and Neck 35. Statistical analysis for factors associated with non-response was done using Generalized Linear Mixed Models. Results: 289 patients were eligible for analysis. Mean age was 68.4 years and 68.5% were male. Restrictions in Activities of Daily Living [OR 4.46 (2.04–9.78)] and Instrumental Activities of Daily Living [OR 4.33 (2.27–8.24)], impaired mobility on Timed Up and Go test [OR 3.95 (1.85–8.45)], cognitive decline [OR 4.85 (2.28–10.35)] and assisted living (OR 5.54 (2.63–11.67)] were significantly associated with non-response. Frailty screening, with Geriatric 8 and Groningen Frailty Indicator, was also associated with non-response [OR, respectively, 2.64 (1.51–4.59) and 2.52 (1.44–4.44)]. All findings remained significant when adjusted for other factors that were significantly associated with non-response, such as higher age, longer study duration and subsequent death. Conclusion: Frail HNC patients respond significantly worse to follow-up PROMs. The drop-out and underrepresentation of frail patients in studies may lead to attrition bias, and as a result underestimating the effect sizes of associations. This is of importance when handling and interpreting such data. [ABSTRACT FROM AUTHOR]

• Limited data exist to guide the delineation for PORT of parotid and submandibular gland cancers. • Radiographic-anatomy, natural history of these cancers and their extension pathways are described. • Are included the risk of local tumor spread, perineural invasion risks and regional spread. Intensity-modulated radiotherapy has been widely used routinely in recent past years for post-operative radiotherapy of salivary gland cancers Because of the sharp dose fall off outside of target volumes with IMRT, each volume must be strictly and rigorously defined, as the areas not specifically included in the target volume will not be treated to a therapeutic dose. The selection and delineation of these volumes is complex and requires extensive knowledge of parotid and submandibular gland cancer radiographic-anatomy, natural history and extension pathways (including local tumor spread, PNI risks and regional spread), which are detailed in the present article. [ABSTRACT FROM AUTHOR]

The response of the major salivary glands, the parotid glands, to radiation dose is patient-specific. This study was designed to investigate whether parotid gland changes seen in weekly CT during treatment, quantified by delta-radiomics features (Δfeatures), could improve the prediction of moderate-to-severe xerostomia at 12 months after radiotherapy (Xer12m). Parotid gland Δfeatures were extracted from in total 68 planning and 340 weekly CTs, representing geometric, intensity and texture characteristics. Bootstrapped forward variable selection was performed to identify the best predictors of Xer12m. The predictive contribution of the resulting Δfeatures to a pre-treatment reference model, based on contralateral parotid gland mean dose and baseline xerostomia scores (Xerbaseline) only, was evaluated. Xer12m was reported by 26 (38%) of the 68 patients included. The most predictive Δfeature was the contralateral parotid gland surface change, which was significantly associated with Xer12m for all weeks (p < 0.04), but performed best for week 3 (ΔPG-surfacew3; p < 0.001). Moreover, ∆PG-surfacew3 showed a significant predictive contribution in addition to the pre-treatment reference model (likelihood-ratio test; p = 0.003), resulting in a significantly better model performance (AUCtrain = 0.92; AUCtest = 0.93) compared to that of the pre-treatment model (AUCtrain = 0.82; AUCtest = 0.82). These results suggest that mid-treatment parotid gland changes substantially improve the prediction of late radiation-induced xerostomia. [ABSTRACT FROM AUTHOR]

Simple Summary: While the dosimetric advantages of proton therapy over conventional treatment for CSI are typically emphasized for spine fields, only lens dose reduction has been reported for brain fields. In this retrospective in silico planning study, the aim is to assess the potential gains of proton CSI for organs at risk in the whole-brain part of CSI. Different optimization techniques and beam arrangements as well as pencil beam spot editing were employed to determine the potential gains. The study shows that: (1) cochlear sparing is impractical, (2) improving the lens dose is possible mainly by adding a posterior field direction, and (3) an incremental scalp dose reduction is possible, particularly in adult patients. Proton therapy is a promising modality for craniospinal irradiation (CSI), offering dosimetric advantages over conventional treatments. While significant attention has been paid to spine fields, for the brain fields, only dose reduction to the lens of the eye has been reported. Hence, the objective of this study is to assess the potential gains and feasibility of adopting different treatment planning techniques for the entire brain within the CSI target. To this end, eight previously treated CSI patients underwent retrospective replanning using various techniques: (1) intensity modulated proton therapy (IMPT) optimization, (2) the modification/addition of field directions, and (3) the pre-optimization removal of superficially placed spots. The target coverage robustness was evaluated and dose comparisons for lenses, cochleae, and scalp were conducted, considering potential biological dose increases. The target coverage robustness was maintained across all plans, with minor reductions when superficial spot removal was utilized. Single- and multifield optimization showed comparable target coverage robustness and organ-at-risk sparing. A significant scalp sparing was achieved in adults but only limited in pediatric cases. Superficial spot removal contributed to scalp V30 Gy reduction at the expense of lower coverage robustness in specific cases. Lens sparing benefits from multiple field directions, while cochlear sparing remains impractical. Based on the results, all investigated plan types are deemed clinically adoptable. [ABSTRACT FROM AUTHOR]

