A radiotherapy community data-driven approach to determine which complexity metrics best predict the impact of atypical TPS beam modeling on clinical dose calculation accuracy.

PURPOSE: To quantify the impact of treatment planning system beam model parameters, based on the actual spread in radiotherapy community data, on clinical treatment plans and determine which complexity metrics best describe the impact beam modeling errors have on dose accuracy. METHODS: Ten beam modeling parameters for a Varian accelerator were modified in RayStation to match radiotherapy community data at the 2.5, 25, 50, 75, and 97.5 percentile levels. These modifications were evaluated on 25 patient cases, including prostate, non-small cell lung, H&N, brain, and mesothelioma, generating 1,000 plan perturbations. Differences in the mean planned dose to clinical target volumes (CTV) and organs at risk (OAR) were evaluated with respect to the planned dose using the reference (50th-percentile) parameter values. Correlation between CTV dose differences, and 18 different complexity metrics were evaluated using linear regression; R-squared values were used to determine the best metric. RESULTS: Perturbations to MLC offset and transmission parameters demonstrated the greatest changes in dose: up to 5.7% in CTVs and 16.7% for OARs. More complex clinical plans showed greater dose perturbation with atypical beam model parameters. The mean MLC Gap and Tongue & Groove index (TGi) complexity metrics best described the impact of TPS beam modeling variations on clinical dose delivery across all anatomical sites; similar, though not identical, trends between complexity and dose perturbation were observed among all sites. CONCLUSION: Extreme values for MLC offset and MLC transmission beam modeling parameters were found to most substantially impact the dose distribution of clinical plans and careful attention should be given to these beam modeling parameters. The mean MLC Gap and TGi complexity metrics were best suited to identifying clinical plans most sensitive to beam modeling errors; this could help provide focus for clinical QA in identifying unacceptable plans.

A virtual audit system for intensity-modulated radiation therapy credentialing in Japan Clinical Oncology Group clinical trials: A pilot study.

PURPOSE: The Medical Physics Working Group of the Radiation Therapy Study Group at the Japan Clinical Oncology Group is currently developing a virtual audit system for intensity-modulated radiation therapy dosimetry credentialing. The target dosimeters include films and array detectors, such as ArcCHECK (Sun Nuclear Corporation, Melbourne, Florida, USA) and Delta4 (ScandiDos, Uppsala, Sweden). This pilot study investigated the feasibility of our virtual audit system using previously acquired data. METHODS: We analyzed 46 films (32 and 14 in the axial and coronal planes, respectively) from 29 institutions. Global gamma analysis between measured and planned dose distributions used the following settings: 3%/3 mm criteria (the dose denominator was 2 Gy), 30% threshold dose, no scaling of the datasets, and 90% tolerance level. In addition, 21 datasets from nine institutions were obtained for array evaluation. Five institutions used ArcCHECK, while the others used Delta4. Global gamma analysis was performed with 3%/2 mm criteria (the dose denominator was the maximum calculated dose), 10% threshold dose, and 95% tolerance level. The film calibration and gamma analysis were conducted with in-house software developed using Python (version 3.9.2). RESULTS: The means ± standard deviations of the gamma passing rates were 99.4 ± 1.5% (range, 92.8%-100%) and 99.2 ± 1.0% (range, 97.0%-100%) in the film and array evaluations, respectively. CONCLUSION: This pilot study demonstrated the feasibility of virtual audits. The proposed virtual audit system will contribute to more efficient, cheaper, and more rapid trial credentialing than on-site and postal audits; however, the limitations should be considered when operating our virtual audit system.

IAEA methodology for on-site end-to-end IMRT/VMAT audits: an international pilot study.

