Publications by authors named "Alan McWilliam"

42 Publications

Optimising use of 4D-CT phase information for radiomics analysis in lung cancer patients treated with stereotactic body radiotherapy.

Phys Med Biol 2021 Apr 21. Epub 2021 Apr 21.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom., The University of Manchester, Manchester, Manchester, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.

Purpose: 4D-CT is routine imaging for lung cancer patients treated with stereotactic body radiotherapy. No studies have investigated optimal 4D phase selection for radiomics. We aim to determine how phase data should be used to identify prognostic biomarkers for distant failure, and test whether stability assessment is required. A phase selection approach will be developed to aid studies with different 4D protocols, and account for patient differences.

Methods: 186 features were extracted from the tumour and peritumour on all phases for 258 patients. Feature values were selected from phase features using four methods: A) mean across phases, B) median across phases, C) 50% phase, and D) the most stable phase (closest in value to two neighbours), coined personalised selection. Four levels of stability assessment were also analysed, with inclusion of: 1) all features, 2) stable features across all phases, 3) stable features across phase and neighbour phases, and 4) features averaged over neighbour phases. Clinical-radiomics models were built for twelve combinations of feature type and assessment method. Model performance was assessed by concordance index and fraction of new information from radiomic features.

Results: The most stable phase spanned the whole range but was most often near exhale. All radiomic signatures provided new information for distant failure prediction. The personalised model had the highest concordance index (0.77), and 58% of new information was provided by radiomic features when no stability assessment was performed.

Conclusion: The most stable phase varies per-patient and selecting this improves model performance compared to standard methods. We advise the single most stable phase should be determined by minimising feature differences to neighbour phases. Stability assessment over all phases decreases performance by excessively removing features. Instead, averaging of neighbour phases should be used when stability is of concern. The models suggest that higher peritumoural intensity predicts distant failure.
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http://dx.doi.org/10.1088/1361-6560/abfa34DOI Listing
April 2021

Novel methodology to assess the effect of contouring variation on treatment outcome.

Med Phys 2021 Mar 26. Epub 2021 Mar 26.

Division of Cancer Studies - School of Medical Sciences - Faculty of Biology- Medicine and Health, University of Manchester, Manchester, M20 4BX, UK.

Purpose: Contouring variation is one of the largest systematic uncertainties in radiotherapy, yet its effect on clinical outcome has never been analyzed quantitatively. We propose a novel, robust methodology to locally quantify target contour variation in a large patient cohort and find where this variation correlates with treatment outcome. We demonstrate its use on biochemical recurrence for prostate cancer patients.

Method: We propose to compare each patient's target contours to a consistent and unbiased reference. This reference was created by auto-contouring each patient's target using an externally trained deep learning algorithm. Local contour deviation measured from the reference to the manual contour was projected to a common frame of reference, creating contour deviation maps for each patient. By stacking the contour deviation maps, time to event was modeled pixel-wise using a multivariate Cox proportional hazards model (CPHM). Hazard ratio (HR) maps for each covariate were created, and regions of significance found using cluster-based permutation testing on the z-statistics. This methodology was applied to clinical target volume (CTV) contours, containing only the prostate gland, from 232 intermediate- and high-risk prostate cancer patients. The reference contours were created using ADMIRE® v3.4 (Elekta AB, Sweden). Local contour deviations were computed in a spherical coordinate frame, where differences between reference and clinical contours were projected in a 2D map corresponding to sampling across the coronal and transverse angles every 3°. Time to biochemical recurrence was modeled using the pixel-wise CPHM analysis accounting for contour deviation, patient age, Gleason score, and treated CTV volume.

Results: We successfully applied the proposed methodology to a large patient cohort containing data from 232 patients. In this patient cohort, our analysis highlighted regions where the contour variation was related to biochemical recurrence, producing expected and unexpected results: (a) the interface between prostate-bladder and prostate-seminal vesicle interfaces where increase in the manual contour relative to the reference was related to a reduction of risk of biochemical recurrence by 4-8% per mm and (b) the prostate's right, anterior and posterior regions where an increase in the manual contour relative to the reference contours was related to an increase in risk of biochemical recurrence by 8-24% per mm.

Conclusion: We proposed and successfully applied a novel methodology to explore the correlation between contour variation and treatment outcome. We analyzed the effect of contour deviation of the prostate CTV on biochemical recurrence for a cohort of more than 200 prostate cancer patients while taking basic clinical variables into account. Applying this methodology to a larger dataset including additional clinically important covariates and externally validating it can more robustly identify regions where contour variation directly relates to treatment outcome. For example, in the prostate case we use to demonstrate our novel methodology, external validation will help confirm or reject the counter-intuitive results (larger contours resulting in higher risk). Ultimately, the results of this methodology could inform contouring protocols based on actual patient outcomes.
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http://dx.doi.org/10.1002/mp.14865DOI Listing
March 2021

Dose surface maps of the heart can identify regions associated with worse survival for lung cancer patients treated with radiotherapy.