Purpose: To identify trends in incidence and survival of NPC, subdivided by EBV status and histopathological subtype, over a 30-year period in the Netherlands. Methods: Anonymized data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Databank (PALGA) for the period 1989–2018 were linked to identify and classify NPC cases. Results: Incidence of NPC remained stable, with an annual percentage change (APC) of − 0.2. (95% CI − 0.9; 0.5). EBV testing became routine only in the last decade, the incidence of EBV-positive tumors remained stable over this period (APC 1.2, 95% CI − 1.3; 3.8). An increase in EBV-negative tumors (APC: 7.1, 95% CI 2.5; 11.9) and a decrease in untested tumors were found (APC: − 10.7, 95% CI − 15.7; − 5.7). The incidence of non-keratinizing, differentiated tumors increased (APC: 3.8, (95% CI 2.2; 5.5) while the incidence of other histological subtypes remained stable. Overall survival was better in patients diagnosed after 1998 (hazard ratio 0.8, 95% CI 0.6; 0.9). EBV status, histology, stage, and age were independently associated with relative excess risk of dying, but period of diagnosis was not. Conclusion: Testing for EBV increased over time, and a stable incidence of EBV-positive NPC over the last 10 years. The rising incidence of non-keratinizing, differentiated NPC mirrors data from the US and suggests a shift in non-endemic regions. [ABSTRACT FROM AUTHOR]

Purpose: Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC).Methods and Materials: Forty patients with EC treated with a transthoracic esophagectomy with (n = 20) or without (n = 20) nCRT (CROSS study regimen) were included. Cardiovascular magnetic resonance imaging (1.5 Tesla) for left ventricular (LV) function, late gadolinium enhancement, and T1 mapping were performed. Extracellular volume (ECV), as a surrogate for collagen burden, was measured for all LV segments separately. The dose-response relationship between ECV and mean radiation dose per LV myocardial segment was evaluated using a mixed-model analysis.Results: Seventeen nCRT and 16 control patients were suitable for analysis. The mean time after treatment was 67.6 ± 8.1 (nCRT) and 122 ± 35 (controls) months (P = .02). In nCRT patients, we found a significantly higher mean global ECV of 28.2% compared with 24.0% in the controls (P < .001). After nCRT, LV myocardial segments with elevated ECV had received significantly higher radiation doses. In addition, a linear dose-effect relation was found with a 0.136% point increase of ECV for each Gy (P < .001). There were no differences in LV function measures and late gadolinium enhancement between both groups.Conclusions: Myocardial ECV was significantly higher in long-term EC survivors after nCRT compared with surgery only. Moreover, this ECV increase was linear with the radiation dose per LV segment, indicating radiation-induced myocardial fibrosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate utilization of mental healthcare among head and neck cancer (HNC) patients from diagnosis to 2 years after treatment, in relation to psychological symptoms, mental disorders, need for mental healthcare, and sociodemographic, clinical and personal factors. Methods: Netherlands Quality of life and Biomedical Cohort study data as measured before treatment, at 3 and 6 months, and at 1 and 2 years after treatment was used (n = 610). Data on mental healthcare utilization (iMCQ), psychological symptoms (Hospital Anxiety and Depression Scale, Cancer Worry Scale), mental disorders (CIDI interview), need for mental healthcare (Supportive Care Needs Survey Short‐Form 34, either as continuous outcome indicating the level of need or dichotomized into unmet need (yes/no)) and several sociodemographic, clinical and personal factors were collected. Factors associated with mental healthcare utilization were investigated using generalized estimating equations (p < 0.05). Results: Of all HNC patients, 5%–9% used mental healthcare per timepoint. This was 4%–14% in patients with mild‐severe psychological symptoms, 4%–17% in patients with severe psychological symptoms, 15%–35% in patients with a mental disorder and 5%–16% in patients with an unmet need for mental healthcare. Among all patients, higher symptoms of anxiety, a higher need for mental healthcare, lower age, higher disease stage, lower self‐efficacy and higher social support seeking were significantly associated with mental healthcare utilization. Conclusion: Mental health care utilization among HNC patients is limited, and is related to psychological symptoms, need for mental healthcare, and sociodemographic, clinical and personal factors. [ABSTRACT FROM AUTHOR]

