Considerations for study design in the DAHANCA 35 trial of protons versus photons for head and neck cancer.

Proton radiotherapy offers a dosimetric advantage compared to photon therapy in sparing normal tissue, but the clinical evidence for toxicity reductions in the treatment of head and neck cancer is limited. The Danish Head and Neck Cancer Group (DAHANCA) has initiated the DAHANCA 35 randomised trial to clarify the value of proton therapy (NCT04607694). The DAHANCA 35 trial is performed in an enriched population of patients selected by an anticipated benefit of proton therapy to reduce the risk of late dysphagia or xerostomia based on normal tissue complication probability (NTCP) modelling. We present our considerations on the trial design and a test of the selection procedure conducted before initiating the randomised study.

Dose and robustness comparison of nominal, daily and accumulated doses for photon and proton treatment of sinonasal cancer.

INTRODUCTION: The aim was to evaluate and compare the dosimetric effect and robustness towards day-to-day anatomical and setup variations in the delivered dose for photon and proton treatments of sinonasal cancer (SNC) patients. MATERIALS AND METHODS: Photon (VMAT) and proton (IMPT) plans were optimized retrospectively for 24 SNC patients. Synthetic CTs (synCT) were obtained by deforming the planning CT (pCT) to the anatomy of every daily cone-beam CT. Both VMAT and IMPT plans were recalculated on the synCTs. The recalculated daily dose was accumulated over the whole treatment on the pCT. Target coverage and dose to organs and risk (OARs) were evaluated for all patients for the nominal, daily and accumulated dose distribution. RESULTS: In general, dose to OARs farther away from the target, including brain, chiasm and contralateral optic nerve, was lower for proton plans than photon plans. Whereas, OARs in proximity of the target received a lower dose for photon plans. For proton plans, the target coverage (volume of CTV receiving 95% of prescribed dose), V95%, fell below 99% for 9/24 patients in one or more fractions. For photon plans, 4/24 patients had one or more fractions where V95% fell below 99%. For accumulated doses, V95% was below 99% only in two cases, but above 98% for all patients. CONCLUSION: Photon and proton treatment have different strengths regarding OAR sparing. The robustness was high for both treatment modalities. Patient selection for either proton or photon radiation therapy of SNC patients should be based on a case-by-case comparison.

A comparison of two methods for segmentation of functional volumes in radiotherapy planning of lung cancer patients.

BACKGROUND: In radiotherapy (RT) of lung cancer, dose to functional lung (FL) volumes segmented with two different methods (perfusion SPECT (Q-SPECT) and 4D-CT (4D) ventilation (V)) have been shown to correlate with the incidence of radiation pneumonitis (RP). This study aims to compare the FL volumes identified by both methods. MATERIAL AND METHODS: Thirty lung cancer patients had a 4D and Q-SPECT prior to treatment. Seventeen of these patients also had a ventilation SPECT (V-SPECT). FL sub-volumes were segmented automatically, using cut-off values. The volumes were compared in terms of overlap fraction (OF) relative to the minimal volume, and intersection fraction (IF) of the FL volume relative to the total lung volume (VLung). RESULTS: Cut-off values suggested in literature for Q-SPECT and 4D-V resulted in volumes differing in size by a median 18% [6%;31%], and a median OF and IF of 0.48 [0.23;0.70] and 0.09 [0.02;0.25], respectively. Segmenting volumes of comparable size of about 1/3 of VLung (FL-m(1/3), m = method) resulted in a median OF and IF of 0.43 [0.23;0.58] and 0.12 [0.06;0.19], respectively. Twenty-five patients (83%) had a reasonable overlap between FL-Q(1/3) and FL-4D-V(1/3) volumes, with OF values above 0.33. IF increased significantly (p = .036) compared to using fixed cut-off values. Similarly, volumes of comparable size of about 1/3 VLung were produced for V-SPECT, and FL-Q(1/3), FL-V(1/3), and FL-4D-V(1/3) were compared. The overlaps and intersections of FL-V(1/3) with FL-Q(1/3) volumes were significantly (p<.001) larger than the corresponding overlaps and intersections of FL-Q(1/3) with FL-4D(1/3) and FL-V(1/3) with FL-4D(1/3). CONCLUSION: The Q-SPECT and 4D-V methods do not segment entirely the same FL volumes. A reasonable overlap of the volumes along with the findings of other studies that both correlate to RP incidence, suggests that a combination of both volumes, e.g. using the IF, may be useful in RT treatment planning.

