Risk factor analysis for a rapid progression of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a growing global health concern. Identifying individuals in routine clinical care with new-onset CKD at high risk of rapid progression of the disease is imperative to guide allocation of prophylactic interventions, but community-based data are limited. We aimed to examine the risk of rapid progression, kidney failure, hospitalization and death among adults with incident CKD stage G3 and to clarify the association between predefined risk markers and rapid CKD progression. METHODS: Using plasma creatinine measurements for the entire Danish population from both hospitals and primary care, we conducted a nationwide, population-based cohort study, including adults in Denmark with incident CKD stage G3 in 2017-2020. We estimated 3-year risks of rapid progression (defined by a confirmed decline in estimated glomerular filtration rate of ≥5 mL/min/1.73 m2/year), kidney failure, all-cause hospitalization and death. To examine risk markers, we constructed a heat map showing the risk of rapid progression based on predefined markers: albuminuria, sex, diabetes and hypertension/cardiovascular disease. RESULTS: Among 133 443 individuals with incident CKD stage G3, the 3-year risk of rapid progression was 14.6% [95% confidence interval (CI) 14.4-14.8]. The 3-year risks of kidney failure, hospitalization and death were 0.3% (95% CI 0.3-0.4), 53.3% (95% CI 53.0-53.6) and 18.1% (95% CI 17.9-18.4), respectively. In the heat map, the 3-year risk of rapid progression ranged from 7% in females without albuminuria, hypertension/cardiovascular disease or diabetes, to 46%-47% in males and females with severe albuminuria, diabetes and hypertension/cardiovascular disease. CONCLUSION: This population-based study shows that CKD stage G3 is associated with considerable morbidity in a community-based setting and underscores the need for optimized prophylactic interventions among such patients. Moreover, our data highlight the potential of using easily accessible markers in routine clinical care to identify individuals who are at high risk of rapid progression.

Utilisation of hospital-based specialist palliative care in patients with gynaecological cancer: Temporal trends, predictors and association with high-intensity end-of-life care.

OBJECTIVE: To examine hospital-based specialist palliative care (SPC) utilisation among patients with gynaecological cancer, including temporal trends, predictors and associations with high-intensity end-of-life care. METHODS: We conducted a nationwide registry-based study for all patients dying from gynaecological cancer in Denmark during 2010-2016. We estimated the proportions of patients receiving SPC by year of death and used regression analyses to examine predictors of SPC utilisation. Use of high-intensity end-of-life care according to SPC utilisation was compared by regression analyses adjusting for type of gynaecological cancer, year of death, age, comorbidities, residential region, marital/cohabitation status, income level and migrant status. RESULTS: Among 4502 patients dying from gynaecological cancer, the proportion of patients receiving SPC increased from 24.2% in 2010 to 50.7% in 2016. Young age, three or more comorbidities, residence outside the Capital Region and being immigrant/descendant were associated with increased SPC utilisation, whereas income, cancer type and stage were not. SPC was associated with lower high-intensity end-of-life care utilisation. Particularly, when compared with patients not receiving SPC, patients who accessed SPC >30 days before death had 88% lower risk of intensive care unit admissions within 30 days before death (adjusted relative risk: 0.12 (95% CI: 0.06; 0.24)) and 96% lower risk of surgery within 14 days before death (adjusted relative risk: 0.04 (95% CI: 0.01; 0.31)). CONCLUSIONS: Among patients dying from gynaecological cancer, SPC utilisation increased over time and age, comorbidities, residential region and migrant status were associated with access to SPC. Furthermore, SPC was associated with lower use of high-intensity end-of-life care.

Plan robustness evaluation strategies in whole-pelvic proton therapy for high-risk prostate cancer patients within a randomised clinical trial.