Background: Adaptive proton therapy workflows rely on accurate imaging throughout the treatment course. Our centre currently utilizes weekly repeat CTs (rCTs) for treatment monitoring and plan adaptations. However, deep learning‐based methods have recently shown to successfully correct CBCT images, which suffer from severe imaging artifacts, and generate high quality synthetic CT (sCT) images which enable CBCT‐based proton dose calculations. Purpose: To compare daily CBCT‐based sCT images to planning CTs (pCT) and rCTs of head and neck (HN) cancer patients to investigate the dosimetric accuracy of CBCT‐based sCTs in a scenario mimicking actual clinical practice. Methods: Data of 56 HN cancer patients, previously treated with proton therapy was used to generate 1.962 sCT images, using a previously developed and trained deep convolutional neural network. Clinical IMPT treatment plans were recalculated on the pCT, weekly rCTs and daily sCTs. The dosimetric accuracy of sCTs was compared to same day rCTs and the initial planning CT. As a reference, rCTs were also compared to pCTs. The dose difference between sCTs and rCTs/pCT was quantified by calculating the D98 difference for target volumes and Dmean difference for organs‐at‐risk. To investigate the clinical relevancy of possible dose differences, NTCP values were calculated for dysphagia and xerostomia. Results: For target volumes, only minor dose differences were found for sCT versus rCT and sCT versus pCT, with dose differences mostly within ±1.5%. Larger dose differences were observed in OARs, where a general shift towards positive differences was found, with the largest difference in the left parotid gland. Delta NTCP values for grade 2 dysphagia and xerostomia were within ±2.5% for 90% of the sCTs. Conclusions: Target doses showed high similarity between rCTs and sCTs. Further investigations are required to identify the origin of the dose differences at OAR levels and its relevance in clinical decision making. [ABSTRACT FROM AUTHOR]

Objectives Materials and Methods Results Conclusion We assessed the radiation dosages (Dmean) on implant regions to identify the threshold for implant loss in patients with an intraoral malignancy treated with dental implants to support a mandibular denture during ablative surgery before volumetric‐modulated arc therapy (VMAT).Data was collected prospectively from 28 patients treated surgically for an intraoral malignancy, followed by postoperative radiotherapy (VMAT) and analyzed retrospectively. Patients received 2 implants in the native mandible during ablative surgery. Implant‐specific Dmean values were retrieved from the patients' files. Radiographic bone loss was measured 1 year after implant placement and during the last follow‐up appointment. Implant survival was analyzed with the Kaplan–Meier method. Univariate logistic regression and Cox‐regression analyses were performed to investigate the effect of increasing implant‐specific radiation dosages on implant loss.Five out of 56 placed implants were lost during follow‐up (median 36.0 months, IQR 39.0). Radiographically, peri‐implant bone loss occurred in implants with a Dmean > 40 Gy. Implant loss occurred only in implants with a Dmean > 50 Gy.An implant‐specific Dmean higher than 50 Gy is related to more peri‐implant bone loss and, eventually, implant loss. [ABSTRACT FROM AUTHOR]