Air variability in maxillary sinus during radiotherapy for sinonasal carcinoma.

INTRODUCTION: The aim was to characterise patterns and predictability of aeration changes in the ipsilateral maxillary sinus during intensity-modulated radiotherapy (IMRT) for sinonasal cancer (SNC), and in a sample evaluate the dosimetric effects of aeration changes for both photon and proton therapy. MATERIALS AND METHODS: The study included patients treated with IMRT for SNC in a single institution in 2009-2017. The volume of air in the ipsilateral maxillary sinus was recorded in 1578 daily cone beam computer tomography (CBCT) from 53 patients. Patterns of changing air volumes were categorised as 'stable', increasing', 'decreasing', or 'erratic'. For the prediction analysis, categorisation was performed based both on the entire treatment course and the first five fractions (F1-5). Photon and proton therapy plans were generated for four patients, the one from each category with the largest aeration variation. Synthetic CT images were generated for each CBCT and all plans were recalculated on the daily synthetic CTs. RESULTS: The absolute volume of air varied considerably during the treatment course, ranging from 0 to 25.9 cm3. Changes within a single participant varied in the range of 0-18.7 cm3. In the categorisation of patterns, most patients had increasing aeration of the sinus. Generally, patterns of aeration could not be predicted from F1-5. Patients categorised as increasing in F1-5 had the best prediction, with 78% predicted correctly as increasing for the entire treatment course. The numeric correlation coefficients for target coverage and air volume were low for 3/4 scenarios (photons 0.03-0.23, protons 0.26-0.48). No straightforward correlation between the dosimetric effect and the volume changes could be detected in the sample test of four patients for neither photon nor proton therapy. CONCLUSION: The variation of aeration was large and unpredictable. No clear dosimetric consequences of the aeration variation were evident for neither IMRT nor proton therapy for the patients investigated.

Beam characterization and feasibility study for a small animal irradiation platform at clinical proton therapy facilities.

A deeper understanding of biological mechanisms to promote more efficient treatment strategies in proton therapy demands advances in preclinical radiation research. However this is often limited by insufficient availability of adequate infrastructures for precision image guided small animal proton irradiation. The project SIRMIO aims at filling this gap by developing a portable image-guided research platform for small animal irradiation, to be used at clinical facilities and allowing for a precision similar to a clinical treatment, when scaled down to the small animal size. This work investigates the achievable dosimetric properties of different lowest energy clinical proton therapy beams, manipulated by a dedicated portable beamline including active focusing after initial beam energy degradation and collimation. By measuring the lateral beam size in air close to the beam nozzle exit and the laterally integrated depth dose in water, an analytical beam model based on the beam parameters of the clinical beam at the Rinecker Proton Therapy Center was created for the lowest available clinical beam energy. The same approach was then applied to estimate the lowest energy beam model of different proton therapy facilities, Paul Scherrer Institute, Centre Antoine Lacassagne, Trento Proton Therapy Centre and the Danish Centre for Particle Therapy, based on their available beam commissioning data. This comparison indicated similar beam properties for all investigated sites, with emittance values of a few tens of mm·mrad. Finally, starting from these beam models, we simulated propagation through a novel beamline designed to manipulate the beam energy and size for precise small animal irradiation, and evaluated the resulting dosimetric properties in water. For all investigated initial clinical beams, similar dosimetric results suitable for small animal irradiation were found. This work supports the feasibility of the proposed SIRMIO beamline, promising suitable beam characteristics to allow for precise preclinical irradiation at clinical treatment facilities.

Late toxicity in the brain after radiotherapy for sinonasal cancer: Neurocognitive functioning, MRI of the brain and quality of life.