BACKGROUND: Inter-fractional anatomical changes challenge robust delivery of whole-pelvic proton therapy for high-risk prostate cancer. Pre-treatment robust evaluation (PRE) takes uncertainties in isocenter shifts and distal beam edge in treatment plans into account. Using weekly control computed tomography scans (cCTs), the aim of this study was to evaluate the PRE strategy by comparing to an off-line during-treatment robust evaluation (DRE) while also assessing plan robustness with respect to protocol planning constraints. MATERIAL AND METHODS: Treatment plans and cCTs from ten patients included in the pilot phase of the PROstate PROTON Trial 1 were analysed. Treatment planning followed protocol guidelines with 78 Gy to the primary clinical target volume (CTVp) and 56 Gy to the elective target (CTVe) in 39 fractions. Recalculations of the treatment plans were performed for a total of 64 cCTs and dose/volume measures corresponding to clinical constraints were evaluated for this DRE against the simulated scenario interval from the PRE. RESULTS: Of the 64 cCTs, 59 showed DRE CTVp measures within the robustness range from the PRE; this was also the case for 39 of the cCTs for the CTVe measures. However, DRE CTVe coverage was still within constraints for 57 of the 64 cCTs. DRE dose/volume measures for CTVp fulfilled target coverage constraints in 59 of 64 cCTs. All DRE measures for the rectum, bladder, and bowel were inside the PRE range in 63, 39, and 31 cCTs, respectively. CONCLUSION: The PRE strategy predicted the DRE scenarios for CTVp and rectum. CTVe, bladder, and bowel showed more complex anatomical variations than simulated by the PRE isocenter shift. Both original and recalculated nominal treatment plans showed robust treatment delivery in terms of target coverage.

Towards harmonizing clinical linear energy transfer (LET) reporting in proton radiotherapy: a European multi-centric study.

BACKGROUND: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed. MATERIALS AND METHODS: Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters. RESULTS: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using non-harmonized LET calculations increased inter-center dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1. CONCLUSION: Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.

Direct costs of antineoplastic and supportive treatment for progressive multiple myeloma in a tax-based health system.

Aim: To estimate current real-world costs of drugs and supportive care for the treatment of multiple myeloma in a tax-based health system. Methods: Forty-one patients were included from a personalized medicine study (2016-2019). Detailed information was collected from patient journals and hospital registries to estimate the total and mean costs using inverse probability weighting of censored data. Results: Total observed (censored) costs for the 41 patients was €8.84 million during 125 treatment years, with antineoplastic drugs as the main cost driver (€5.6 million). Individual costs showed large variations. Mean 3-year cost per patient from first progression was €182,103 (€131,800-232,405). Conclusion: Prediction of real-world costs is hindered by the availability of detailed costing data. Micro-costing analyses are needed for budgeting and real-world evaluation of cost-effectiveness.

Lay abstract In recent years, there has been a dramatic improvement in the treatment of multiple myeloma due to the introduction of new drugs. These drugs have significantly increased survival but have also had an immense impact on healthcare budgets. In this study, we used detailed treatment information for multiple myeloma patients in combination with billing data from the hospital pharmacy at a Danish hospital to calculate individual cost histories for both drugs and supportive care. Using these data, we estimated the mean 3-year cost of a multiple myeloma patient to be €182.103, but we also found large variation between patients, causing an uncertainty of €50.000 in either direction. We believe that detailed costing studies, similar to the present one, are necessary for evaluation of cost-effectiveness of drugs in clinical practice.

Social Inequalities in Life Expectancy and Mortality in People With Dementia in the United Kingdom.

INTRODUCTION: Inequalities in life expectancy and mortality by social deprivation in the general population of the United Kingdom are widening. For people with dementia, data on potential gradients in life expectancy and mortality by social deprivation are sparse. This study aimed to explore potential differentials in life expectancy and mortality in people with dementia according to social deprivation. METHODS: Using The Health Improvement Network (THIN) primary care database, we included people with a diagnosis of dementia in the United Kingdom in 2000 to 2016 and obtained data on age at death and mortality. Comparisons were made according to social deprivation quintiles adjusting for age at diagnosis. RESULTS: Among 166,268 people with dementia there were no differences in life expectancy and mortality in the most deprived compared with the least deprived. This pattern has been stable during the study period, as no increasing inequalities in life expectancy and mortality according to social deprivation were found. DISCUSSION: Contrary to the general population, there were limited inequalities in life expectancy and mortality according to social deprivation for people with dementia.