Phys Imaging Radiat Oncol 2020 Jul 30;15:46-51. Epub 2020 Jul 30.

Division of Clinical Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK.

Background And Purpose: For lung cancer patients treated with radiotherapy, radiation dose to the heart has been associated with overall survival, with volumetric dose statistics widely presented. However, critical cardiac structures are present on the hearts surface, where this approach may be sub-optimal. In this work we present a methodology for creating cardiac surface dose maps and identify regions where excess dose is associated with in worse overall survival.

Material And Methods: A modified cylindrical coordinate system was implemented to map the cardiac surface dose for lung cancer patients. Validation was performed by mapping the cardiac chambers for 55 patients, fitting a point spread function (PSF) to the blurred edge. To account for this uncertainty, dose maps were blurred by a 2D-Gaussian with width described by the PSF. Permutation testing identified regions where excess dose was associated with worse patient survival. The 99th percentile of the max t-value then defined a cardiac surface region to extract dose, from each patient, to be analysed in a multivariable cox-proportional hazards survival model.

Results: Cardiac surface maps were created for 648 lung cancer patients. Cardiac surface dose maps were blurred with a 2D- Gaussian filter of size σ = 4.3° and σ = 1.3units to account for mapping uncertainties. Permutation testing identified significant differences across the surface of the right atria, p < 0.001, at all timepoints. The median dose to the region defined by the 99th percentile of the maximum t-value was 18.5 Gy. Multivariable analysis showed the dose to this region was significantly associated with survival, hazard ratio 1.01 Gy, p = 0.03, controlling for confounding variables.

Conclusions: Cardiac surface mapping was successfully implemented and identified a region where excess dose was associated with worse patient survival. This region extended over the right atria, potentially suggesting an interaction with the hearts electrical conduction system.
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http://dx.doi.org/10.1016/j.phro.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807666PMC
July 2020

Sarcopenia in cancer: Risking more than muscle loss.

Tech Innov Patient Support Radiat Oncol 2020 Dec 9;16:50-57. Epub 2020 Nov 9.

Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK.

Sarcopenia is characterised by progressive and extensive skeletal muscle degeneration and is associated with functional decline. Sarcopenia has primary and secondary aetiology, arising as a result of the ageing process or through chronic cytokine-mediated inflammation (associated with health conditions including cancer), respectively. Diagnosis of sarcopenia is dependent upon detection of reduced skeletal muscle strength, mass and performance. A combination of non-radiological and radiological methods can be used to assess each of these in turn to accurately diagnose sarcopenia. Sarcopenia is known to adversely affect outcomes of patients with various forms of cancer. Early identification of sarcopenia is imperative in improving patient care and overall prognosis. Various interventions, such as resistance exercise, nutritional support, and amino acid and vitamin supplementation have shown promise in the management of sarcopenia. However, further insight into novel interventions and indeed, assessment of the benefits of management of sarcopenia in terms of survival, are required to better support cancer patients.
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http://dx.doi.org/10.1016/j.tipsro.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769854PMC
December 2020

Influence of abiraterone and enzalutamide on body composition in patients with metastatic castration resistant prostate cancer.

Cancer Treat Res Commun 2020 1;25:100256. Epub 2020 Dec 1.

Manchester Cancer Research Centre, Division of Cancer Sciences, University of Manchester, 555 Wilmslow Road, Manchester M204GJ, United Kingdom; Department of Medical Oncology, Istituto Oncologico della Svizzera Italiana, Via Ospedale 12,6500 Bellinzona, Switzerland.

Introduction: Loss of skeletal muscle (SM) and gain of subcutaneous fat (SCF) are known side-effects of androgen-deprivation in treatment of prostate cancer. Scarce data is available concerning the effects of abiraterone/pred (ABI) on body composition and no published data regarding enzalutamide (ENZA). Our objective was to analyse the effects of ENZA on SM/SCF and to compare the results with ABI in patients with metastatic castration-resistant prostate-cancer (mCRPC).

Patients And Methods: 54 patients starting ABI (n = 17) or ENZA (n = 37) at a single-centre between 2012 and 2018 were retrospectively identified. SM and SCF were assessed using CT-scans at baseline and after a median of 10.8 months on treatment. A deep learning image-segmentation software was used to quantify SM and SCF. In a subgroup of patients receiving ENZA within a trial, we investigated change of SM using serial timepoints.

Results: Median time of treatment with ABI/ENZA was 14.6 months. A significant loss of SM compared to baseline was observed for ENZA (mean loss 5.2%, p<0.0001) and ABI (mean loss 3.0%, p = 0.02). SCF was not significantly altered. The effects of both drugs did not differ significantly. Loss of SM occurred early on during treatment with ENZA.