PURPOSE: The aim of the study was to evaluate neurocognitive late effects, structural alterations and associations between cognitive impairment and radiation doses as well as cerebral tissue damage after radiotherapy for sinonasal cancer. Furthermore, the aim was to report quality of life (QoL) and self-reported cognitive capacity. MATERIALS AND METHODS: Recurrence-free patients previously treated with intensity-modulated radiotherapy with a curative intent were eligible for the study. Study examinations comprised comprehensive neurocognitive testing, MRI of the brain, and self-reported outcomes. RESULTS: A total of 27 patients were included. Median age was 67 years (range 47-83). The majority of test outcomes were below normative values in any degree, and 37% of the participants had clinically significant neurocognitive impairment when compared with normative data. Correlations between absorbed doses to specific substructures of the brain and neurocognitive outcomes were present for Wechsler's Adult Intelligence Scale-digit span and Controlled Oral Word Association Test-S. Structural MRI revealed macroscopic abnormalities in three patients; infarction (n = 1), diffuse white matter intensities (n = 2) and necrosis (n = 1). In the analysis of atrophy of cerebral tissue, no correlations were present with neither radiation dose to cerebral substructures nor neurocognitive impairment. The global QoL of the cohort was 75. The most affected outcomes were 'fatigue', 'insomnia', and 'drowsiness'. A total of 59% of participants reported significantly impaired quality of sleep. Self-reported cognitive function revealed that 'memory' was the most affected cognitive domain. For the domains of 'memory' and 'language', self-reported functioning was associated with objectively measured neurocognitive outcomes. CONCLUSION: Cerebral toxicity after radiotherapy for sinonasal cancer was substantial. Clinically significant cognitive impairment was present in more than one third of the participants, and several dose-response associations were present. Furthermore, the presence of macroscopic radiation sequelae indicated considerable impact of radiotherapy on brain tissue.

Proton therapy and the European Particle Therapy Network: The past, present and future.

Proton therapy is delivered to selected cancer patients presenting with rare tumours, for which a dose escalation paradigm and/or a reduced dose-bath to the organs at risk is pursued. It is a costly treatment with an additional cost factor of 2-3 when compared to photon radiotherapy. Notwithstanding the 180'000 patients treated with protons, scars robust clinical evidence is available to justify the administration of this treatment modality. The European Particle Therapy Network (EPTN) was created in 2015 to answer the critical European needs for cooperation among protons and carbon ions centres in the framework of clinical research networks. EPTN with other European groups will launch a number of prospective clinical trials that could be practice changing if positive. Alternative way to generate clinical data could be provided by alternative methodologies, such as the Dutch model-based approach, or could be provided by European infrastructure projects.

NTCP model validation method for DAHANCA patient selection of protons versus photons in head and neck cancer radiotherapy.

Introduction: Prediction models using logistic regression may perform poorly in external patient cohorts. However, there is a need to standardize and validate models for clinical use. The purpose of this project was to describe a method for validation of external NTCP models used for patient selection in the randomized trial of protons versus photons in head and neck cancer radiotherapy, DAHANCA 35. Material and methods: Organs at risk of 588 patients treated primarily with IMRT in the randomized controlled DAHANCA19 trial were retrospectively contoured according to recent international recommendations. Dose metrics were extracted using MatLab and all clinical parameters were retrieved from the DAHANCA database. The model proposed by Christianen et al. to predict physician-rated dysphagia was validated through the closed testing, where change of the model intercept, slope and individual beta's were tested for significant prediction improvements. Results: Six months prevalence of dysphagia in the validation cohort was 33%. The closed testing procedure for physician-rated dysphagia showed that the Christianen et al. model needed an intercept refitting for the best match for the Danish patients. The intercept update increased the risk of dysphagia for the validation cohort by 7.9 ± 2.5% point. For the raw model performance, the Brier score (mean squared residual) was 0.467, which improved significantly with a new intercept to 0.415. Conclusions: The previously published Dutch dysphagia model needed an intercept update to match the Danish patient cohort. The implementation of a closed testing procedure on the current validation cohort allows quick and efficient validation of external NTCP models for patient selection in the future.

IMRT - Biomarkers for dose escalation, dose de-escalation and personalized medicine in radiotherapy for head and neck cancer.

Radiotherapy (RT) is an integral component in the management of head and neck cancer. Despite progress in several respects, a noteworthy proportion of the treated patients do not achieve complete response after RT. Regardless of novel dose delivery technologies, RT for head and neck cancer is still associated with acute as well as late toxicity. These challenges could potentially be addressed by means of personalized treatment. In this paper, we discuss the possibilities for dose escalation, dose de-escalation and allocation to systemic concomitant treatment based on prognostic and predictive markers for tumor control as well as predictive markers for normal tissue radiosensitivity.

Reliability and validity of the Positive Mental Health Questionnaire in a sample of Spanish university students.

