Brain Re-Irradiation Or Chemotherapy: a phase II randomised trial of re-irradiation and chemotherapy in patients with recurrent glioblastoma (BRIOChe) - protocol for a multi-centre open-label randomised trial.

INTRODUCTION: Glioblastoma (GBM) is the most common adult primary malignant brain tumour. The condition is incurable and, despite aggressive treatment at first presentation, almost all tumours recur after a median of 7 months. The aim of treatment at recurrence is to prolong survival and maintain health-related quality of life (HRQoL). Chemotherapy is typically employed for recurrent GBM, often using nitrosourea-based regimens. However, efficacy is limited, with reported median survivals between 5 and 9 months from recurrence. Although less commonly used in the UK, there is growing evidence that re-irradiation may produce survival outcomes at least similar to nitrosourea-based chemotherapy. However, there remains uncertainty as to the optimum approach and there is a paucity of available data, especially with regards to HRQoL. Brain Re-Irradiation Or Chemotherapy (BRIOChe) aims to assess re-irradiation, as an acceptable treatment option for recurrent IDH-wild-type GBM. METHODS AND ANALYSIS: BRIOChe is a phase II, multi-centre, open-label, randomised trial in patients with recurrent GBM. The trial uses Sargent's three-outcome design and will recruit approximately 55 participants from 10 to 15 UK radiotherapy sites, allocated (2:1) to receive re-irradiation (35 Gy in 10 daily fractions) or nitrosourea-based chemotherapy (up to six, 6-weekly cycles). The primary endpoint is overall survival rate for re-irradiation patients at 9 months. There will be no formal statistical comparison between treatment arms for the decision-making primary analysis. The chemotherapy arm will be used for calibration purposes, to collect concurrent data to aid interpretation of results. Secondary outcomes include HRQoL, dexamethasone requirement, anti-epileptic drug requirement, radiological response, treatment compliance, acute and late toxicities, progression-free survival. ETHICS AND DISSEMINATION: BRIOChe obtained ethical approval from Office for Research Ethics Committees Northern Ireland (reference no. 20/NI/0070). Final trial results will be published in peer-reviewed journals and adhere to the ICMJE guidelines. TRIAL REGISTRATION NUMBER: ISRCTN60524.

"Why am I still suffering?": Experience of long-term fatigue and neurocognitive changes in oropharyngeal cancer survivors following (chemo)radiotherapy.

Background: Late effects of cancer treatment, such as neurocognitive deficits and fatigue, can be debilitating. Other than head and neck-specific functional deficits such as impairments in swallowing and speech, little is known about survivorship after oropharyngeal cancer. This study examines the lived experience of fatigue and neurocognitive deficits in survivors of oropharyngeal squamous cell cancer and impact on their daily lives. Methods: This work is part of the multicentre mixed method ROC-oN study (Radiotherapy for Oropharyngeal Cancer and impact on Neurocognition), evaluating fatigue and neurocognitive function in patients following radiotherapy +/- chemotherapy for oropharyngeal cancer and impact on quality of life. Semi-structured interviews were conducted in adults treated with radiotherapy (+/-chemotherapy) for oropharyngeal squamous cell carcinoma >/=24 months from completing treatment. Reflexive thematic analysis performed. Results: 21 interviews (11 men and 10 women; median age 58 years and median time post-treatment 5 years) were conducted and analysed, yielding six themes: (1) unexpected burden of fatigue, (2) noticing changes in neurocognitive function, (3) the new normal, (4) navigating changes, (5)insufficient awareness and (6)required support. Participants described fatigue that persisted beyond the acute post-treatment period and changes in neurocognitive abilities across several domains. Paid and unpaid work, emotions and mood were impacted. Participants described navigating the new normal by adopting self-management strategies and accepting external support. They reported lack of recognition of these late effects, being poorly informed and being unprepared. Follow-up services were thought to be inadequate. Conclusions: Fatigue and neurocognitive impairment were frequently experienced by survivors of oropharyngeal cancer, at least two years after treatment. Patients felt ill-prepared for these late sequelae, highlighting opportunities for improvement of patient information and support services.

Preventing Suicide and Promoting Mental Health Among Student-Athletes From Diverse Backgrounds.

Suicide and contributing mental health conditions in athletes are shared concerns within health care and society at large. This commentary focuses on suicide risk among athletes and the role of sports medicine professionals in preventing suicide and promoting mental health. In this commentary, we draw on the scientific literature and our clinical experiences to pose and answer these questions: Does suicide risk among athletes vary by sociodemographic factors (eg, sex, gender, race/ethnicity, family income, sexual orientation) or if injured? Do sociodemographic differences influence access to and benefits from services among athletes? How do I know my athletes are at risk for suicide? What do I do if one of my athletes shares with me that they have considered suicide? Within our commentary, we review the current literature and clinical practices regarding these questions and close with actionable suggestions and recommendations for future directions.