Conclusion: Treatment with ENZA seems to lead to a loss of SM which is comparable to that of ABI. Further evaluation in larger patient-cohorts is warranted. In routine care, counselling of patients about side effects of ABI/ENZA should include discussions about SM loss.
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http://dx.doi.org/10.1016/j.ctarc.2020.100256DOI Listing
December 2020

Automated gross tumor volume contour generation for large-scale analysis of early-stage lung cancer patients planned with 4D-CT.

Med Phys 2021 Feb 30;48(2):724-732. Epub 2020 Dec 30.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Purpose: Patients with early-stage lung cancer undergoing stereotactic ablative radiotherapy receive four-dimensional computed tomography (4D-CT) for treatment planning. Often, an internal gross target volume (iGTV), which approximates the motion envelope of a tumor over the breathing cycle, is delineated without defining a gross tumor volume (GTV). However, the GTV volume and shape are important parameters for prognostic and dose modelling, and there is interest in radiomic features extracted from the GTV and surrounding tissue. We demonstrate and validate a method to generate the GTV from an iGTV contour to aid retrospective analysis on routine data.

Method: It is possible to reconstruct the geometry of a tumor with knowledge of tumor motion and the motion envelope formed during respiration. To demonstrate this, the tumor motion path was estimated with local rigid registration, and the iGTV positioned incrementally at stations along the reverse path. It is shown that the tumor volume is the largest set common to the intersection of the iGTV at these positions, hence can be derived. This was implemented for 521 lung lesions on 4D-CT. Eleven patients with a GTV delineation performed by a radiation oncologist on a reference phase (50%) were used for validation. The generated GTV was compared to that delineated by the expert using distance-to-agreement (DTA), volume, and distance between centres of mass. An overall success rate was determined by detecting registration inaccuracy and performing a quality check on the routine iGTV. For successfully generated contours, GTV volume was compared to iGTV volume in a prognostic model for overall survival.

Results: For the validation dataset, DTA mean (0.79 - 1.55 mm) and standard deviation (0.68 - 1.51 mm) were comparable to expected observer variation. Difference in volume was < 5 cm , and average difference in position was 1.21 mm. Deviations in shape and position were mainly caused by observer differences in iGTV and GTV interpretation as opposed to algorithm performance. For the complete dataset, an acceptable contour was generated for 94% of patients using statistical and visual assessment to detect failures. Generated GTV volumes improved prognostic model performance over iGTV volumes.

Conclusion: A method to generate a GTV from an iGTV and 4D-CT dataset was developed. This method facilitates data analysis of patients with early-stage lung cancer treated in the routine setting, that is, data mining, prognostic modeling, and radiomics. Generation failure detection removes the need for visual assessment of all contours, reducing a time-consuming aspect of big-data analysis. Favorable prognostic performance of generated GTV volumes over iGTV ones demonstrates opportunities to use this methodology for future study.
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http://dx.doi.org/10.1002/mp.14644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986204PMC
February 2021

Cardiac Toxicity of Thoracic Radiotherapy: Existing Evidence and Future Directions.

J Thorac Oncol 2021 02 3;16(2):216-227. Epub 2020 Dec 3.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom; The Christie NHS Foundation Trust, Manchester, United Kingdom.

The impact of radiotherapy on the heart has become an area of interest in recent years. Many different cardiac dose-volume constraints have been associated with cardiac toxicity and survival; however, no consistent constraint has been found. Many patients undergoing treatment for lung cancer have risk factors for cardiovascular disease or known cardiac comorbidities; however, there is little evidence on the effects of radiotherapy on the heart in these patients. We aim to provide a summary of the existing literature on cardiac toxicity of lung cancer radiotherapy, propose strategies to avoid and manage cardiac toxicity, and suggest avenues for future research.
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http://dx.doi.org/10.1016/j.jtho.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870458PMC
February 2021

Predictive value of vascular calcification identified in 4D planning CT of lung cancer patients treated with stereotactic body radiation therapy.

Phys Med 2020 Oct 7;78:173-178. Epub 2020 Oct 7.

Division of Cancer Science, University of Manchester, Manchester, UK; Radiotherapy Related Research, The Christie Foundation Trust, Manchester, UK.

Purpose: The aim was to identify vascular calcification in 4DCT scan of lung cancer patients and establish the association between overall survival (OS) and vascular calcification, as surrogate for vascular health.

Methods: Vascular calcification within the thoracic cavity were segmented in 334 lung cancer patients treated with stereotactic body radiation therapy (SBRT). This has been done automatically on 4D planning CT and average reconstruction scans. Correlation between cardiac comorbidity and calcification volumes was evaluated for patients with recorded Adult Co-Morbidity Evaluation (n = 303). Associations between the identified calcifications and OS were further investigated.