Background: The IAEA has developed and tested an on-site, end-to-end IMRT/VMAT dosimetry audit methodology for head and neck cases using an anthropomorphic phantom. The audit methodology is described, and the results of the international pilot testing are presented.Material and methods: The audit utilizes a specially designed, commercially available anthropomorphic phantom capable of accommodating a small volume ion chamber (IC) in four locations (three in planning target volumes (PTVs) and one in an organ at risk (OAR)) and a Gafchromic film in a coronal plane for the absorbed dose to water and two-dimensional dose distribution measurements, respectively. The audit consists of a pre-visit and on-site phases. The pre-visit phase is carried out remotely and includes a treatment planning task and a set of computational exercises. The on-site phase aims at comparing the treatment planning system (TPS) calculations with measurements in the anthropomorphic phantom following an end-to-end approach. Two main aspects were tested in the pilot study: feasibility of the planning constraints and the accuracy of IC and film results in comparison with TPS calculations. Treatment plan quality was scored from 0 to 100.Results: Forty-two treatment plans were submitted by 14 institutions from 10 countries, with 79% of them having a plan quality score over 90. Seventeen sets of IC measurement results were collected, and the average measured to calculated dose ratio was 0.988 ± 0.016 for PTVs and 1.020 ± 0.029 for OAR. For 13 film measurement results, the average gamma passing rate was 94.1% using criteria of 3%/3 mm, 20% threshold and global gamma.Conclusions: The audit methodology was proved to be feasible and ready to be adopted by national dosimetry audit networks for local implementation.

Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension.

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

Improving the modelling of a multi-leaf collimator with tilted leaf sides used in radiotherapy.

Background and purpose: Multi-leaf collimators (MLCs) with tilted leaf sides have a complex transmission behaviour that is not easily matched by radiotherapy treatment planning systems (TPSs). We sought to develop an MLC model that can accurately match test fields and clinically relevant plans at different centres. Materials and methods: Two new MLC models were developed and evaluated within a research version of a commercial TPS. Prototype I used adjusted-constant transmissions and Prototype II used variable transmissions at the tongue-and-groove and leaf-tip regions. Three different centres evaluated these prototypes for a tilted MLC and compared them with their initial MLC model using test fields and patient-specific quality-assurance measurements of clinically relevant plans. For the latter, gamma passing rates (GPR) at 2 %/2mm were recorded. Results: For the prototypes the same set of MLC parameters could be used at all centres, with only a slight adjustment of the offset parameter. For centres A and C, average GPR were >95 % and within 0.5 % GPR difference between the standard, and prototype models. In center B, prototypes I and II improved the agreement in clinically relevant plans, with an increase in GPR of 2.3 % ± 0.8 % and 3.0 ± 0.8 %, respectively. Conclusions: The prototype MLC models were either similar or superior to the initial MLC model, and simpler to configure because fewer trade-offs were required. Prototype I performed comparably to the more sophisticated Prototype II and its configuration can be easily standardized, which can be useful to reduce variability and improve safety in clinical practice.

Technical recommendations for implementation of Volumetric Modulated Arc Therapy and Helical Tomotherapy Total Body Irradiation.

As a component of myeloablative conditioning before allogeneic hematopoietic stem cell transplantation (HSCT), Total Body Irradiation (TBI) is employed in radiotherapy centers all over the world. In recent and coming years, many centers are changing their technical setup from a conventional TBI technique to multi-isocenter conformal arc therapy techniques such as Volumetric Modulated Arc Therapy (VMAT) or Helical Tomotherapy (HT). These techniques allow better homogeneity and control of the target prescription dose, and provide more freedom for individualized organ-at-risk sparing. The technical design of multi-isocenter/multi-plan conformal TBI is complex and should be developed carefully. A group of early adopters with conformal TBI experience using different treatment machines and treatment planning systems came together to develop technical recommendations and share experiences, in order to assist departments wishing to implement conformal TBI, and to provide ideas for standardization of practices.

Atomic force microscopy to characterize binding properties of α7-containing nicotinic acetylcholine receptors on neurokinin-1 receptor-expressing medullary respiratory neurons.