Technical note: Optimization functions for re-irradiation treatment planning.

BACKGROUND: Although re-irradiation is increasingly used in clinical practice, almost no dedicated planning software exists. PURPOSE: Standard dose-based optimization functions were adjusted for re-irradiation planning using accumulated equivalent dose in 2-Gy fractions (EQD2) with rigid or deformable dose mapping, tissue-specific α/ß, treatment-specific recovery coefficients, and voxelwise adjusted EQD2 penalization levels based on the estimated previously delivered EQD2 (EQD2deliv ). METHODS: To demonstrate proof-of-concept, 35 Gy in 5 fractions was planned to a fictitious spherical relapse planning target volume (PTV) in three separate locations following previous prostate treatment on a virtual human phantom. The PTV locations represented one repeated irradiation scenario and two re-irradiation scenarios. For each scenario, three re-planning strategies with identical PTV dose-functions but various organ at risk (OAR) EQD2-functions was used: 1) reRTregular : Regular functions with fixed EQD2 penalization levels larger than EQD2deliv for all OAR voxels. 2) reRTreduce : As reRTregular , but with lower fixed EQD2 penalization levels aiming to reduce OAR EQD2. 3) reRTvoxelwise : As reRTregular and reRTreduce , but with voxelwise adjusted EQD2 penalization levels based on EQD2deliv . PTV near-minimum and near-maximum dose (D98% /D2% ), homogeneity index (HI), conformity index (CI) and accumulated OAR EQD2 (α/ß = 3 Gy) were evaluated. RESULTS: For the repeated irradiation scenario, all strategies resulted in similar dose distributions. For the re-irradiation scenarios, reRTreduce and reRTvoxelwise reduced accumulated average and near-maximum EQD2 by ˜1-10 Gy for all relevant OARs compared to reRTregular . The reduced OAR doses for reRTreduce came at the cost of distorted dose distributions with D98% = 92.3%, HI = 12.0%, CI = 73.7% and normal tissue hot spots ≥150% for the most complex scenario, while reRTregular (D98% = 98.1%, HI = 3.2%, CI = 94.2%) and reRTvoxelwise (D98%  = 96.9%, HI = 6.1%, CI = 93.7%) fulfilled PTV coverage without hot spots. CONCLUSIONS: The proposed re-irradiation-specific EQD2-based optimization functions introduce novel planning possibilities with flexible options to guide the trade-off between target coverage and OAR sparing with voxelwise adapted penalization levels based on EQD2deliv .

Neurocognitive function following (chemo)radiotherapy for nasopharyngeal cancer and other head and neck cancers: A systematic review.

When radiotherapy is used in the treatment of head and neck cancers, the brain commonly receives incidental doses of radiotherapy with potential for neurocognitive changes and subsequent impact on quality of life. This has not been widely investigated to date. A systematic search of MEDLINE, EMBASE, Psycinfo Info and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases was conducted. Of 2077 records screened, 20 were eligible comprising 1308 patients. There were no randomised studies and 73.3% of included patients were from single center studies. IMRT was delivered in 72.6% of patients, and chemotherapy used in 61%. There was considerable heterogeneity in methods. Narrative synthesis was therefore carried out. Most studies demonstrated inferior neurocognitive outcomes when compared to control groups at 12 months and beyond radiotherapy. Commonly affected neurocognitive domains were memory and language which appeared related to radiation dose to hippocampus, temporal lobe, and cerebellum. Magnetic Resonance Imaging could be valuable in the detection of early microstructural and functional changes, which could be indicative of future neurocognitive changes. In studies investigating quality of life, the presence of neurocognitive impairment was associated with inferior quality of life outcomes. (Chemo)radiotherapy for head and neck cancer appears to be associated with a risk of long-term neurocognitive impairment. Few studies were identified, with substantial variation in methodology, thus limiting conclusions. High quality large prospective head and neck cancer studies using standardised, sensitive, and reliable neurocognitive tests are needed.

Brain Re-Irradiation Robustly Accounting for Previously Delivered Dose.