Results: The volume of calcification from the average scan was significantly lower than from each phase (p < 0.001). The highest level of correlations between cardiac comorbidity and volume of the calcifications were found for one phase representing inhale and two phases representing exhale with the least motion blurring due to respiration (p < 0.005). The volume of the calcifications was subsequently averaged over these three phases. The average of calcification volumes over the three phases (denoted by inhale-exhale) showed the highest likelihood in univariate analysis and was chosen as vascular calcification measure. Cox-model suggested that tumor volume (Hazard Ratio [HR] = 1.46, p < 0.01) and inhale-exhale volume (HR = 1.05, p < 0.05) are independent factors predicting OS after adjusting for age, sex, and performance status.

Conclusion: It was feasible to use. It 4DCT scan for identifying thoracic calcifications in lung cancer patients treated with SBRT. Calcification volumes from inhale-exhale phases had the highest correlation with overall cardiac comorbidity and the average of the calcification volume obtained from these phases was an independent predictive factor for OS.
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http://dx.doi.org/10.1016/j.ejmp.2020.09.010DOI Listing
October 2020

Image Based Data Mining Using Per-voxel Cox Regression.

Front Oncol 2020 21;10:1178. Epub 2020 Jul 21.

The University of Manchester, Radiotherapy Related Research, Manchester, United Kingdom.

Image Based Data Mining (IBDM) is a novel analysis technique allowing the interrogation of large amounts of routine radiotherapy data. Using this technique, unexpected correlations have been identified between dose close to the prostate and biochemical relapse, and between dose to the base of the heart and survival in lung cancer. However, most analyses to date have considered only dose when identifying a region of interest, with confounding variables accounted for , most often using a multivariate Cox regression. In this work, we introduce a novel method to account for confounding variables directly in the analysis, by performing a Cox regression in every voxel of the dose distribution, and apply it in the analysis of a large cohort of lung cancer patients. Our method produces three-dimensional maps of hazard for clinical variables, accounting for dose at each spatial location in the patient. Results confirm that a region of interest exists in the base of the heart where those patients with poor performance status (PS), PS > 1, have a stronger adverse reaction to incidental dose, but that the effect changes when considering other clinical variables, with patient age becoming dominant. Analyses such as this will help shape future clinical trials in which hypotheses generated by the analysis will be tested.
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http://dx.doi.org/10.3389/fonc.2020.01178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386130PMC
July 2020

Identification of patterns of tumour change measured on CBCT images in NSCLC patients during radiotherapy.

Phys Med Biol 2020 10 30;65(21):215001. Epub 2020 Oct 30.

Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom. Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.

In this study, we propose a novel approach to investigate changes in the visible tumour and surrounding tissues with the aim of identifying patterns of tumour change during radiotherapy (RT) without segmentation on the follow-up images. On-treatment cone-beam computed tomography (CBCT) images of 240 non-small cell lung cancer (NSCLC) patients who received 55 Gy of RT were included. CBCTs were automatically aligned onto planning computed tomography (planning CT) scan using a two-step rigid registration process. To explore density changes across the lung-tumour boundary, eight shells confined to the shape of the gross tumour volume (GTV) were created. The shells extended 6 mm inside and outside of the GTV border, and each shell is 1.5 mm thick. After applying intensity correction on CBCTs, the mean intensity was extracted from each shell across all CBCTs. Thereafter, linear fits were created, indicating density change over time in each shell during treatment. The slopes of all eight shells were clustered to explore patterns in the slopes that show how tumours change. Seven clusters were obtained, 97% of the patients were clustered into three groups. After visual inspection, we found that these clusters represented patients with little or no density change, progression and regression. For the three groups, the survival curves were not significantly different between the groups, p-value = 0.51. However, the results show that definite patterns of tumour change exist, suggesting that it may be possible to identify patterns of tumour changes from on-treatment CBCT images.
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http://dx.doi.org/10.1088/1361-6560/aba7d3DOI Listing
October 2020

Cardiac sub-volume targeting demonstrates regional radiosensitivity in the mouse heart.

Radiother Oncol 2020 11 12;152:216-221. Epub 2020 Jul 12.

Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, United Kingdom. Electronic address:

Background And Purpose: Radiation-induced cardiac toxicity (RICT) remains one of the most critical dose limiting constraints in radiotherapy. Recent studies have shown higher doses to the base of the heart are associated with worse overall survival in lung cancer patients receiving radiotherapy. This work aimed to investigate the impact of sub-volume heart irradiation in a mouse model using small animal image-guided radiotherapy.

Materials And Methods: C57BL/6 mice were irradiated with a single fraction of 16 Gy to the base, middle or apex of the heart using a small animal radiotherapy research platform. Cone beam CT and echocardiography were performed at baseline and at 10 week intervals until 50 weeks post-treatment. Structural and functional parameters were correlated with mean heart dose (MHD) and volume of heart receiving 5 Gy (V5).