RBE for proton radiation therapy - a Nordic view in the international perspective.

BACKGROUND: This paper presents an insight into the critical discussions and the current strategies of the Nordic countries for handling the variable proton relative biological effectiveness (RBE) as presented at The Nordic Collaborative Workshop for Particle Therapy that took place at the Skandion Clinic on 14th and 15th of November 2019. MATERIAL AND METHODS: In the current clinical practice at the two proton centres in operation at the date, Skandion Clinic, and the Danish Centre for Particle Therapy, a constant proton RBE of 1.1 is applied. The potentially increased effectiveness at the end of the particle range is however considered at the stage of treatment planning at both places based on empirical observations and knowledge. More elaborated strategies to evaluate the plans and mitigate the problem are intensely investigated internationally as well at the two centres. They involve the calculation of the dose-averaged linear energy transfer (LETd) values and the assessment of their distributions corroborated with the distribution of the dose and the location of the critical clinical structures. RESULTS: Methods and tools for LETd calculations are under different stages of development as well as models to account for the variation of the RBE with LETd, dose per fraction, and type of tissue. The way they are currently used for evaluation and optimisation of the plans and their robustness are summarised. A critical but not exhaustive discussion of their potential future implementation in the clinical practice is also presented. CONCLUSIONS: The need for collaboration between the clinical proton centres in establishing common platforms and perspectives for treatment planning evaluation and optimisation is highlighted as well as the need of close interaction with the research academic groups that could offer a complementary perspective and actively help developing methods and tools for clinical implementation of the more complex metrics for considering the variable effectiveness of the proton beams.

Geographical variation in palliative cancer care in a tax-based healthcare system: drug reimbursement in Denmark.

BACKGROUND: In Denmark, a tax-based universal healthcare setting, drug reimbursement for terminal illness (DRTI) should be equally accessible for all terminally ill patients. Examining DRTI status by regions provides new knowledge on inequality in palliative care provision and associated factors. This study aims to investigate geographical variation in DRTI among terminally ill cancer patients. METHODS: We linked socioeconomic and medical data from 135 819 Danish cancer decedents in the period 2007-15 to regional healthcare characteristics. We analyzed associations between region of residence and DRTI. Prevalence ratios (PR) for DRTI were estimated using generalized linear models adjusted for patient factors (age, gender, comorbidity and socioeconomic profile) and multilevel models adjusted for both patient factors and regional healthcare capacity (patients per general practitioner, numbers of hospital and hospice beds). RESULTS: DRTI allocation differed substantially across Danish regions. Healthcare capacity was associated with DRTI with a higher probability of DRTI among patients living in regions with high compared with low hospice bed supply (PR 1.13, 95% CI 1.10-1.17). Also, the fully adjusted PR of DRTI was 0.94 (95% CI 0.91-0.96) when comparing high with low number of hospital beds. When controlled for both patient and regional healthcare characteristics, the PR for DRTI was 1.17 (95% CI 1.14-1.21) for patients living in the Central Denmark Region compared with the Capital Region. CONCLUSION: DRTI status varied across regions in Denmark. The variation was associated with the distribution of healthcare resources. These findings highlight difficulties in ensuring equal access to palliative care even in a universal healthcare system.

Towards proton arc therapy: physical and biologically equivalent doses with increasing number of beams in pediatric brain irradiation.