WHAT IS KNOWN ON THE SUBJECT?: In general, the current studies of positive mental health use questionnaires or parts thereof. However, while these questionnaires evaluate aspects of positive mental health, they fail to measure the construct itself. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: The widespread use and the lack of specific questionnaires for evaluating the positive mental health construct justify the need to measure the robustness of the Positive Mental Health Questionnaire. Also six factors are proposed to measure positive mental health. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The availability of a good questionnaire to measure positive mental health in university students is useful not only to promote mental health but also to strengthen the curricula of future professionals. ABSTRACT: Introduction Nursing has a relevant role in managing mental health. It is important to identify and thereafter to enhance positive aspects of mental health among university nursing students. Aim The aim of the present study was to analyse the psychometric properties of the Positive Mental Health Questionnaire (PMHQ) in terms of reliability and validity using confirmatory factor analysis in a sample of university students. Method A cross-sectional study was carried out in a sample of 1091 students at 4 nursing schools in Catalonia, Spain. The reliability of the PMHQ was measured by means of Cronbach's alpha coefficient, and the test-retest stability was measured with the intraclass correlation coefficient (ICC). Confirmatory factor analysis was used to determine the validity of the factorial structure. Results Cronbach's alpha coefficient was satisfactory (>0.70) for four of the six subscales or dimensions and ranged from 0.54 to 0.79. ICC analysis was satisfactory for the six subscales or dimensions. The hypothesis was confirmed in the analysis of the correlations between subclasses and the overall scale, with the strongest correlations being found between the majority of the subscales and the overall scale. Confirmatory factor analysis showed that the model proposed for the factors fit the data satisfactorily. Discussion This scale is a valid and reliable instrument for evaluating positive mental health in university students. Implications for Practice A good questionnaire to measure positive mental health in university students is useful not only to promote mental health but also to strengthen the curricula of future professionals.

Comprehensive Sclerotinia Stem Rot Screening of Soybean Germplasm Requires Multiple Isolates of Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum population variability directly affects Sclerotinia stem rot (SSR) resistance breeding programs. In the north-central United States, however, soybean germplasm selection has often involved only a single isolate. Forty-four S. sclerotiorum isolates from Illinois, Michigan, Minnesota, Nebraska, Wisconsin, Poland, and across 11 different host species were evaluated for variation in isolate in vitro growth, in vitro oxalate production, and in planta aggressiveness on the susceptible soybean 'Williams 82'. Significant differences (P < 0.0001) were detected in isolate in planta aggressiveness, in vitro growth, and in vitro oxalate production. Furthermore, diverse isolate characteristics were observed within all hosts and locations of collection. Aggressiveness was not correlated to colony growth and was only weakly correlated (r = 0.26, P < 0.0001) to isolate oxalate production. In addition, the host or location of collection did not explain isolate aggressiveness. Isolate oxalic acid production, however, may be partially explained by the host (P < 0.05) and location (P < 0.01) of collection. Using a representative subset of nine S. sclerotiorum isolates and soybean genotypes exhibiting susceptible or resistant responses (determined using a single isolate), a significant interaction (P = 0.04) was detected between isolates and genotypes when SSR severity was evaluated. Our findings suggest that screening of S. sclerotiorum-resistant soybean germplasm should be performed with multiple isolates to account for the overall diversity of S. sclerotiorum isolates found throughout the soybean-growing regions of the United States.

Partial resistance to homologous challenge infections of the digenean Echinostoma caproni in ICR mice.

In the present paper, we analyse the effect of a primary infection of ICR mice with Echinostoma caproni (Trematoda: Echinostomatidae) on the generation of resistance against homologous challenge infections. In ICR mice, E. caproni induces chronic infections concomitantly with strong responses characterized by the development of T-helper 1 (Th1)-type local immune responses with elevated levels of local interferon-gamma (IFN-γ) and inflammatory and antibody responses. Here, the effect of the response generated against a primary infection with E. caproni in the generation of resistance against subsequent homologous infections was analysed. For this purpose, ICR mice were challenged with metacercariae of E. caproni and the results obtained showed that primary infection induces partial resistance against subsequent homologous infections in ICR mice. This resistance was expressed as a reduced rate of infection, worm recovery and worm size, indicating that primary infection induces changes in the host, making a hostile environment for the development of the parasite.

Prophylactic Swallowing Exercises in Head and Neck Cancer Radiotherapy.