Results: All irradiated mice showed a time dependent increase in left ventricle wall thickness in diastole of ~0.2 mm detected at 10 weeks post-treatment, with the most significant and persistent changes occurring in the heart base-irradiated animals. Similarly, statistically different functional effects (p < 0.01) were observed in base-irradiated animals which showed the most significant decreases compared to controls. The observed functional changes did not correlate with MHD and V5 (R < 0.1), indicating that whole heart dosimetry parameters do not predict physiological changes resulting from cardiac sub-volume irradiation.

Conclusions: This is the first report demonstrating the structural and functional consequences of sub-volume targeting in the mouse heart and reverse translates clinical observations indicating the heart base as a critical radiosensitive region.
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http://dx.doi.org/10.1016/j.radonc.2020.07.016DOI Listing
November 2020

Protecting the Heart: A Practical Approach to Account for the Full Extent of Heart Motion in Radiation Therapy Planning.

Int J Radiat Oncol Biol Phys 2020 11 4;108(4):1082-1090. Epub 2020 Jul 4.

Radiotherapy-Related Research, University of Manchester, Manchester, United Kingdom; The Christie NHS Trust, Manchester, United Kingdom.

Purpose: Emerging evidence suggests that the heart is more radiosensitive than previously assumed; therefore, accounting for heart motion in radiation therapy planning is becoming more critical. In this study, we determined how much heart delineations based on 3-dimensional (3D) computed tomography (CT), 4-dimensional (4D) average projection (AVG), and maximum intensity projection (MIP) images should be extended to represent the full extent of heart motion during 4D imaging acquisition.

Methods And Materials: The 3D and 4D CT scans of 10 lung cancer patients treated with stereotactic ablative radiation therapy were used. Median surfaces were derived from heart delineations of 3 observers on the 3D CT, AVG, MIP, and 25% exhale scans. Per patient, the 25% exhale contour was propagated on every phase of the 4D scan. The union of all 4D phase delineations (U4D) represented the full extent of heart motion during imaging acquisition. Surface distances from U4D to 3D, AVG, and MIP volumes were calculated. Distances in the most extreme surface points (1.5 cm most superoinferior, 10% most right/left/anteroposterior) were used to derive margins accounting only for systematic (delineation) errors.

Results: Heart delineations on the MIP were the closest to the full extent of motion, requiring only ≤2.5-mm margins. Delineations on the AVG and 3D scans required margins up to 3.4 and 7.1 mm, respectively. The largest margins were for the inferior, right, and anterior aspects for the delineations on the 3D, AVG, and MIP scans, respectively.

Conclusion: Delineations on 3D, AVG, or MIP scans required extensions for representing the heart's full extent of motion, with the MIP requiring the smallest margins. Research including daily imaging to determine the random components for the margins and dosimetric measurements to determine the relevance of creating a planning organ at risk volume of the heart is required.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.068DOI Listing
November 2020

Novel Methodology to Investigate the Effect of Radiation Dose to Heart Substructures on Overall Survival.

Int J Radiat Oncol Biol Phys 2020 11 23;108(4):1073-1081. Epub 2020 Jun 23.

Division of Clinical Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.

Purpose: For patients with lung cancer treated with radiation therapy, a dose to the heart is associated with excess mortality; however, it is often not feasible to spare the whole heart. Our aim is to define cardiac substructures and dose thresholds that optimally reduce early mortality.

Methods And Materials: Fourteen cardiac substructures were delineated on 5 template patients with representative anatomies. One thousand one hundred sixty-one patients with non-small cell lung cancer were registered nonrigidly to these 5 template anatomies, and their radiation therapy doses were mapped. Mean and maximum dose to each substructure were extracted, and the means were evaluated as input to prediction models. The cohort was bootstrapped into 2 variable reduction techniques: elastic net least absolute shrinkage and selection operator and the random survival forest model. Each method was optimized to extract variables contributing most to overall survival, and model coefficients were evaluated to select these substructures. The most important variables common to both models were selected and evaluated in multivariable Cox-proportional hazard models. A threshold dose was defined, and Kaplan-Meier survival curves plotted.

Results: Nine hundred seventy-eight patients remained after visual quality assurance of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery, and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, a hazard ratio of 1.01/Gy, and P = .03 after accounting for tumor volume (P < .001), N stage (P < .01), and performance status (P = .01). The optimal threshold for the maximum dose, equivalent dose in 2-Gy fractions, was 23 Gy. Kaplan-Meier survival curves showed a significant split (log-rank P = .008).

Conclusions: The maximum dose to the combined cardiac region encompassing the right atrium, right coronary artery, and ascending aorta was found to have the greatest effect on patient survival. A maximum equivalent dose in 2-Gy fractions of 23 Gy was identified for consideration as a dose limit in future studies.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.031DOI Listing
November 2020

Radiotherapy-Related Lymphopenia Affects Overall Survival in Patients With Lung Cancer.

J Thorac Oncol 2020 10 14;15(10):1624-1635. Epub 2020 Jun 14.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom; Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.