Despite improvements to treatment, patients with head and neck cancer (HNC) still experience radiation-induced xerostomia due to salivary gland damage. The stem cells of the parotid gland (PG), concentrated in the gland's main ducts (stem cell rich [SCR] region), play a critical role in the PG's response to radiation. Treatment optimization requires a dose metric that properly accounts for the relative contributions of dose to this SCR region and the PG's remainder (non-SCR region) to the risk of xerostomia in normal tissue complication probability (NTCP) models for xerostomia. Treatment and toxicity data of 1013 prospectively followed patients with HNC treated with definitive radiation therapy (RT) were used. The regeneration-weighted dose, enabling accounting for the hypothesized different effects of dose to the SCR and non-SCR region on the risk of xerostomia, was defined as D reg PG = D mean SCR region + r × D mean non-SCR region, where D reg is the regeneration-weighted dose, D mean is the mean dose, and r is the weighting factor. Considering the different volumes of these regions, r > 3.6 in D reg PG demonstrates an enhanced effect of the SCR region. The most predictive value of r was estimated in 102 patients of a previously published trial testing stem cell sparing RT. For each endpoint, D reg PG, dose to other organs, and clinical factors were used to develop NTCP models using multivariable logistic regression analysis in 663 patients. The models were validated in 350 patients. Dose to the contralateral PG was associated with daytime, eating-related, and physician-rated grade ≥2 xerostomia. Consequently, r was estimated and found to be smaller than 3.6 for most PG function–related endpoints. Therefore, the contribution of D mean SCR region to the risk of xerostomia was larger than predicted by D mean PG. Other frequently selected predictors were pretreatment xerostomia and D mean oral cavity. The validation showed good discrimination and calibration. Tools for clinical implementation of stem cell sparing RT were developed: regeneration-weighted dose to the parotid gland that accounted for regional differences in radiosensitivity within the gland and NTCP models that included this new dose metric and other prognostic factors. [ABSTRACT FROM AUTHOR]

Background: Personalized treatment is increasingly required for oropharyngeal squamous cell carcinoma (OPSCC) patients due to emerging new cancer subtypes and treatment options. Outcome prediction model can help identify low or high‐risk patients who may be suitable to receive de‐escalation or intensified treatment approaches. Purpose: To develop a deep learning (DL)‐based model for predicting multiple and associated efficacy endpoints in OPSCC patients based on computed tomography (CT). Methods: Two patient cohorts were used in this study: a development cohort consisting of 524 OPSCC patients (70% for training and 30% for independent testing) and an external test cohort of 396 patients. Pre‐treatment CT‐scans with the gross primary tumor volume contours (GTVt) and clinical parameters were available to predict endpoints, including 2‐year local control (LC), regional control (RC), locoregional control (LRC), distant metastasis‐free survival (DMFS), disease‐specific survival (DSS), overall survival (OS), and disease‐free survival (DFS). We proposed DL outcome prediction models with the multi‐label learning (MLL) strategy that integrates the associations of different endpoints based on clinical factors and CT‐scans. Results: The multi‐label learning models outperformed the models that were developed based on a single endpoint for all endpoints especially with high AUCs ≥ 0.80 for 2‐year RC, DMFS, DSS, OS, and DFS in the internal independent test set and for all endpoints except 2‐year LRC in the external test set. Furthermore, with the models developed, patients could be stratified into high and low‐risk groups that were significantly different for all endpoints in the internal test set and for all endpoints except DMFS in the external test set. Conclusion: MLL models demonstrated better discriminative ability for all 2‐year efficacy endpoints than single outcome models in the internal test and for all endpoints except LRC in the external set. [ABSTRACT FROM AUTHOR]

Simple Summary: Many head and neck cancer patients report sexual problems. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. This effect seems to differ between men and women. Men reported change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction, while women reported change in desire, arousal, and orgasm. These findings are helpful to improve information on sexuality and sexual care in head and neck cancer patients. The aim of this study was to investigate changes in sexuality and sexual dysfunction in head and neck cancer (HNC) patients in the first two years after treatment, in relation to the type of treatment. Data were used of 588 HNC patients participating in the prospective NETherlands Quality of life and Biomedical Cohort Study (NET-QUBIC) from diagnosis to 3, 6, 12 and 24 months after treatment. Primary outcome measures were the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). The total scores of the IIEF and FSFI were dichotomized into sexual (dys)function. In men, type of treatment was significantly associated with change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction. In women, type of treatment was significantly associated with change in desire, arousal, and orgasm. There were significant differences between treatment groups in change in dysfunctional sexuality. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. Changes in sexuality and sexual dysfunction in HNC patients were related to treatment, with an acute negative effect of chemoradiation. This effect on the various domains of sexuality seems to differ between men and women. [ABSTRACT FROM AUTHOR]