(1) Background: The STRIDeR (Support Tool for Re-Irradiation Decisions guided by Radiobiology) planning pathway aims to facilitate anatomically appropriate and radiobiologically meaningful re-irradiation (reRT). This work evaluated the STRIDeR pathway for robustness compared to a more conservative manual pathway. (2) Methods: For ten high-grade glioma reRT patient cases, uncertainties were applied and cumulative doses re-summed. Geometric uncertainties of 3, 6 and 9 mm were applied to the background dose, and LQ model robustness was tested using α/ß variations (values 1, 2 and 5 Gy) and the linear quadratic linear (LQL) model δ variations (values 0.1 and 0.2). STRIDeR robust optimised plans, incorporating the geometric and α/ß uncertainties during optimisation, were also generated. (3) Results: The STRIDeR and manual pathways both achieved clinically acceptable plans in 8/10 cases but with statistically significant improvements in the PTV D98% (p < 0.01) for STRIDeR. Geometric and LQ robustness tests showed comparable robustness within both pathways. STRIDeR plans generated to incorporate uncertainties during optimisation resulted in a superior plan robustness with a minimal impact on PTV dose benefits. (4) Conclusions: Our results indicate that STRIDeR pathway plans achieved a similar robustness to manual pathways with improved PTV doses. Geometric and LQ model uncertainties can be incorporated into the STRIDeR pathway to facilitate robust optimisation.

Toxicity Prediction in Pelvic Radiotherapy Using Multiple Instance Learning and Cascaded Attention Layers.

Modern radiotherapy delivers treatment plans optimised on an individual patient level, using CT-based 3D models of patient anatomy. This optimisation is fundamentally based on simple assumptions about the relationship between radiation dose delivered to the cancer (increased dose will increase cancer control) and normal tissue (increased dose will increase rate of side effects). The details of these relationships are still not well understood, especially for radiation-induced toxicity. We propose a convolutional neural network based on multiple instance learning to analyse toxicity relationships for patients receiving pelvic radiotherapy. A dataset comprising of 315 patients were included in this study; with 3D dose distributions, pre-treatment CT scans with annotated abdominal structures, and patient-reported toxicity scores provided for each participant. In addition, we propose a novel mechanism for segregating the attentions over space and dose/imaging features independently for a better understanding of the anatomical distribution of toxicity. Quantitative and qualitative experiments were performed to evaluate the network performance. The proposed network could predict toxicity with 80% accuracy. Attention analysis over space demonstrated that there was a significant association between radiation dose to the anterior and right iliac of the abdomen and patient-reported toxicity. Experimental results showed that the proposed network had outstanding performance for toxicity prediction, localisation and explanation with the ability of generalisation for an unseen dataset.

The Relationship Between Eating Disorders, Disordered Eating, and Injury in Athletes: A Critically Appraised Topic.

CLINICAL SCENARIO: Eating disorders (EDs) and disordered eating (DE) result in numerous physical and psychological complications for female and male athletes. Besides bone-related injury, little research exists investigating what injuries EDs and/or DE contribute to. CLINICAL QUESTION: Are EDs and/or DE a risk factor for injury incidence in athletes? SUMMARY OF KEY FINDINGS: We searched for prospective studies assessing EDs or DE as a risk factor for injury in female or male athletes high school age and older. Our search returned 5 studies. One study found Eds, or DE were not a risk for any type of injury in female cross-country and track-and-field athletes. Two studies found a possible relationship between EDs or DE, as one contributing factor of others, in the incidence of bone stress injuries (BSIs) in female athletes who compete in various sports. One study found female, but not male, cross-country and track-and-field athletes with a history of EDs were more at risk for stress fractures than those without a history. One study found Eds, or DE were not a risk for BSI in female runners and triathletes. CLINICAL BOTTOM LINE: Large and important gaps in the literature exist investigating injuries related to EDs or DE outside of BSIs. There is low-moderate evidence that EDs and/or DE are either a sole, or contributing, risk factor for BSIs in female athletes. STRENGTH OF RECOMMENDATION: Grade B evidence exists to support the idea that EDs and/or DE are a risk factor for a specific type of injury (BSI) in female athletes only.

Treatment plan optimisation for reirradiation.

BACKGROUND: The STRIDeR (Support Tool for Re-Irradiation Decisions guided by Radiobiology) project aims to create a clinically viable re-irradiation planning pathway within a commercial treatment planning system (TPS). Such a pathway should account for previously delivered dose, voxel-by-voxel, taking fractionation effects, tissue recovery and anatomical changes into account. This work presents the workflow and technical solutions in the STRIDeR pathway. METHODS: The pathway was implemented in RayStation (version 9B DTK) to allow an original dose distribution to be used as background dose to guide optimisation of re-irradiation plans. Organ at risk (OAR) planning objectives in equivalent dose in 2 Gy fractions (EQD2) were applied cumulatively across the original and re-irradiation treatments, with optimisation of the re-irradiation plan performed voxel-by-voxel in EQD2. Different approaches to image registration were employed to account for anatomical change. Data from 21 patients who received pelvic Stereotactic Ablative Radiotherapy (SABR) re-irradiation were used to illustrate the use of the STRIDeR workflow. STRIDeR plans were compared to those produced using a standard manual method. RESULTS: The STRIDeR pathway resulted in clinically acceptable plans in 20/21 cases. Compared to plans produced using the laborious manual method, less constraint relaxation was required or higher re-irradiation doses could be prescribed in 3/21. CONCLUSION: The STRIDeR pathway used background dose to guide radiobiologically meaningful, anatomically-appropriate re-irradiation treatment planning within a commercial TPS. This provides a standardised and transparent approach, offering more informed re-irradiation and improved cumulative OAR dose evaluation.