Introduction: Lymphopenia after radiotherapy has an adverse effect on the patient's outcome. However, the relationship between radiotherapy dose delivery and lymphopenia is not fully understood. This work used image-based data mining to identify anatomical regions where the received dose is correlated with severe lymphopenia.

Methods: A total of 901 patients with lung cancer were analyzed. A Cox model was used to assess prognostic factors of overall survival (OS). Two matched groups were defined-patients with lymphopenia of grade 3 or higher and patients without lymphopenia of grade 3-based on tumor volume, baseline lymphocytes, and prescribed dose. Then, data mining was used to identify regions where dose correlates significantly with lymphopenia of grade 3 or higher. For this, dose matrices were aligned using registration of the computed tomography images to one reference patient. Mean dose distributions were obtained for the two groups, and organs of significance were detected. Dosimetric parameters from the identified organs that had the highest correlation with lymphocytes at nadir were selected. Multivariable analysis was conducted for lymphopenia of grade 3 or higher on the full lung cohort, and the model was tested on 305 patients with esophageal cancer.

Results: Adjusted Cox regression revealed that lymphopenia of grade 3 or higher is an independent factor of OS. The anatomical regions identified were the heart, lung, and thoracic vertebrae. Dosimetric parameters for lymphopenia included thoracic vertebrae V, mean lung dose, and mean heart dose, which were further validated in the esophageal cancer cohort.

Conclusions: We report that severe lymphopenia during radiotherapy is a poor prognostic factor for OS in patients with lung cancer and could be mitigated by minimizing thoracic vertebrae V, mean lung dose, and mean heart dose to limit the irradiation of stem cells and blood pool.
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http://dx.doi.org/10.1016/j.jtho.2020.06.008DOI Listing
October 2020

Comparison of radiographer interobserver image registration variability using cone beam CT and MR for cervix radiotherapy.

Br J Radiol 2020 Aug 16;93(1112):20200169. Epub 2020 Jun 16.

Department of Radiotherapy, The Christie NHS Foundation Trust, Manchester, UK.

Objectives: The aim of this study was to assess the consistency of therapy radiographers performing image registration using cone beam computed tomography (CBCT)-CT, magnetic resonance (MR)-CT, and MR-MR image guidance for cervix cancer radiotherapy and to assess that MR-based image guidance is not inferior to CBCT standard practice.

Methods: 10 patients receiving cervix radiation therapy underwent daily CBCT guidance and magnetic resonance (MR) imaging weekly during treatment. Offline registration of each MR image, and corresponding CBCT, to planning CT was performed by five radiographers. MR images were also registered to the earliest MR interobserver variation was assessed using modified Bland-Altman analysis with clinically acceptable 95% limits of agreement (LoA) defined as ±5.0 mm.

Results: 30 CBCT-CT, 30 MR-CT and 20 MR-MR registrations were performed by each observer. Registration variations between CBCT-CT and MR-CT were minor and both strategies resulted in 95% LoA over the clinical threshold in the anteroposterior direction (CBCT-CT ±5.8 mm, MR-CT ±5.4 mm). MR-MR registrations achieved a significantly improved 95% LoA in the anteroposterior direction (±4.3 mm). All strategies demonstrated similar results in lateral and longitudinal directions.

Conclusion: The magnitude of interobserver variations between CBCT-CT and MR-CT were similar, confirming that MR-CT radiotherapy workflows are comparable to CBCT-CT image-guided radiotherapy. Our results suggest MR-MR radiotherapy workflows may be a superior registration strategy.

Advances In Knowledge: This is the first publication quantifying interobserver registration of multimodality image registration strategies for cervix radical radiotherapy patients.
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http://dx.doi.org/10.1259/bjr.20200169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446016PMC
August 2020

Impact of small residual setup errors after image guidance on heart dose and survival in non-small cell lung cancer treated with curative-intent radiotherapy.

Radiother Oncol 2020 11 14;152:177-182. Epub 2020 Apr 14.

Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, UK.

Background And Purpose: A recent study of NSCLC patients showed small residual setup errors (shifts) in the direction of the heart following image-guidance were significantly related to overall survival. This study of the dosimetric effects of these residual shifts investigates the hypothesis that observed survival differences were related to a change in heart dose.

Materials And Methods: Accumulated doses including shifts for each fraction were determined for 475 NSCLC patients. Planning CTs and corresponding dose distributions were deformed to a reference. Image-based data-mining techniques were then applied to the difference between the planned and accumulated dose (Δdose) to determine where Δdose relates to 1-year survival. The significance of Δdose in the identified region was assessed using multivariable Cox analysis. The cohort was then split into octiles, based upon planned dose to the region, and multivariable Cox analysis performed for each sub-cohort to explore the dose response relationship. The identified dose threshold for damage was then tested in an independent validation cohort of 1482 NSCLC patients from the same institution.