In the present study, we used atomic force microscopy (AFM) to examine the ligand-binding properties of α7-containing nicotinic acetylcholine receptors (nAChRs) expressed on neurons from the ventral respiratory group. We also determined the effect of acute and prolonged exposure to nicotine on the binding probability of nAChRs. Neurons from neonatal (postnatal day 5-10) and juvenile rats (3-4 weeks old) were cultured. Internalization of Alexa Fluor 488-conjugated substance P was used to identify respiratory neurons that expressed the neurokinin-1 receptor (NK1-R), a recognized marker of ventral respiratory group neurons. To assess functional changes in nAChRs, AFM probes conjugated with anti-α7 subunit nAChR antibody were used to interact cyclically with the surface of the soma of NK1-R-positive neurons. Measurements were made of the frequency of antibody adhesion to the α7 receptor subunit and of the detachment forces between the membrane-attached receptor and the AFM probe tip. Addition of α-bungarotoxin (a specific antagonist of α7 subunit-containing nAChRs) to the cell bath produced a 69% reduction in binding to the α7 subunit (P < 0.05, n = 10), supporting specificity of binding. Acute exposure to nicotine (1 µM added to culture media) produced an 80% reduction in nAChR antibody binding to the α7 subunit (P < 0.05, n = 9). Prolonged incubation (72 h) of the cell culture in nicotine significantly reduced α7 binding in a concentration-dependent manner. Collectively, these findings demonstrate that AFM is a sensitive tool for assessment of functional changes in nAChRs expressed on the surface of living NK1-R-expressing medullary neurons. Moreover, these data demonstrate that nicotine exposure decreases the binding probability of α7 subunit-containing nAChRs.

A critical evaluation of the PTW 2D-ARRAY seven29 and OCTAVIUS II phantom for IMRT and VMAT verification.

Quality assurance (QA) for intensity- and volumetric-modulated radiotherapy (IMRT and VMAT) has evolved substantially. In recent years, various commercial 2D and 3D ionization chamber or diode detector arrays have become available, allowing for absolute verification with near real time results, allowing for streamlined QA. However, detector arrays are limited by their resolution, giving rise to concerns about their sensitivity to errors. Understanding the limitations of these devices is therefore critical. In this study, the sensitivity and resolution of the PTW 2D-ARRAY seven29 and OCTAVIUS II phantom combination was comprehensively characterized for use in dynamic sliding window IMRT and RapidArc verification. Measurement comparisons were made between single acquisition and a multiple merged acquisition techniques to improve the effective resolution of the 2D-ARRAY, as well as comparisons against GAFCHROMIC EBT2 film and electronic portal imaging dosimetry (EPID). The sensitivity and resolution of the 2D-ARRAY was tested using two gantry angle 0° modulated test fields. Deliberate multileaf collimator (MLC) errors of 1, 2, and 5 mm and collimator rotation errors were inserted into IMRT and RapidArc plans for pelvis and head & neck sites, to test sensitivity to errors. The radiobiological impact of these errors was assessed to determine the gamma index passing criteria to be used with the 2D-ARRAY to detect clinically relevant errors. For gamma index distributions, it was found that the 2D-ARRAY in single acquisition mode was comparable to multiple acquisition modes, as well as film and EPID. It was found that the commonly used gamma index criteria of 3% dose difference or 3 mm distance to agreement may potentially mask clinically relevant errors. Gamma index criteria of 3%/2 mm with a passing threshold of 98%, or 2%/2 mm with a passing threshold of 95%, were found to be more sensitive. We suggest that the gamma index passing thresholds may be used for guidance, but also should be combined with a visual inspection of the gamma index distribution and calculation of the dose difference to assess whether there may be a clinical impact in failed regions.

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial.