Prognostic factors for patients with anal cancer treated with conformal radiotherapy-a systematic review.

AIMS: Anal cancer is primarily treated using concurrent chemoradiotherapy (CRT), with conformal techniques such as intensity modulated radiotherapy (IMRT) and volumetric arc therapy (VMAT) now being the standard techniques utilised across the world. Despite this, there is still very limited consensus on prognostic factors for outcome following conformal CRT. This systematic review aims to evaluate the existing literature to identify prognostic factors for a variety of oncological outcomes in anal cancer, focusing on patients treated with curative intent using contemporary conformal radiotherapy techniques. MATERIALS AND METHODS: A literature search was conducted using Medline and Embase to identify studies reporting on prognostic factors for survival and cancer-related outcomes after conformal CRT for anal cancer. The prognostic factors which were identified as significant in univariable and multivariable analysis, along with their respective factor effects (where available) were extracted. Only factors reported as prognostic in more than one study were included in the final results. RESULTS: The results from 19 studies were analysed. In both univariable and multivariable analysis, N stage, T stage, and sex were found to be the most prevalent and reliable clinical prognostic factors for the majority of outcomes explored. Only a few biomarkers have been identified as prognostic by more than one study - pre-treatment biopsy HPV load, as well as the presence of leukocytosis, neutrophilia and anaemia at baseline measurement. The results also highlight the lack of studies with large cohorts exploring the prognostic significance of imaging factors. CONCLUSION: Establishing a set of prognostic and potentially predictive factors for anal cancer outcomes can guide the risk stratification of patients, aiding the design of future clinical trials. Such trials will in turn provide us with greater insight into how to effectively treat this disease using a more personalised approach.

Optimising tumour coverage and organ at risk sparing for hypofractionated re-irradiation in glioblastoma.

BACKGROUND AND PURPOSE: Re-irradiation may be used for recurrent glioblastoma (GBM) patients. In some cases Planning Target Volume (PTV) under-coverage is necessary to meet organ at risk (OAR) constraints. This study aimed to develop a Volumetric Modulated Arc Therapy planning solution for GBM re-irradiation including a means of assessing if target coverage would be achievable and how much PTV 'cropping' would be required to meet OAR constraints, based on PTV volume and OAR proximity. MATERIALS AND METHODS: For 10 PTVs, 360°, 180°, two coplanar 180° and 180° + non-coplanar 45° arc arrangements were compared using 35 Gy in 10 fractions. Using the preferred arrangement, dose fall-off was modelled to determine the separation required between PTV and OAR to ensure OAR dose constraints were met, with data presented graphically. To evaluate the graph as an aid to planning, seven cases with overlap were replanned in two treatment planning systems (TPSs). RESULTS: There were no significant dosimetric differences between arc arrangements. 180° was preferred due to shorter treatment times. The graph, which indicated if 95% PTV coverage would be achievable based on PTV volume and OAR proximity, was employed in seven cases to guide planning in two TPSs. Plans were deliverable. CONCLUSIONS: Re-irradiation treatment planning can be challenging, especially when PTV under-coverage is necessary. 180° was considered optimal. To assist in the planning process, graphical guidance was produced to inform planners whether PTV under-coverage would be necessary and how much PTV 'cropping' would be required to meet constraints during optimisation.

Dose summation and image registration strategies for radiobiologically and anatomically corrected dose accumulation in pelvic re-irradiation.