Results: Permutation testing identified a small region in the heart base where Δdose significantly correlated with 1-year survival. Δdose in this region showed no correlation with common clinical variables, and was significant in multivariable Cox regression (p < 0.001, hazard ratio 1.221/Gy), with increasing change in dose from plan resulting in greater risk of death. Octile analysis revealed Δdose to be significant only in the 7th octile, planning dose 16.2-23.4 Gy, suggesting a steep dose-effect relation for heart damage in this range. Taking 16.2 Gy as a conservative threshold dose, this result was successfully validated, with a significant difference being seen between patients with a region dose above or below 16.2 Gy.

Conclusions: This study suggests the relation between residual set-up errors and survival is explained by changes in cardiac dose, and identifies an area at the heart base where dose is correlated with survival. Our results suggest the dose threshold for cardiac damage is between 16.2 and 23.4 Gy in the base of the heart, which was validated in an independent cohort. However, the dose effect in other regions of the heart should also be investigated.
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http://dx.doi.org/10.1016/j.radonc.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707351PMC
November 2020

Characterizing local dose perturbations due to gas cavities in magnetic resonance-guided radiotherapy.

Med Phys 2020 Jun 21;47(6):2484-2494. Epub 2020 Apr 21.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Purpose: Due to differences in attenuation and the electron return effect (ERE), the presence of gas can increase the risk of toxicity in organs at risk (OAR) during magnetic resonance-guided radiotherapy (MRgRT). Current adaptive MRgRT workflows using density overrides negate gas from the dose calculation, meaning that the effects of ERE around gas are not taken into account. In order to achieve an accurate adaptive MRgRT treatment, we should be able to quickly evaluate whether gas present during treatment causes dose constraint violation during an MRgRT fraction. We propose an analytic method for predicting dose perturbations caused by air cavities in OARs during MRgRT.

Method: Ten virtual water phantoms were created: nine containing a centrally located spherical air cavity and a reference phantom without an air cavity. Monte Carlo dose calculations were produced to irradiate the phantoms with a single 7 MV photon beam under the influence of a 1.5 T transverse magnetic field (Monaco 5.19.02 Treatment Panning System (TPS) (Elekta AB, Stockholm, Sweden)). Dose distributions of the phantoms with and without air cavities were compared. We used a spherical coordinate system originating in the center of the cavity to sample the dose distributions and calculate the dose perturbation as a result of the presence of each air cavity, ∆D%(θ,Φ) . Dose effects due to ERE and differences in attenuation due to density changes were considered separately. Least squared analysis was used to fit the calculated dose perturbations to mathematical functions. Effects due to ERE were fit to a modulated sinusoidal function and those due to attenuation differences were fit to a 2D Gaussian function. We used the fits to derive a single equation describing dose perturbations around spherical air cavities as a function of angles, θ, Φ, distance from cavity surface, d, and cavity radius, r. We measured the fitting error by calculating the residual error (RE); the difference between the calculated and fitted dose perturbation.

Results: Both ERE and differences in attenuation contribute toward the total dose effects of air cavities in MRgRT. Whereas ERE dominates close to the surface of the cavities, attenuation effects dominate at distances >0.5 cm from the cavities. We showed that dose effects around a spherical air cavity (≤1 cm from the surface) due to ERE fit a modulated sinusoidal function with mean (RE) ≤-1.4E-5% and root mean square error (rms) (RE) ≤4.1%. Effects due to attenuation differences fit a Gaussian function with mean (RE) ≤0.7% and rms (RE) ≤1.8%. Our general equation, which we verified using multiple sizes of spherical and cylindrical air cavity, fits Monte Carlo simulated data with mean (RE) ≤±0.9% and rms (RE) ≤6.9%.

Conclusion: We show that local dose perturbations around unplanned spherical air cavities during MRgRT can be well characterized analytically. We present an equation that can be incorporated into the clinical workflow to allow for fast evaluation of dose effects of unplanned gas. We also envision this method contributing to the clinical implementation of real time adaptive radiotherapy (ART) for MRgRT using MRI planning.
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http://dx.doi.org/10.1002/mp.14120DOI Listing
June 2020

A pilot study on dosimetric and radiomics analysis of urethral strictures following HDR brachytherapy as monotherapy for localized prostate cancer.

Br J Radiol 2020 Feb 2;93(1106):20190760. Epub 2019 Dec 2.

Mount Vernon Cancer Centre, Northwood, United Kingdom.

Objective: A cohort of high dose-rate (HDR) monotherapy patients was analyzed to (i) establish the frequency of non-malignant urethral stricture; (ii) explore the relation between stricture formation with the dose distribution along the length of the urethra, and MRI radiomics features of the prostate gland.

Methods: A retrospective review of treatment records of patients who received 19 Gy single fraction of HDR brachytherapy (BT) was carried out. A matched pair analysis used one control for each stricture case matched with pre-treatment International Prostate Symptom Score (IPSS) score, number of needles used and clinical target volume volume for each stricture case identified.For all data sets, pre-treatment weighted MRI images were used to define regions of interests along the urethra and within the whole prostate gland. MRI textural radiomics features-energy, contrast and homogeneity were selected. Wilcoxon signed-rank test was performed to investigate significant differences in dosimetric parameters and MRI radiomics feature values between cases and controls.