Background: Proton arcs have shown potential to reduce the dose to organs at risks (OARs) by delivering the protons from many different directions. While most previous studies have been focused on dynamic arcs (delivery during rotation), an alternative approach is discrete arcs, where step‐and‐shoot delivery is used over a large number of beam directions. The major advantage of discrete arcs is that they can be delivered at existing proton facilities. However, this advantage comes at the expense of longer treatment times. Purpose: To exploit the dosimetric advantages of proton arcs, while achieving reasonable delivery times, we propose a partitioning approach where discrete arc plans are split into subplans to be delivered over different fractions in the treatment course. Methods: For three oropharyngeal cancer patients, four different arc plans have been created and compared to the corresponding clinical IMPT plan. The treatment plans are all planned to be delivered in 35 fractions, but with different delivery approaches over the fractions. The first arc plan (1×30) has 30 directions to be delivered every fraction, while the others are partitioned into subplans with 10 and 6 beam directions, each to be delivered every third (3×10), fifth fraction (5×6), or seventh fraction (7×10). All plans are assessed with respect to delivery time, target robustness over the treatment course, doses to OARs and NTCP for dysphagia and xerostomia. Results: The delivery time (including an additional delay of 30 s between the discrete directions to simulate manual interaction with the treatment control system) is reduced from on average 25.2 min for the 1×30 plan to 9.2 min for the 3×10 and 7×10 plans and 5.7 min for the 5×6 plans. The delivery time for the IMPT plan is 7.9 min. When accounting for the combination of delivery time, target robustness, OAR sparing, and NTCP reduction, the plans with 10 directions in each fraction are the preferred choice. Both the 3×10 and 7×10 plans show improved target robustness compared to the 1×30 plans, while keeping OAR doses and NTCP values at almost as low levels as for the 1×30 plans. For all patients the NTCP values for dysphagia are lower for the partitioned plans with 10 directions compared to the IMPT plans. NTCP reduction for xerostomia compared to IMPT is seen in two of the three patients. The best results are seen for the first patient, where the NTCP reductions for the 7×10 plan are 1.6 p.p. (grade 2 xerostomia) and 1.5 p.p. (grade 2 dysphagia). The corresponding NTCP reductions for the 1×30 plan are 2.7 p.p. (xerostomia, grade 2) and 2.0 p.p. (dysphagia, grade 2). Conclusions: Discrete proton arcs can be implemented at any proton facility with reasonable treatment times using a partitioning approach. The technique also makes the proton arc treatments more robust to changes in the patient anatomy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this prospective cohort study was to estimate the relationship between the course of HRQOL in the first 2 years after diagnosis and treatment of head and neck cancer (HNC) and personal, clinical, psychological, physical, social, lifestyle, HNC-related, and biological factors. Methods: Data were used from 638 HNC patients of the NETherlands QUality of life and BIomedical Cohort study (NET-QUBIC). Linear mixed models were used to investigate factors associated with the course of HRQOL (EORTC QLQ-C30 global quality of life (QL) and summary score (SumSc)) from baseline to 3, 6, 12, and 24 months after treatment. Results: Baseline depressive symptoms, social contacts, and oral pain were significantly associated with the course of QL from baseline to 24 months. Tumor subsite and baseline social eating, stress (hyperarousal), coughing, feeling ill, and IL-10 were associated with the course of SumSc. Post-treatment social contacts and stress (avoidance) were significantly associated with the course of QL from 6 to 24 months, and social contacts and weight loss with the course of SumSc. The course of SumSc from 6 to 24 months was also significantly associated with a change in financial problems, speech problems, weight loss, and shoulder problems between baseline and 6 months. Conclusion: Baseline clinical, psychological, social, lifestyle, HNC-related, and biological factors are associated with the course of HRQOL from baseline to 24 months after treatment. Post-treatment social, lifestyle, and HNC-related factors are associated with the course of HRQOL from 6 to 24 months after treatment. [ABSTRACT FROM AUTHOR]