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. METHODS: We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3-6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. FINDINGS: 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5-61·3), six (4·3%; 95% CI 1·6-9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2-8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2-5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5-6·2) of 138 men, three (2·2%; 0·5-6·3) of 137, and none (0·0%; 97·5% CI 0·0-2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. INTERPRETATION: Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. FUNDING: Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.

Optimised conformal total body irradiation: a heterogeneous practice, so where next?

The use of volumetric arc therapy and inverse planning has been in routine use in radiotherapy for two decades. However, use in total body irradiation (TBI) has been more recent and few guidelines exist as to how to plan or verify. This has led to heterogeneous approaches. The goal of this review is to provide an overview of current advanced planning and dosimetry verification protocols used in optimised conformal TBI as a basis for investigating the need for greater standardisation in TBI.

Evaluation of a novel phantom for the quality assurance of a six-degree-of-freedom couch 3D-printed at multiple centres.

This study aimed to validate a bespoke 3D-printed phantom for use in quality assurance (QA) of a 6 degrees-of-freedom (6DoF) treatment couch. A novel phantom design comprising a main body with internal cube structures, was fabricated at five centres using Polylactic Acid (PLA) material, with an additional phantom produced incorporating a PLA-stone hybrid material. Correctional setup shifts were determined using image registration by 3D-3D matching of high HU cube structures between obtained cone-beam computer tomography (CBCT) images to reference CTs, containing cubes with fabricated rotational offsets of 3.5°, 1.5° and -2.5° in rotation, pitch, and roll, respectively. Average rotational setup shifts were obtained for each phantom. The reproducibility of 3D-printing was probed by comparing the internal cube size as well as Hounsfield Units between each of the uniquely produced phantoms. For the five PLA phantoms, the average rot, pitch and roll correctional differences from the fabricated offsets were -0.3 ± 0.2°, -0.2 ± 0.5° and 0.2 ± 0.3° respectively, and for the PLA hybrid these differences were -0.09 ± 0.14°, 0.30 ± 0.00° and 0.03 ± 0.10°. There was found to be no statistically significant difference in average cube size between the five PLA printed phantoms, with the significant difference (P < 0.05) in HU of one phantom compared to the others attributed to setup choice and material density. This work demonstrated the capability producing a novel 3D-printed 6DoF couch QA phantom design, at multiple centres, with each unique model capable of sub-degree couch correction.

Prioritizing clinical trial quality assurance for photons and protons: A failure modes and effects analysis (FMEA) comparison.

BACKGROUND AND PURPOSE: The Global Clinical Trials RTQA Harmonization Group (GHG) set out to evaluate and prioritize clinical trial quality assurance. METHODS: The GHG compiled a list of radiotherapy quality assurance (QA) tests performed for proton and photon therapy clinical trials. These tests were compared between modalities to assess whether there was a need for different types of assessments per modality. A failure modes and effects analysis (FMEA) was performed to assess the risk of each QA failure. RESULTS: The risk analysis showed that proton and photon therapy shared four out of five of their highest-risk failures (end-to-end anthropomorphic phantom test, phantom tests using respiratory motion, pre-treatment patient plan review of contouring/outlining, and on-treatment/post-treatment patient plan review of dosimetric coverage). While similar trends were observed, proton therapy had higher risk failures, driven by higher severity scores. A sub-analysis of occurrence × severity scores identified high-risk scores to prioritize for improvements in RTQA detectability. A novel severity scaler was introduced to account for the number of patients affected by each failure. This scaler did not substantially alter the ranking of tests, but it elevated the QA program evaluation to the top 20th percentile. This is the first FMEA performed for clinical trial quality assurance. CONCLUSION: The identification of high-risk errors associated with clinical trials is valuable to prioritize and reduce errors in radiotherapy and improve the quality of trial data and outcomes, and can be applied to optimize clinical radiotherapy QA.

Universal evaluation of MLC models in treatment planning systems based on a common set of dynamic tests.