BACKGROUND: Re-irradiation (reRT) is a promising technique for patients with localized recurrence in a previously irradiated area but presents major challenges. These include how to deal with anatomical change between two courses of radiotherapy and integration of radiobiology when summating original and re-irradiation doses. The Support Tool for Re-Irradiation Decisions guided by Radiobiology (STRIDeR) project aims to develop a software tool for use in a commercial treatment planning system to facilitate more informed reRT by accounting for anatomical changes and incorporating radiobiology. We evaluated three approaches to dose summation, incorporating anatomical change and radiobiology to differing extents. METHODS: In a cohort of 21 patients who previously received pelvic re-irradiation the following dose summation strategies were compared: (1) Rigid registration (RIR) and physical dose summation, to reflect the current clinical approach, (2) RIR and radiobiological dose summation in equivalent dose in 2 Gy fractions (EQD2), and (3) Patient-specific deformable image registration (DIR) with EQD2 dose summation. RESULTS: RIR and physical dose summation (Strategy 1) resulted in high cumulative organ at risk (OAR) doses being 'missed' in 14% of cases, which were highlighted by EQD2 dose summation (Strategy 2). DIR (with EQD2 dose summation; Strategy 3) resulted in improved OAR overlap and distance to agreement metrics compared to RIR (with EQD2 dose summation; Strategy 2) and was consistently preferred in terms of clinical utility. DIR was considered to have a clinically important impact on dose summation in 38% of cases. CONCLUSION: Re-irradiation cases require individualized assessment when considering dose summation with the previous treatment plan. Fractionation correction is necessary to meaningfully assess cumulative doses and reduce the risk of unintentional OAR overdose. DIR can add clinically relevant information in selected cases, especially for significant anatomical change. Robust solutions for cumulative dose assessment offer the potential for future improved understanding of cumulative OAR tolerances.

An international Delphi consensus for pelvic stereotactic ablative radiotherapy re-irradiation.

INTRODUCTION: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat metastatic oligorecurrence and locoregional recurrences but limited evidence/guidance exists in the setting of pelvic re-irradiation. An international Delphi study was performed to develop statements to guide practice regarding patient selection, pre-treatment investigations, treatment planning, delivery and cumulative organs at risk (OARs) constraints. MATERIALS AND METHODS: Forty-one radiation oncologists were invited to participate in three online surveys. In Round 1, information and opinion was sought regarding participants' practice. Guidance statements were developed using this information and in Round 2 participants were asked to indicate their level of agreement with each statement. Consensus was defined as ≥75% agreement. In Round 3, any statements without consensus were re-presented unmodified, alongside a summary of comments from Round 2. RESULTS: Twenty-three radiation oncologists participated in Round 1 and, of these, 21 (91%) and 22 (96%) completed Rounds 2 and 3 respectively. Twenty-nine of 44 statements (66%) achieved consensus in Round 2. The remaining 15 statements (34%) did not achieve further consensus in Round 3. Consensus was achieved for 10 of 17 statements (59%) regarding patient selection/pre-treatment investigations; 12 of 13 statements (92%) concerning treatment planning and delivery; and 7 of 14 statements (50%) relating to OARs. Lack of agreement remained regarding the minimum time interval between irradiation courses, the number/size of pelvic lesions that can be treated and the most appropriate cumulative OAR constraints. CONCLUSIONS: This study has established consensus, where possible, in areas of patient selection, pre-treatment investigations, treatment planning and delivery for pelvic SABR re-irradiation for metastatic oligorecurrence and locoregional recurrences. Further research into this technique is required, especially regarding aspects of practice where consensus was not achieved.

A feasibility study of hyoscine butylbromide (buscopan) to improve image quality of cone beam computed tomography during abdominal/pelvic Stereotactic Ablative Radiotherapy.

OBJECTIVES: Cone beam computed tomography (CBCT) is used for image guidance of stereotactic ablative radiotherapy (SABR), but it is susceptible to bowel motion artefacts. This trial evaluated the impact of hyoscine butylbromide (buscopan) on CBCT image quality and its feasibility within a radiotherapy workflow. METHODS: A single-centre feasibility trial (ISRCTN24362767) was performed in patients treated with SABR for abdominal/pelvic oligorecurrence. Buscopan was administered to separate cohorts by intramuscular (IM) or intravenous (i.v.) injection on alternate fractions, providing within-patient control data. 4-point Likert scales were used to assess overall image quality (ranging from excellent to impossible to use) and bowel motion artefact (ranging from none to severe). Feasibility was determined by patient/radiographer questionnaires and toxicity assessment. Descriptive statistics are presented. RESULTS: 16 patients were treated (8 by IM and 8 by i.v. buscopan). The percentage of images of excellent quality with/without buscopan was 47 vs 29% for IM buscopan and 65 vs 40% for i.v. buscopan. The percentage of images with no bowel motion artefact with/without buscopan was 24.6 vs 8.9% for IM buscopan and 25.8 vs 7% for i.v. buscopan. Four patients (25%) reported dry mouth. 14 patients (93%) would accept buscopan as routine. 11 radiographers (92%) reported no delay in treatments. CONCLUSIONS: A trend towards improved image quality/reduced bowel motion artefact was observed with IM/i.v. buscopan. Buscopan was well tolerated with limited impact on workflow. ADVANCES IN KNOWLEDGE: This is the first trial of buscopan within a radiotherapy workflow. It demonstrated a trend to improved image quality and feasibility of use.