Background: Proton arc therapy may improve physical dose conformity and reduce concerns of elevated linear energy transfer (LET) and relative biological effectiveness (RBE) at the end of the proton range, while offering more degrees of freedom for normal tissue sparing. To explore the potential of proton arc therapy, we studied the effect of increasing the number of beams on physical and biologically equivalent dose conformity in the setting of pediatric brain tumors. Material and methods: A cylindrical phantom (Ø = 150 mm) with central cylindrical targets (Ø = 25 and 30 mm) was planned with increasing number of equiangular coplanar proton beams (from 3 to 36). For four anonymized pediatric brain tumor patients, two 'surrogate' proton arc plans (18 equiangular coplanar or sagittal beams) and a reference plan with 3 non-coplanar beams were constructed. Biologically equivalent doses were calculated using two RBE scenarios: RBE1.1; and RBELET, the physical dose weighted by the LET. For both RBE scenarios, dose gradients were assessed, and doses to cognitive brain structures were reported. Results: Increasing the number of beams resulted in an improved dose gradient and reduced volume exposed to intermediate LET levels, at the expense of increased low-dose and low-LET volumes. Most of the differences between the two RBE scenarios were seen around the prescription dose level, where the isodose volumes increased with the RBELET plans, e.g. up to 63% in the 3-beam plan for the smallest phantom target. Overall, the temporal lobes were better spared with the sagittal proton arc surrogate plans, e.g. a mean dose of 3.9 Gy compared to 6 Gy in the reference 3-beam plan (median value, RBE1.1). Conclusion: Proton arc therapy has the potential to improve dose gradients to better spare cognitive brain structures. However, this is at the expense of increased low-dose/low-LET volumes, with possible implications for secondary cancer risks.

Radiation doses to brain substructures associated with cognition in radiotherapy of pediatric brain tumors.

Background: Several brain substructures associated with cognition (BSCs) are located close to typical pediatric brain tumors. Pediatric patients therefore have considerable risks of neurocognitive impairment after brain radiotherapy. In this study, we investigated the radiation doses received by BSCs for three common locations of pediatric brain tumor entities. Material and methods: For ten patients in each group [posterior fossa ependymoma (PFE), craniopharyngioma (CP), and hemispheric ependymoma (HE)], the cumulative fraction of BSCs volumes receiving various dose levels were analyzed. We subsequently explored the differences in dose pattern between the three groups and used available dose response models from the literature to estimate treatment-induced intelligence quotient (IQ) decline. Results: Doses to BSCs were found to differ considerably between the groups, depending on their position relative to the tumor. Large inter-patient variations were observed in the ipsilateral structures of the HE groups, and at low doses for all three groups. IQ decline estimates differed depending on the model applied, presenting larger variations in the HE group. Conclusion: While there were notable differences in the dose patterns between the groups, the extent of estimated IQ decline depended more on the model applied. This inter-model variability should be considered in dose-effect assessments on cognitive outcomes of pediatric patients.

Dosimetric comparison of five different techniques for craniospinal irradiation across 15 European centers: analysis on behalf of the SIOP-E-BTG (radiotherapy working group).

PURPOSE: Conventional techniques (3D-CRT) for craniospinal irradiation (CSI) are still widely used. Modern techniques (IMRT, VMAT, TomoTherapy®, proton pencil beam scanning [PBS]) are applied in a limited number of centers. For a 14-year-old patient, we aimed to compare dose distributions of five CSI techniques applied across Europe and generated according to the participating institute protocols, therefore representing daily practice. MATERIAL AND METHODS: A multicenter (n = 15) dosimetric analysis of five different techniques for CSI (3D-CRT, IMRT, VMAT, TomoTherapy®, PBS; 3 centers per technique) was performed using the same patient data, set of delineations and dose prescription (36.0/1.8 Gy). Different treatment plans were optimized based on the same planning target volume margin. All participating institutes returned their best treatment plan applicable in clinic. RESULTS: The modern radiotherapy techniques investigated resulted in superior conformity/homogeneity-indices (CI/HI), particularly in the spinal part of the target (CI: 3D-CRT:0.3 vs. modern:0.6; HI: 3D-CRT:0.2 vs. modern:0.1), and demonstrated a decreased dose to the thyroid, heart, esophagus and pancreas. Dose reductions of >10.0 Gy were observed with PBS compared to modern photon techniques for parotid glands, thyroid and pancreas. Following this technique, a wide range in dosimetry among centers using the same technique was observed (e.g., thyroid mean dose: VMAT: 5.6-24.6 Gy; PBS: 0.3-10.1 Gy). CONCLUSIONS: The investigated modern radiotherapy techniques demonstrate superior dosimetric results compared to 3D-CRT. The lowest mean dose for organs at risk is obtained with proton therapy. However, for a large number of organs ranges in mean doses were wide and overlapping between techniques making it difficult to recommend one radiotherapy technique over another.