PURPOSE: To demonstrate the feasibility of characterising MLCs and MLC models implemented in TPSs using a common set of dynamic beams. MATERIALS AND METHODS: A set of tests containing synchronous (SG) and asynchronous sweeping gaps (aSG) was distributed among twenty-five participating centres. Doses were measured with a Farmer-type ion chamber and computed in TPSs, which provided a dosimetric characterisation of the leaf tip, tongue-and-groove, and MLC transmission of each MLC, as well as an assessment of the MLC model in each TPS. Five MLC types and four TPSs were evaluated, covering the most frequent combinations used in radiotherapy departments. RESULTS: Measured differences within each MLC type were minimal, while large differences were found between MLC models implemented in clinical TPSs. This resulted in some concerning discrepancies, especially for the HD120 and Agility MLCs, for which differences between measured and calculated doses for some MLC-TPS combinations exceeded 10%. These large differences were particularly evident for small gap sizes (5 and 10 mm), as well as for larger gaps in the presence of tongue-and-groove effects. A much better agreement was found for the Millennium120 and Halcyon MLCs, differences being within ± 5% and ± 2.5%, respectively. CONCLUSIONS: The feasibility of using a common set of tests to assess MLC models in TPSs was demonstrated. Measurements within MLC types were very similar, but TPS dose calculations showed large variations. Standardisation of the MLC configuration in TPSs is necessary. The proposed procedure can be readily applied in radiotherapy departments and can be a valuable tool in IMRT and credentialing audits.

Endogenous brain-derived neurotrophic factor in the nucleus tractus solitarius tonically regulates synaptic and autonomic function.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are highly expressed in the nucleus tractus solitarius (nTS), the principal target of cardiovascular primary afferent input to the brainstem. However, little is known about the role of BDNF signaling in nTS in cardiovascular homeostasis. We examined whether BDNF in nTS modulates cardiovascular function in vivo and regulates synaptic and/or neuronal activity in isolated brainstem slices. Microinjection of BDNF into the rat medial nTS (mnTS), a region critical for baroreflex control of sympathetic outflow, produced dose-dependent increases in mean arterial pressure (MAP), heart rate (HR), and lumbar sympathetic nerve activity (LSNA) that were blocked by the tyrosine kinase inhibitor K252a. In contrast, immunoneutralization of endogenous BDNF (anti-BDNF), or microinjection of K252a alone, decreased MAP, HR, and LSNA. The effects of anti-BDNF were abolished by blockade of ionotropic glutamate receptors, indicating a role for glutamate signaling in the response to BDNF. In vitro, BDNF reduced the amplitude of miniature EPSCs as well as solitary tract (TS) evoked EPSC amplitude and action potential discharge (APD) in second-order nTS neurons. BDNF effects on EPSCs were independent of GABAergic signaling and abolished by AMPA receptor blockade. In contrast, K252a increased spontaneous EPSC frequency and TS evoked EPSC amplitude. BDNF also attenuated APD evoked by injection of depolarizing current into second-order neurons, indicating reduced intrinsic neuronal excitability. Our data demonstrate that BDNF signaling in mnTS plays a tonic role in regulating cardiovascular function, likely via modulation of primary afferent glutamatergic excitatory transmission and neural activity.

Hypoxia activates nucleus tractus solitarii neurons projecting to the paraventricular nucleus of the hypothalamus.