Purpose: Treatment decision-making in advanced-stage laryngeal squamous cell carcinoma (LSCC) is difficult due to the high recurrence rates and the desire to preserve laryngeal functions. New predictive markers for radiosensitivity are needed to facilitate treatment choices. In early stage glottic LSCC treated with primary radiotherapy, expression of hypoxia (HIF-1α and CA-IX) and proliferation (Ki-67) tumour markers showed prognostic value for local control. The objective of this study is to examine the prognostic value of tumour markers for hypoxia and proliferation on locoregional recurrent disease and disease-specific mortality in a well-defined cohort of patients with locally advanced LSCC treated with primary, curatively intended radiotherapy. Methods: In pre-treatment biopsy tissues from a homogeneous cohort of 61 patients with advanced stage (T3–T4, M0) LSCC primarily treated with radiotherapy, expression of HIF-1α, CA-IX and Ki-67 was evaluated with immunohistochemistry. Demographic data (age and sex) and clinical data (T- and N-status) were retrospectively collected from the medical records. Cox regression analysis was performed to assess the relation between marker expression, demographic and clinical data, and locoregional recurrence and disease-specific mortality. Results: Patients with high expression of HIF-1α developed significantly more often a locoregional recurrence (39%) compared to patients with a low expression (21%) (p = 0.002). The expression of CA-IX and Ki-67 showed no association with locoregional recurrent disease. HIF-1α, CA-IX and Ki-67 were not significantly related to disease-specific mortality. Clinical N-status was an independent predictor of recurrent disease (p < 0.001) and disease-specific mortality (p = 0.003). Age, sex and T-status were not related to locoregional recurrent disease or disease-specific mortality. Conclusion: HIF-1α overexpression and the presence of regional lymph node metastases at diagnosis were independent predictors of locoregional recurrent disease after primary treatment with curatively intended radiotherapy in patients with locally advanced LSCC. [ABSTRACT FROM AUTHOR]

Purpose: Medical imaging has become increasingly important in diagnosing and treating oncological patients, particularly in radiotherapy. Recent advances in synthetic computed tomography (sCT) generation have increased interest in public challenges to provide data and evaluation metrics for comparing different approaches openly. This paper describes a dataset of brain and pelvis computed tomography (CT) images with rigidly registered cone‐beam CT (CBCT) and magnetic resonance imaging (MRI) images to facilitate the development and evaluation of sCT generation for radiotherapy planning. Acquisition and Validation Methods: The dataset consists of CT, CBCT, and MRI of 540 brains and 540 pelvic radiotherapy patients from three Dutch university medical centers. Subjects' ages ranged from 3 to 93 years, with a mean age of 60. Various scanner models and acquisition settings were used across patients from the three data‐providing centers. Details are available in a comma separated value files provided with the datasets. Data Format and Usage Notes: The data is available on Zenodo (https://doi.org/10.5281/zenodo.7260704, https://doi.org/10.5281/zenodo.7868168) under the SynthRAD2023 collection. The images for each subject are available in nifti format. Potential Applications: This dataset will enable the evaluation and development of image synthesis algorithms for radiotherapy purposes on a realistic multi‐center dataset with varying acquisition protocols. Synthetic CT generation has numerous applications in radiation therapy, including diagnosis, treatment planning, treatment monitoring, and surgical planning. [ABSTRACT FROM AUTHOR]

Purpose Respiratory impacts in pencil beam scanned proton therapy (PBS-PT) are accounted by extensive 4D dose calculations, where deformable image registration (DIR) is necessary for estimating deformation vector fields (DVFs). We aim here to evaluate the dosimetric errors induced by different DIR algorithms in their resulting 4D dose calculations by using ground truth(GT)-DVFs from 4DMRI. Materials and methods Six DIR methods: ANACONDA, Morfeus, B-splines, Demons, CT Deformable, and Total Variation, were respectively applied to nine 4DCT-MRI liver data sets. The derived DVFs were then used as input for 4D dose calculation. The DIR induced dosimetric error was assessed by individually comparing the resultant 4D dose distributions to those obtained with GT-DVFs. Both single-/three-field plans and single/rescanned strategies were investigated. Results Differences in 4D dose distributions among different DIR algorithms, and compared to the results using GT-DVFs, were pronounced. Up to 40 % of clinically relevant dose calculation points showed dose differences of 10 % or more between the GT. Differences in V 95 (CTV) reached up to 11.34 ± 12.57 %. The dosimetric errors became in general less substantial when applying multiple-field plans or using rescanning. Conclusion Intrinsic geometric errors by DIR can influence the clinical evaluation of liver 4D PBS-PT plans. We recommend the use of an error bar for correctly interpreting individual 4D dose distributions. [ABSTRACT FROM AUTHOR]