Teaching Cancer Patients the Value of Correct Positioning During Radiotherapy Using Visual Aids and Practical Exercises.

The aim of this study was to investigate if teaching patients about positioning before radiotherapy treatment would (a) reduce the residual rotational set-up errors, (b) reduce the number of repositionings and (c) improve patients' sense of control by increasing self-efficacy and reducing distress. Patients were randomized to either standard care (control group) or standard care and a teaching session combining visual aids and practical exercises (intervention group). Daily images from the treatment sessions were evaluated off-line. Both groups filled in a questionnaire before and at the end of the treatment course on various aspects of cooperation with the staff regarding positioning. Comparisons of residual rotational set-up errors showed an improvement in the intervention group compared to the control group. No significant differences were found in number of repositionings, self-efficacy or distress. Results show that it is possible to teach patients about positioning and thereby improve precision in positioning. Teaching patients about positioning did not seem to affect self-efficacy or distress scores at baseline and at the end of the treatment course.

Effect of Anticoagulation on Hospitalization Costs After Intracranial Hemorrhage in Atrial Fibrillation: A Registry Study.

BACKGROUND AND PURPOSE: Intracranial hemorrhage (ICH) is the most feared adverse event with oral anticoagulant therapy in patients with atrial fibrillation. The health economic aspects of resuming oral anticoagulant therapy after ICH are unknown. The aim was to estimate hospitalization costs of thromboembolism and hemorrhage subsequent to ICH in 2 patient groups with atrial fibrillation surviving the first 90 days post ICH: (1) patients resuming warfarin therapy within 90 days post ICH and (2) patients discontinuing therapy. METHODS: Retrospective data from Danish national registries were linked to identify patients with atrial fibrillation who suffered an ICH between January 1, 1997, and April 1, 2011. Study start was 90 days after incident ICH. Mortality was evaluated using the Kaplan-Meier estimate. Occurrence of hospitalization-requiring thromboembolism and hemorrhage was used to estimate hospitalization costs by linkage of International Classification of Diseases, Tenth Revision, codes to Danish Diagnosis-Related Group tariffs. The effect of resuming warfarin therapy on average 3-year hospitalization costs was estimated by regression analysis adjusted for between-group differences in baseline characteristics. RESULTS: In the inclusion period, 2162 patients had an ICH; 1098 survived the first 90 days and were included for analysis, and of those, 267 resumed warfarin therapy. Therapy resumption reduced the mean 3-year hospitalization cost of hospitalized patients significantly by US$ 1588 (95% confidence interval, -2925 to -251) and was significantly correlated with fewer hospitalization days per hospitalized patient (-4.6 [95% confidence interval, -7.6 to -1.6]). The marginal effect of therapy resumption on hospitalization costs per patient was US$ -407 (95% confidence interval, -815 to 2). CONCLUSIONS: Resuming warfarin therapy within 90 days after ICH in patients with atrial fibrillation is associated with a decrease in average hospitalization costs.

Adaptive radiotherapy strategies for pelvic tumors - a systematic review of clinical implementations.