Peripheral chemoreceptor afferent information is sent to the nucleus tractus solitarii (nTS), integrated, and relayed to other brain regions to alter cardiorespiratory function. The nTS projects to the hypothalamic paraventricular nucleus (PVN), but activation and phenotype of these projections during chemoreflex stimulation is unknown. We hypothesized that activation of PVN-projecting nTS neurons occurs primarily at high intensities of hypoxia. We assessed ventilation and cardiovascular parameters in response to increasing severities of hypoxia. Retrograde tracers were used to label nTS PVN-projecting neurons and, in some rats, rostral ventrolateral medulla (RVLM)-projecting neurons. Immunohistochemistry was performed to identify nTS cells that were activated (Fos-immunoreactive, Fos-IR), catecholaminergic, and GABAergic following hypoxia. Conscious rats underwent 3 h normoxia (n = 4, 21% O(2)) or acute hypoxia (12, 10, or 8% O(2); n = 5 each). Hypoxia increased ventilation and the number of Fos-IR nTS cells (21%, 13 ± 2; 12%, 58 ± 4; 10%, 166 ± 22; 8%, 186 ± 6). Fos expression after 10% O(2) was similar whether arterial pressure was allowed to decrease (-13 ± 1 mmHg) or was held constant. The percentage of PVN-projecting cells activated was intensity dependent, but contrary to our hypothesis, PVN-projecting nTS cells exhibiting Fos-IR were found at all hypoxic intensities. Notably, at all intensities of hypoxia, ∼75% of the activated PVN-projecting nTS neurons were catecholaminergic. Compared with RVLM-projecting cells, a greater percentage of PVN-projecting nTS cells was activated by 10% O(2). Data suggest that increasing hypoxic intensity activates nTS PVN-projecting cells, especially catecholaminergic, PVN-projecting neurons. The nTS to PVN catecholaminergic pathway may be critical even at lower levels of chemoreflex activation and more important to cardiorespiratory responses than previously considered.

Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial.

BACKGROUND: Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. METHODS: We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. FINDINGS: 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0-59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival. INTERPRETATION: Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. FUNDING: Cancer Research UK (CRUK/03/005).

Volumetric modulated arc therapy (VMAT): a review of clinical outcomes-what is the clinical evidence for the most effective implementation?

Modern conformal radiation therapy using techniques such as modulation, image guidance and motion management have changed the face of radiotherapy today offering superior conformity, efficiency, and reproducibility to clinics worldwide. This review assesses the impact of these advanced radiotherapy techniques on patient toxicity and survival rates reported from January 2017 to September 2020. The main aims are to establish if dosimetric and efficiency gains correlate with improved survival and reduced toxicities and to answer the question 'What is the clinical evidence for the most effective implementation of VMAT?'. Compared with 3DCRT, improvements have been reported with VMAT in prostate, locally advanced cervical carcinoma and various head and neck applications, leading to the shift in technology to VMAT. Other sites such as thoracic neoplasms and nasopharyngeal carcinomas have observed some improvement with VMAT although not in line with improved dosimetric measures, and the burden of toxicity and the incidence of cancer related deaths remain high, signaling the need to further mitigate toxicity and increase survival. As technological advancement continues, large randomised long-term clinical trials are required to determine the way-forward and offer site-specific recommendations. These studies are usually expensive and time consuming, therefore utilising pooled real-world data in a prospective nature can be an alternative solution to comprehensively assess the efficacy of modern radiotherapy techniques.

SEAFARER - A new concept for validating radiotherapy patient specific QA for clinical trials and clinical practice.

BACKGROUND: The quality of radiotherapy delivery has been shown to significantly impact clinical outcomes including patient survival. To identify errors, institutions perform Patient Specific Quality Assurance (PSQA) assessing each individual radiotherapy plan prior to starting patient treatments. Externally administered Dosimetry Audits have found problems despite institutions passing their own PSQA. Hence a new audit concept which assesses the institution's ability to detect errors with their routine PSQA is needed. METHODS: Purposefully introduced edits which simulated treatment delivery errors were embedded into radiation treatment plans of participating institutions. These were designed to produce clinically significant changes yet were mostly within treatment delivery specifications. Actual impact was centrally assessed for each plan. Institutions performed PSQA on each plan, without knowing which contained errors. RESULTS: Seventeen institutions using six radiation treatment planning systems and two delivery systems performed PSQA on twelve plans each. Seventeen erroneous plans (across seven institutions) passed PSQA despite causing >5% increase in spinal cord dose relative to the original plans. Six plans (from four institutions) passed despite a >10% increase. CONCLUSIONS: This novel audit concept evolves beyond testing an institution's ability to deliver a single test case, to increasing the number of errors caught by institutions themselves, thus increasing quality of radiation therapy and impacting every patient treated. Administered remotely this audit also provides advantages in cost, environmental impact, and logistics.