Ultra hypofractionated extended nodal irradiation using volumetric modulated arc therapy for oligorecurrent pelvic nodal prostate cancer.

Prostate cancer (PCa) may recur after primary treatment but no standard of care exists for patients with pelvic nodal relapse. Based on obervational data, Extended Nodal Irradiation (ENI) might be associated with fewer treatment failures than Stereotactic Ablative Radiotherapy (SABR) to the involved node(s) alone. Ultra hypofractionated ENI is yet to be evaluated in this setting, but it could provide a therapeutic advantage if PCa has a low α/ß ratio in addition to patient convenience/resource benefits. This volumetric modulated arc therapy (VMAT) planning study developed a class solution for 5-fraction Extended Nodal Irradiation (ENI) plus a simultaneous integrated boost (SIB) to involved node(s). Ten patients with oligorecurrent nodal disease after radical prostatectomy/post-operative prostate bed radiotherapy were selected. Three plans were produced for each dataset to deliver 25 Gy in 5 fractions ENI plus SIBs of 40, 35 and 30 Gy. The biologically effective dose (BED) formula was used to determine the remaining dose in 5 fractions that could be delivered to re-irradiated segments of organs at risk (OARs). Tumour control probability (TCP) and normal tissue complication probability (NTCP) were calculated using the LQ-Poisson Marsden and Lyman-Kutcher-Burman models respectively. Six patients had an OAR positioned within planning target volume node (PTVn), which resulted in reduced target coverage to PTV node in six, five and four instances for 40, 35 and 30 Gy SIB plans respectively. In these instances, only 30 Gy SIB plans had a median PTV coverage >90% (inter-quartile range 90-95). No OAR constraint was exceeded for 30 Gy SIB plans, including where segments of OARs were re-irradiated. Gross tumour volume node (GTVn) median TCP was 95.7% (94.4-96), 90.7% (87.1-91.2) and 78.6% (75.8-81.1) for 40, 35 and 30 Gy SIB plans respectively, where an α/ß ratio of 1.5 was assumed. SacralPlex median NTCP was 43.2% (0.7-61.2), 12.1% (0.6-29.7) and 2.5% (0.5-5.1) for 40, 35 and 30 Gy SIB plans respectively. NTCP for Bowel_Small was <0.3% and zero for other OARs for all three plan types. Ultra hypofractionated ENI planning for pelvic nodal relapsed PCa appears feasible with encouraging estimates of nodal TCP and low estimates of NTCP, especially where a low α/ß ratio is assumed and a 30 Gy SIB is delivered. This solution should be further evaluated within a clinical trial and compared against SABR to involved node(s) alone.

Predicting outcomes in anal cancer patients using multi-centre data and distributed learning - A proof-of-concept study.

BACKGROUND AND PURPOSE: Predicting outcomes is challenging in rare cancers. Single-institutional datasets are often small and multi-institutional data sharing is complex. Distributed learning allows machine learning models to use data from multiple institutions without exchanging individual patient-level data. We demonstrate this technique in a proof-of-concept study of anal cancer patients treated with chemoradiotherapy across multiple European countries. MATERIALS AND METHODS: atomCAT is a three-centre collaboration between Leeds Cancer Centre (UK), MAASTRO Clinic (The Netherlands) and Oslo University Hospital (Norway). We trained and validated a Cox proportional hazards regression model in a distributed fashion using data from 281 patients treated with radical, conformal chemoradiotherapy for anal cancer in three institutions. Our primary endpoint was overall survival. We selected disease stage, sex, age, primary tumour size, and planned radiotherapy dose (in EQD2) a priori as predictor variables. RESULTS: The Cox regression model trained across all three centres found worse overall survival for high risk disease stage (HR = 2.02), male sex (HR = 3.06), older age (HR = 1.33 per 10 years), larger primary tumour volume (HR = 1.05 per 10 cm3) and lower radiotherapy dose (HR = 1.20 per 5 Gy). A mean concordance index of 0.72 was achieved during validation, with limited variation between centres (Leeds = 0.72, MAASTRO = 0.74, Oslo = 0.70). The global model performed well for risk stratification for two out of three centres. CONCLUSIONS: Using distributed learning, we accessed and analysed one of the largest available multi-institutional cohorts of anal cancer patients treated with modern radiotherapy techniques. This demonstrates the value of distributed learning in outcome modelling for rare cancers.