Many head and neck cancer (HNC) survivors experience reduced quality of life due to radiotherapy (RT)-related dysphagia. The aim of this prospective randomized trial was to evaluate the impact of prophylactic swallowing exercises on swallowing-related outcomes in HNC patients treated with curative RT. Patients treated with primary RT for HNC were candidates for this randomized protocol. Participants in the exercise group were instructed to perform swallowing exercises at home. Participants in the control group were given standard care. Patients were evaluated with modified barium swallow and several other secondary outcome measures at four and nine different time points, respectively. Data were analyzed according to intention-to-treat analyses. A total of 44 consecutive patients were included; 22 in each group. In general, there was no difference between the two groups regarding any of the dysphagia outcomes during and after treatment. Adherence to exercises was poor and dropouts due to especially fatigue were very frequent in both groups. Systematic swallowing exercises had no impact on swallowing outcomes within the first year after RT. Despite repeated supervised sessions, adherence to exercises was a major issue and dropouts were frequent in both the intervention and control group.

HERO (Health Economics in Radiation Oncology): a pan-European project on radiotherapy resources and needs.

Radiotherapy continues to evolve at a rapid rate in technology and techniques, with both driving up costs in an era in which health care budgets are of increasing concern at every governmental level. Against this background, it is clear that the radiotherapy community needs to quantify the costs of state of the art practice and then to justify those costs through rigorous cost-effectiveness analyses. The European Society for Radiotherapy and Oncology-Health Economics in Radiation Oncology project is directed towards tackling this issue in the European context. The first step has been to provide a validated picture of the European radiotherapy landscape in terms of the availability of equipment, personnel and guidelines. An 84-item questionnaire was distributed to the 40 countries of the European Cancer Observatory, of which 34 provided partial or complete responses. There was a huge variation in the availability and sophistication of treatment equipment and staffing levels across Europe. The median number of MV units per million inhabitants was 5.3, but there was a seven-fold variation across the European countries. Likewise, although average staffing figures per million inhabitants were 12.8 for radiation oncologists, 7.6 for physicists, 3.5 for dosimetrists, 26.6 for radiation therapists and 14.8 for nurses, there was a 20-fold variation, even after grouping personnel with comparable duties in the radiotherapy process. Guidelines for capital and human resources were declared for most countries, but without explicitly providing metrics for developing capital and human resource inventories in many cases. Although courses delivered annually per resource item ­ be it equipment or staff ­ increase with decreasing gross national income (GNI) per capita, differences were observed in equipment and staff availability in countries with a higher GNI/n, indicating that health policy has a significant effect on the provision of services. Although more needs to be done to increase access to radiotherapy in Europe, the situation has improved considerably since the comparable RadioTherapy for Cancer: QUAnification of Infrastructure and Staffing Needs (QUARTS) study reported in 2005.

Real-time segmentation of multiple implanted cylindrical liver markers in kilovoltage and megavoltage x-ray images.

Gold markers implanted in or near a tumor can be used as x-ray visible landmarks for image based tumor localization. The aim of this study was to develop and demonstrate fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in cone-beam CT (CBCT) projections, for real-time motion management. Thirteen patients treated with conformal stereotactic body radiation therapy in three fractions had 2-3 cylindrical gold markers implanted in the liver prior to treatment. At each fraction, the projection images of a pre-treatment CBCT scan were used for automatic generation of a 3D marker model that consisted of the size, orientation, and estimated 3D trajectory of each marker during the CBCT scan. The 3D marker model was used for real-time template based segmentation in subsequent x-ray images by projecting each marker's 3D shape and likely 3D motion range onto the imager plane. The segmentation was performed in intra-treatment kV images (526 marker traces, 92,097 marker projections) and MV images (88 marker traces, 22,382 marker projections), and in post-treatment CBCT projections (42 CBCT scans, 71,381 marker projections). 227 kV marker traces with low mean contrast-to-noise ratio were excluded as markers were not visible due to MV scatter. Online segmentation times measured for a limited dataset were used for estimating real-time segmentation times for all images. The percentage of detected markers was 94.8% (kV), 96.1% (MV), and 98.6% (CBCT). For the detected markers, the real-time segmentation was erroneous in 0.2-0.31% of the cases. The mean segmentation time per marker was 5.6 ms [2.1-12 ms] (kV), 5.5 ms [1.6-13 ms] (MV), and 6.5 ms [1.8-15 ms] (CBCT). Fast and reliable real-time segmentation of multiple liver tumor markers in intra-treatment kV and MV images and in CBCT projections was demonstrated for a large dataset.