Abstract Background Tube feeding dependence is a commonly observed debilitating side-effect of curative (chemo-) radiation in head and neck cancer patients that severely affects quality of life. Prevention of this side-effect can be obtained using advanced radiation techniques, such as IMRT. For radiotherapy treatment plan optimization, it has become increasingly important to develop prediction models that enable clinicians to predict the risk of tube feeding dependence for individual patients. To develop such a tool, information regarding the most relevant prognostic factors for tube feeding dependence is necessary. Objectives The primary aim of this systematic review, conducted according to PRISMA guidelines, was to identify prognostic factors that are consistently found to be associated with tube feeding dependence at ≥6 months after treatment. The secondary aim was to identify prognostic factors found to be associated with tube feeding placement and use at <6 months. Data sources Articles were identified through a search in MEDLINE, EMBASE and the Cochrane Library. Approximately 2600 articles were screened and selected by inclusion and exclusion criteria. Results Fourteen retrospective studies were identified that fulfilled the inclusion criteria and reported on prognostic factors for tube feeding dependence at ≥6 months. The studies reported on patient and disease variables, treatment variables and DVH parameters. Two of these studies reported on a model for tube feeding dependence, one including DVH parameters. Additionally, 18 studies were identified that reported on prognostic factors for tube feeding placement and use at <6 months. Conclusions Prognostic factors that were consistently associated with the risk of tube feeding dependence at ≥6 months for head and neck cancer patients treated with (chemo-) radiotherapy were DVH parameters, including dose to the larynx, the pharyngeal constrictor muscle inferior and superior, and the dose to the contralateral parotid gland. Furthermore, advanced tumor and nodal stage, pretreatment weight loss, (concomitant) chemotherapy and prophylactic gastrostomy policy were prognostic for tube feeding dependence ≥6 months. For tube feeding use at less than 6 months, prognostic DVH parameters included dose and volume to the oral mucosa, dose to the contralateral submandibular gland, and also dose to the larynx and the pharyngeal constrictor muscle inferior and superior. Prognostic patients/disease and treatment factors for tube feeding placement and use at less than 6 months were similar to the prognostic factors for tube feeding dependence at ≥6 months, but also included several unique variables such as the use of narcotics prior to treatment and living alone at the time of treatment. [ABSTRACT FROM AUTHOR]

• By considering clinical variables and image features from pre-treatment CT-scans, a hybrid deep learning-based model was implemented for overall survival prediction at two years in stage I-IIIA NSCLC patients. • The proposed model achieved reasonable performance on different patient groups. • The developed hybrid model has the potential to identify patients with high mortality risk and guide clinical decision making. The aim of this study was to develop and evaluate a prediction model for 2-year overall survival (OS) in stage I-IIIA non-small cell lung cancer (NSCLC) patients who received definitive radiotherapy by considering clinical variables and image features from pre-treatment CT-scans. NSCLC patients who received stereotactic radiotherapy were prospectively collected at the UMCG and split into a training and a hold out test set including 189 and 81 patients, respectively. External validation was performed on 228 NSCLC patients who were treated with radiation or concurrent chemoradiation at the Maastro clinic (Lung1 dataset). A hybrid model that integrated both image and clinical features was implemented using deep learning. Image features were learned from cubic patches containing lung tumours extracted from pre-treatment CT scans. Relevant clinical variables were selected by univariable and multivariable analyses. Multivariable analysis showed that age and clinical stage were significant prognostic clinical factors for 2-year OS. Using these two clinical variables in combination with image features from pre-treatment CT scans, the hybrid model achieved a median AUC of 0.76 [95 % CI: 0.65–0.86] and 0.64 [95 % CI: 0.58–0.70] on the complete UMCG and Maastro test sets, respectively. The Kaplan-Meier survival curves showed significant separation between low and high mortality risk groups on these two test sets (log-rank test: p-value < 0.001, p-value = 0.012, respectively) We demonstrated that a hybrid model could achieve reasonable performance by utilizing both clinical and image features for 2-year OS prediction. Such a model has the potential to identify patients with high mortality risk and guide clinical decision making. [ABSTRACT FROM AUTHOR]