Can dosimetry affect local control and survival in patients with early-stage lung cancer treated with Stereotactic Ablative Radiotherapy (SABR)? An analysis of the UK's largest cohort of lung SABR patients.

PURPOSE/OBJECTIVES: A recent study has shown that tight conformity of lung Stereotactic Ablative Radiotherapy (SABR) plans might worsen loco-regional control and can predict distant metastases. The study aims to report overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS), and dosimetry of early-stage lung cancer patients treated with SABR and to try to explore any dosimetric predictor of outcomes. MATERIAL AND METHODS: Patients treated in our institute (May 2009-August 2018) were included. Electronic medical records were reviewed for baseline characteristics, treatment details, and outcomes. Dosimetric data were extracted from Xio and Monaco software. Patients were treated according to the United Kingdom (UK) SABR consortium guidelines. Kaplan-Meier's analysis with log-rank test was used for survival analysis. The univariate and multivariable Cox regression model was used for correlating dosimetric variables and outcomes. RESULTS: We treated 1266 patients with median age of 75 years and 47.4% were male. Median follow up was 56 months. Median OS was 36 months with 1, 2, and 5 years OS of 84.2%, 64.5%, and 31.5%, respectively. Median for PFS and LRFS was not reached. One, 2, and 5 years PFS were 87.4%, 78.4%, and 72.5%, respectively. One, 2, and 5 years LRFS were 98.2%, 95.1%, and 92.5%, respectively. Planning target volume (PTV), dose to 99% volume of PTV (D99), and R50 (volume receiving the 50% dose/volume (PTV)) were significantly associated with OS. PTV, mean lung dose (MLD), V20 (volume of lung minus gross tumour volume (GTV) receiving 20 Gy), V12.5 (volume of lung minus GTV receiving 12.5 Gy), and dose fractionation were significantly associated with PFS. Nothing was associated with LRFS on univariate analysis. R100 of >1.1 was associated with better OS, PFS, and LRFS compared to R100 ≤ 1.1. CONCLUSION: SABR achieves good clinical outcomes in patients with early-stage lung cancer; even in elderly patients with multiple comorbidities. In the largest UK early lung cancer cohort treated with SABR, we found that dosimetry correlates with clinical outcomes. Further validation of these results is needed to guide future optimisation of SABR delivery.

Clinical and dosimetric predictors of radiation pneumonitis in early-stage lung cancer treated with Stereotactic Ablative radiotherapy (SABR) - An analysis of UK's largest cohort of lung SABR patients.

BACKGROUND: Stereotactic Ablative Radiotherapy (SABR) is the standard treatment for early-stage medically inoperable lung cancer. Predictors of radiation pneumonitis (RP) in patients treated with SABR are poorly defined. In this study, we investigate clinical and dosimetric parameters, which can predict symptomatic RP in early-stage lung cancer patients treated with SABR. MATERIALS AND METHODS: Patients treated with lung SABR between May 2009 and August 2018, in a single United Kingdom (UK) radiotherapy center were included. The patient's baseline characteristics, treatment details, and toxicity were retrieved from the electronic medical record. Dosimetric data was extracted from Xio and Monaco treatment planning systems. Patients were treated according to the UK SABR consortium guidelines. RP was graded retrospectively using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, based on available clinical and imaging information. Univariate and multivariate binary logistic regression was performed to determine predictive factors for grade ≥ 2 radiation pneumonitis, using Statistical Package for the Social Sciences (SPSS) statistics version 21 software. The goodness of fit was assessed using the Hosmer and Lemeshow test. The optimal diagnostic threshold was tested using the Receiver operating characteristics (ROC) curve. The chi-square test was carried out to test the different risk factors against the likelihood of developing grade ≥ 2 pneumonitis. RESULTS: A total of 1266 patients included in the analysis. The median age of patients was 75 years. Six hundred sixty-six patients (52.6%) were female. Median follow up was 56 months. Sixty-five percent of patients received 55 Gy in 5 fractions. Forty-three percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and 16.2% had PS of 3. The Median Charlson comorbidity index was 6 (range 2-11). Median Standardized Uptake Value (SUV) max of the tumor was 6.5. Four hundred two patients (31.8%) had confirmed histological diagnosis; other patients were treated based on a radiological diagnosis. The median tumor size was 20 mm (range 4 mm-63 mm). Median Planning Target Volume (PTV) was 30.3 cc. Median values of R100, R50, and D2cm were 1.1, 5.6, 32.8 Gy. The median value of mean lung dose, V20, and V12.5 were 3.9 Gy, 5 %and 9.3% respectively. Eighty-five (6.7%) patients developed symptomatic RP (grade ≥ 2) with only 5(0.4%) developing grade 3 RP. Five percent of patients developed rib fractures but only 28% of these were symptomatic. On univariate analysis lower lobe tumor location, larger tumor size, PTV, mean lung dose, lung V20Gy, and V12.5 Gy were significantly associated with grade ≥ 2 RP. On multivariate analysis, only mean lung dose was associated with grade ≥ 2 pneumonitis. ROC curve analysis showed optimal diagnostic threshold for tumour size, PTV, mean lung dose, V20 and V12.5; are 22.5 mm ((Area Under Curve (AUC)-0.565)), 27.15 cc (AUC-0.58), 3.7 Gy (AUC-0.633), 4.6% (AUC-0.597), 9.5% (AUC-0.616). The incidence of ≥grade 2 RP was significantly high for values higher than the ROC threshold. CONCLUSION: SABR treatment resulted in a very low rate of grade 3 pneumonitis. Lower lobe tumor location, larger tumor size, PTV, mean lung dose, V20, and V12.5 were found to be significant predictors of symptomatic radiation pneumonitis.