UNLABELLED: Introdution: Variation in shape, position and treatment response of both tumor and organs at risk are major challenges for accurate dose delivery in radiotherapy. Adaptive radiotherapy (ART) has been proposed to customize the treatment to these motion/response patterns of the individual patients, but increases workload and thereby challenges clinical implementation. This paper reviews strategies and workflows for clinical and in silico implemented ART for prostate, bladder, gynecological (gyne) and ano-rectal cancers. MATERIAL AND METHODS: Initial identification of papers was based on searches in PubMed. For each tumor site, the identified papers were screened independently by two researches for selection of studies describing all processes of an ART workflow: treatment monitoring and evaluation, decision and execution of adaptations. Both brachytherapy and external beam studies were eligible for review. RESULTS: The review consisted of 43 clinical studies and 51 in silico studies. For prostate, 1219 patients were treated with offline re-planning, mainly to adapt prostate motion relative to bony anatomy. For gyne 1155 patients were treated with online brachytherapy re-planning while 25 ano-rectal cancer patients were treated with offline re-planning, all to account for tumor regression detected by magnetic resonance imaging (MRI)/computed tomography (CT). For bladder and gyne, 161 and 64 patients, respectively, were treated with library-based online plan selection to account for target volume and shape variations. The studies reported sparing of rectum (prostate and bladder cancer), bladder (ano-rectal cancer) and bowel cavity (gyne and bladder cancer) as compared to non-ART. CONCLUSION: Implementations of ART were dominated by offline re-planning and online brachytherapy re-planning strategies, although recently online plan selection workflows have increased with the availability of cone-beam CT. Advantageous dosimetric and outcome patterns using ART was documented by the studies of this review. Despite this, clinical implementations were scarce due to challenges in target/organ re-contouring and suboptimal patient selection in the ART workflows.

Intra-fractional bladder motion and margins in adaptive radiotherapy for urinary bladder cancer.

BACKGROUND: The bladder is a tumour site well suited for adaptive radiotherapy (ART) due to large inter-fractional changes, but it also displays considerable intra-fractional motion. The aim of this study was to assess target coverage with a clinically applied method for plan selection ART and to estimate population-based and patient-specific intra-fractional margins, also relevant for a future re-optimisation strategy. MATERIAL AND METHODS: Nine patients treated in a clinical phase II ART trial of daily plan selection for bladder cancer were included. In the library plans, 5 mm isotropic margins were added to account for intra-fractional changes. Pre-treatment and weekly repeat magnetic resonance imaging (MRI) series were acquired in which a full three-dimensional (3D) volume was scanned every second min for 10 min (a total of 366 scans in 61 series). Initially, the bladder clinical target volume (CTV) was delineated in all scans. The t = 0 min scan was then rigidly registered to the planning computed tomography (CT) and plan selections were simulated using the CTV_0 (at t = 0 min). To assess intra-fractional motion, coverage of the CTV_10 (at t = 10 min) was quantified using the applied PTV. Population-based margins were calculated using the van Herk margin recipe while patient-specific margins were calculated using a linear model. RESULTS: For 49% of the cases, the CTV_10 extended more than 5 mm outside the CTV_0. However, in 58 of the 61 cases (97%) CTV_10 was covered by the selected PTV. Population-based margins of 14 mm Sup/Ant, 9 mm Post and 5 mm Inf/Lat were sufficient to cover the bladder. Using patient-specific margins, the overlap between PTV and bowel-cavity was reduced from 137 cm(3) with the plan selection strategy to 24 cm(3). CONCLUSION: In this phase II ART trial, 5 mm isotropic margin for intra-fractional motion was sufficient even though considerable intra-fractional motion was observed. In online re-optimised ART, population-based margin can be applied although patient-specific margins are preferable.

Normal tissue sparing in a phase II trial on daily adaptive plan selection in radiotherapy for urinary bladder cancer.

UNLABELLED: Background: Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy (RT), making adaptive RT (ART) appealing for this tumour site. We are conducting a clinical phase II trial of daily plan selection-based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial. MATERIAL AND METHODS: All patients received 60 Gy in 30 fractions to the bladder; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy. Daily patient set-up was by use of cone beam computed tomography (CBCT) guidance. The first 5 fractions were delivered with large, population-based (non-adaptive) margins. The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans, corresponding to a small, medium and large size bladder. From fraction 6, daily online plan selection was performed, where the smallest plan covering the bladder was selected prior to each treatment delivery. A total of 600 treatment fractions in the 20 patients were evaluated. RESULTS: Small, medium and large size plans were used almost equally often, with an average of 10, 9 and 11 fractions, respectively. The median volume ratio of the course-averaged PTV (PTV-ART) relative to the non-adaptive PTV was 0.70 (range: 0.46-0.89). A linear regression analysis showed a 183 cm(3) (CI 143-223 cm(3)) reduction in PTV-ART compared to the non-adaptive PTV (R(2) = 0.94). CONCLUSION: Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing, of a magnitude that we expect will translate into a clinically significant reduction of the treatment-related morbidity.