The 3rd ESTRO-EFOMP core curriculum for medical physics experts in radiotherapy.

PURPOSE: To update the 2011 ESTRO-EFOMP core curriculum (CC) for education and training of medical physics experts (MPE)s working in radiotherapy (RT), in line with recent EU guidelines, and to provide a framework for European countries to develop their own curriculum. MATERIAL AND METHODS: Since September 2019, 27 European MPEs representing ESTRO, EFOMP and National Societies, with expertise covering all subfields of RT physics, have revised the CC for recent advances in RT. The ESTRO and EFOMP Education Councils, all European National Societies and international stakeholders have been involved in the revision process. RESULTS: A 4-year training period has been proposed, with a total of 240 ECTS (European Credit Transfer and Accumulation System). Training entrance levels have been defined ensuring the necessary physics and mathematics background. The concept of competency-based education has been reinforced by introducing the CanMEDS role framework. The updated CC includes (ablative) stereotactic-, MR-guided- and adaptive RT, particle therapy, advanced automation, complex quantitative data analysis (big data/artificial intelligence), use of biological images, and personalized treatments. Due to the continuously increasing RT complexity, more emphasis has been given to quality management. Clear requirements for a research project ensure a proper preparation of MPE residents for their central role in science and innovation in RT. CONCLUSION: This updated, 3rd edition of the CC provides an MPE training framework for safe and effective practice of modern RT, while acknowledging the significant efforts needed in some countries to reach this level. The CC can contribute to further harmonization of MPE training in Europe.

Clinical use, challenges, and barriers to implementation of deformable image registration in radiotherapy - the need for guidance and QA tools.

OBJECTIVE: The aim of this study was to evaluate the current status of the clinical use of deformable image registration (DIR) in radiotherapy and to gain an understanding of the challenges faced by centres in clinical implementation of DIR, including commissioning and quality assurance (QA), and to determine the barriers faced. The goal was to inform whether additional guidance and QA tools were needed. METHODS: A survey focussed on clinical use, metrics used, how centres would like to use DIR in the future and challenges faced, was designed and sent to 71 radiotherapy centres in the UK. Data were gathered specifically on which centres we using DIR clinically, which applications were being used, what commissioning and QA tests were performed, and what barriers were preventing the integration of DIR into the clinical workflow. Centres that did not use DIR clinically were encouraged to fill in the survey and were asked if they have any future plans and in what timescale. RESULTS: 51 out of 71 (70%) radiotherapy centres responded. 47 centres reported access to a commercial software that could perform DIR. 20 centres already used DIR clinically, and 22 centres had plans to implement an application of DIR within 3 years of the survey. The most common clinical application of DIR was to propagate contours from one scan to another (19 centres). In each of the applications, the types of commissioning and QA tests performed varied depending on the type of application and between centres. Some of the key barriers were determining when a DIR was satisfactory including which metrics to use, and lack of resources. CONCLUSION: The survey results highlighted that there is a need for additional guidelines, training, better tools for commissioning DIR software and for the QA of registration results, which should include developing or recommending which quantitative metrics to use. ADVANCES IN KNOWLEDGE: This survey has given a useful picture of the clinical use and lack of use of DIR in UK radiotherapy centres. The survey provided useful insight into how centres commission and QA DIR applications, especially the variability among centres. It was also possible to highlight key barriers to implementation and determine factors that may help overcome this which include the need for additional guidance specific to different applications, better tools and metrics.