Fully automated, multi-criterial planning for Volumetric Modulated Arc Therapy - An international multi-center validation for prostate cancer.

BACKGROUND AND PURPOSE: Reported plan quality improvements with autoplanning of radiotherapy of the prostate and seminal vesicles are poor. A system for automated multi-criterial planning has been validated for this treatment in a large international multi-center study. The system is configured with training plans using a mechanism that strives for quality improvements relative to those plans. MATERIAL AND METHODS: Each of the four participating centers included thirty manually generated clinical Volumetric Modulated Arc Therapy prostate plans (manVMAT). Ten plans were used for autoplanning training. The other twenty were compared with an automatically generated plan (autoVMAT). Plan evaluations considered dosimetric plan parameters and blinded side-by-side plan comparisons by clinicians. RESULTS: With equivalent Planning Target Volume (PTV) V95%, D2%, D98%, and dose homogeneity autoVMAT was overall superior for rectum with median differences of 3.4 Gy (p < 0.001) in Dmean, 4.0% (p < 0.001) in V60Gy, and 1.5% (p = 0.001) in V75Gy, and for bladder Dmean (0.9 Gy, p < 0.001). Also the clinicians' plan comparisons pointed at an overall preference for autoVMAT. Advantages of autoVMAT were highly treatment center- and patient-specific with overall ranges for differences in rectum Dmean and V60Gy of [-4,12] Gy and [-2,15]%, respectively. CONCLUSION: Observed advantages of autoplanning were clinically relevant and larger than reported in the literature. The latter is likely related to the multi-criterial nature of the applied autoplanning algorithm, with for each center a dedicated configuration that aims at plan improvements relative to its (clinical) training plans. Large variations among patients in differences between manVMAT and autoVMAT point at inconsistencies in manual planning.

Method for Automatic Selection of Parameters in Normal Tissue Complication Probability Modeling.

PURPOSE: To present a fully automatic method to generate multiparameter normal tissue complication probability (NTCP) models and compare its results with those of a published model, using the same patient cohort. METHODS AND MATERIALS: Data were analyzed from 345 rectal cancer patients treated with external radiation therapy to predict the risk of patients developing grade 1 or ≥2 cystitis. In total, 23 clinical factors were included in the analysis as candidate predictors of cystitis. Principal component analysis was used to decompose the bladder dose-volume histogram into 8 principal components, explaining more than 95% of the variance. The data set of clinical factors and principal components was divided into training (70%) and test (30%) data sets, with the training data set used by the algorithm to compute an NTCP model. The first step of the algorithm was to obtain a bootstrap sample, followed by multicollinearity reduction using the variance inflation factor and genetic algorithm optimization to determine an ordinal logistic regression model that minimizes the Bayesian information criterion. The process was repeated 100 times, and the model with the minimum Bayesian information criterion was recorded on each iteration. The most frequent model was selected as the final "automatically generated model" (AGM). The published model and AGM were fitted on the training data sets, and the risk of cystitis was calculated. RESULTS: The 2 models had no significant differences in predictive performance, both for the training and test data sets (P value > .05) and found similar clinical and dosimetric factors as predictors. Both models exhibited good explanatory performance on the training data set (P values > .44), which was reduced on the test data sets (P values < .05). CONCLUSIONS: The predictive value of the AGM is equivalent to that of the expert-derived published model. It demonstrates potential in saving time, tackling problems with a large number of parameters, and standardizing variable selection in NTCP modeling.