Assessment of fluence- and dose-averaged linear energy transfer with passive luminescence detectors in clinical proton beams.

Objective.This work investigates the use of passive luminescence detectors to determine different types of averaged linear energy transfer (LET-) for the energies relevant to proton therapy. The experimental results are compared to reference values obtained from Monte Carlo simulations.Approach.Optically stimulated luminescence detectors (OSLDs), fluorescent nuclear track detectors (FNTDs), and two different groups of thermoluminescence detectors (TLDs) were irradiated at four different radiation qualities. For each irradiation, the fluence- (LET-f) and dose-averaged LET (LET-d) were determined. For both quantities, two sub-types of averages were calculated, either considering the contributions from primary and secondary protons or from all protons and heavier, charged particles. Both simulated and experimental data were used in combination with a phenomenological model to estimate the relative biological effectiveness (RBE).Main results.All types ofLET-could be assessed with the luminescence detectors. The experimental determination ofLET-fis in agreement with reference data obtained from simulations across all measurement techniques and types of averaging. On the other hand,LET-dcan present challenges as a radiation quality metric to describe the detector response in mixed particle fields. However, excluding secondaries heavier than protons from theLET-dcalculation, as their contribution to the luminescence is suppressed by ionization quenching, leads to equal accuracy betweenLET-fandLET-d. Assessment of RBE through the experimentally determinedLET-dvalues agrees with independently acquired reference values, indicating that the investigated detectors can determineLET-with sufficient accuracy for proton therapy.Significance.OSLDs, TLDs, and FNTDs can be used to determineLET-and RBE in proton therapy. With the capability to determine dose through ionization quenching corrections derived fromLET-, OSLDs and TLDs can simultaneously ascertain dose,LET-, and RBE. This makes passive detectors appealing for measurements in phantoms to facilitate validation of clinical treatment plans or experiments related to proton therapy.

Clinical practice in European centres treating paediatric posterior fossa tumours with pencil beam scanning proton therapy.

BACKGROUND AND PURPOSE: As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques across European PT centres, with special considerations for brainstem and spinal cord sparing. MATERIALS AND METHODS: A survey and a treatment planning comparison were initiated across nineteen European PBS-PT centres treating paediatric patients. The survey assessed all aspects of the treatment chain, including but not limited to delineations, dose constraints and treatment planning. Each centre planned two PF tumour cases for focal irradiation, according to their own clinical practice but based on common delineations. The prescription dose was 54 Gy(RBE) for Case 1 and 59.4 Gy(RBE) for Case 2. For both cases, planning strategies and relevant dose metrics were compared. RESULTS: Seventeen (89 %) centres answered the survey, and sixteen (80 %) participated in the treatment planning comparison. In the survey, thirteen (68 %) centres reported using the European Particle Therapy Network definition for brainstem delineation. In the treatment planning study, while most centres used three beam directions, their configurations varied widely across centres. Large variations were also seen in brainstem doses, with a brainstem near maximum dose (D2%) ranging from 52.7 Gy(RBE) to 55.7 Gy(RBE) (Case 1), and from 56.8 Gy(RBE) to 60.9 Gy(RBE) (Case 2). CONCLUSION: This study assessed the European PBS-PT planning of paediatric PF tumours. Agreement was achieved in e.g. delineation-practice, while wider variations were observed in planning approach and consequently dose to organs at risk. Collaboration between centres is still ongoing, striving towards common guidelines.