Purpose: The phase III 22071-26071 trial was designed to evaluate the addition of panitumumab to adjuvant chemotherapy plus intensity modulated radiotherapy (IMRT) in locally advanced resected squamous cell head and neck cancer. We report the results of the dummy run (DR) performed to detect deviations from protocol guidelines.Methods and Materials: DR datasets consisting of target volumes, organs at risk (OAR) and treatment plans were digitally uploaded, then compared with reference contours and protocol guidelines by six central reviewers. Summary statistics and analyses of potential correlations between delineations and plan characteristics were performed.Results: Of 23 datasets, 20 (87.0%) GTVs were evaluated as acceptable/borderline, along with 13 (56.5%) CTVs and 10 (43.5%) PTVs. All PTV dose requirements were met by 73.9% of cases. Dose constraints were met for 65.2-100% of mandatory OARs. Statistically significant correlations were observed between the subjective acceptability of contours and the ability to meet dose constraints for all OARs (p ≤ 0.01) except for the parotids and spinal cord. Ipsilateral parotid doses correlated significantly with CTV and PTV volumes (p ≤ 0.05).Conclusions: The observed wide variations in treatment planning, despite strict guidelines, confirms the complexity of development and quality assurance of IMRT-based multicentre studies for head and neck cancer. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate an automated treatment planning method for robustly optimized intensity modulated proton therapy (IMPT) plans for oropharyngeal carcinoma patients and to compare the results with manually optimized robust IMPT plans. An atlas regression forest-based machine learning (ML) model for dose prediction was trained on CT scans, contours, and dose distributions of robust IMPT plans of 88 oropharyngeal cancer (OPC) patients. The ML model was combined with a robust voxel and dose volume histogram-based dose mimicking optimization algorithm for 21 perturbed scenarios to generate a machine-deliverable plan from the predicted dose distribution. Machine learning optimization (MLO) configuration was performed using a cross-validation approach with 3 × 8 tuning patients and comprised of adjustments to the mimicking optimization, to generate higher-quality MLO plans. Independent testing of the MLO algorithm was performed with another 25 patients. Plan quality of clinical and MLO plans was evaluated by the clinical target volume (D98% voxel-wise minimum dose >94%), organ at risk (OAR) doses, and the normal tissue complication probability (NTCP) (sum (Σ) of grade-2 and grade-3 dysphagia and xerostomia). Adequate robust target coverage was achieved in 24/25 clinical plans and in 23/25 MLO plans in the primary clinical target volume (CTV). In the elective CTV, 22/25 clinical plans and 24/25 MLO plans passed the robust target coverage evaluation threshold. The MLO average Σgrade 2 and Σgrade 3 NTCPs were comparable to the clinical plans (Σgrade 2 NTCPs: clinical 47.5% vs MLO 48.4%, Σgrade 3 NTCPs: clinical 11.9% vs MLO 12.3%). Significant increases in OAR average doses in MLO plans were found in the pharynx constrictor muscles (163 cGy, P =.002) and cervical esophagus (265 cGy, P =.002). The MLO plans were created within 45 minutes. This study showed that automated MLO planning can generate robustly optimized MLO plans with quality comparable to clinical plans in OPC patients. [ABSTRACT FROM AUTHOR]

Background: Proton radiography (PR) uses highly energetic proton beams to create images where energy loss is the main contrast mechanism. Waterequivalent path length (WEPL) measurements using flat panel PR (FP-PR) have potential for in vivo range verification. However, an accurate WEPL measurement via FP-PR requires irradiation with multiple energy layers, imposing high imaging doses. Purpose: A FP-PR method is proposed for accurate WEPL determination based on a patient-specific imaging field with a reduced number of energies (n) to minimize imaging dose. Methods: Patient-specific FP-PRs were simulated and measured for a head and neck (HN) phantom.An energy selection algorithm estimated spot-wise the lowest energy required to cross the anatomy (Emin) using a water-equivalent thickness map.Starting from Emin, n was restricted to certain values (n = 26, 24, 22, …, 2 for simulations, n = 10 for measurements), resulting in patient-specific FP-PRs. A reference FP-PR with a complete set of energies was compared against patient-specific FP-PRs covering the whole anatomy via mean absolute WEPL differences (MAD), to evaluate the impact of the developed algorithm. WEPL accuracy of patient-specific FP-PRs was assessed using mean relative WEPL errors (MRE) with respect to measured multi-layer ionization chamber PRs (MLIC-PR) in the base of skull, brain, and neck regions. Results: MADs ranged from 2.1 mm (n = 26) to 21.0 mm (n = 2) for simulated FP-PRs, and 7.2 mm for measured FP-PRs (n = 10). WEPL differences below 1 mm were observed across the whole anatomy,except at the phantom surfaces. Measured patient-specific FP-PRs showed good agreement against MLIC-PRs, with MREs of 1.3 ± 2.0%, −0.1 ± 1.0%, and −0.1 ± 0.4% in the three regions of the phantom. Conclusion: A method to obtain accurate WEPL measurements using FP-PR with a reduced number of energies selected for the individual patient anatomy was established in silico and validated experimentally. Patient-specific FP-PRs could provide means of in vivo range verification. [ABSTRACT FROM AUTHOR]