Results: From Nov 2010 to July 2017, there were 178 patients treated with HDR BT delivering 19 Gy in a single dose. With a median follow-up of 28.2 months, a total of 5/178 (3%) strictures were identified.10 patients were included in the matched pair analysis. The urethral dosimetric parameters investigated were not statistically different between cases and controls ( > 0.05). With regards to MRI radiomics feature analysis, significant differences were found in contrast and homogeneity between cases and controls ( < 0.05). However, this did not apply to the energy feature ( = 0.28).

Conclusion: In this matched pair analysis, no association between post-treatment stricture and urethral dosimetry was identified. Our study generated a preliminary clinical hypothesis suggesting that the MRI radiomics features of homogeneity and contrast of the prostate gland can potentially identify patients who develop strictures after HDR BT. Although the sample size is small, this warrants further validation in a larger patient cohort.

Advances In Knowledge: Urethral stricture has been reported as a specific late effect with prostate HDR brachytherapy. Our study reported a relatively low stricture rate of 3% and no association between post-treatment stricture and urethral dosimetry was identified. MRI radiomics features can potentially identify patients who are more prone to develop strictures.
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http://dx.doi.org/10.1259/bjr.20190760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055426PMC
February 2020

Magnetic resonance-guided radiation therapy: A review.

J Med Imaging Radiat Oncol 2020 Feb 23;64(1):163-177. Epub 2019 Oct 23.

Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK.

Magnetic resonance-guided radiation therapy (MRgRT) is a promising approach to improving clinical outcomes for patients treated with radiation therapy. The roles of image guidance, adaptive planning and magnetic resonance imaging in radiation therapy have been increasing over the last two decades. Technical advances have led to the feasible combination of magnetic resonance imaging and radiation therapy technologies, leading to improved soft-tissue visualisation, assessment of inter- and intrafraction motion, motion management, online adaptive radiation therapy and the incorporation of functional information into treatment. MRgRT can potentially transform radiation oncology by improving tumour control and quality of life after radiation therapy and increasing convenience of treatment by shortening treatment courses for patients. Multiple groups have developed clinical implementations of MRgRT predominantly in the abdomen and pelvis, with patients having been treated since 2014. While studies of MRgRT have primarily been dosimetric so far, an increasing number of trials are underway examining the potential clinical benefits of MRgRT, with coordinated efforts to rigorously evaluate the benefits of the promising technology. This review discusses the current implementations, studies, potential benefits and challenges of MRgRT.
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http://dx.doi.org/10.1111/1754-9485.12968DOI Listing
February 2020

Assessing localized dosimetric effects due to unplanned gas cavities during pelvic MR-guided radiotherapy using Monte Carlo simulations.

Med Phys 2019 Dec 29;46(12):5807-5815. Epub 2019 Oct 29.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Purpose: It has been proposed that beam modulation and opposing beam configurations can cancel effects of the Electron Return Effect (ERE) during MR-guided radiotherapy (MRgRT). However, this may not always be the case for unplanned gas cavities outside of the target in the pelvic region. We evaluate dosimetric effects, including effects in the rectal wall, due to unplanned spherical air cavities during MRgRT.

Methods: Nine virtual cuboid water phantoms containing spherical air cavities (0.5-7.5 cm diameter) and a reference phantom without air were created. Monte Carlo dose calculations of 7 MV photons under the influence of a 1.5 T transverse magnetic field were produced using Monaco 5.19.02 Treatment Planning System (TPS) (Elekta AB, Stockholm, Sweden). Cavities in the path of a single and multiple beam plans were considered. Dose distributions of phantoms with and without air cavities were compared (ΔD ) using a spherical coordinate system originating in the center of the cavity. Effects in the rectal wall were quantified by comparing dose volume histogram (DVH) parameters for solid and gaseous filling from simulated rectal wall structures.

Results: Max(ΔD ) of ~70% and 20% were observed around large cavities in the path of a single and multiple beam plans, respectively. Approximately 45 cm of phantom surrounding the largest cavity in a single beam received dose changes of >10%. D in the rectal wall was unchanged when comparing gaseous and solid filling in the path of a single beam; however, D and D increased by up to ~45% and ~63%, respectively.

Conclusions: Unplanned gas cavities in the path of a single beam during pelvic MRgRT with a 1.5 T transverse magnetic field cause dose changes which may impact toxicity in the rectal wall, depending on local dose and fractionation. Effects are reduced but not eliminated with a five-beam plan.
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http://dx.doi.org/10.1002/mp.13857DOI Listing
December 2019

Is tumour sphericity an important prognostic factor in patients with lung cancer?

Radiother Oncol 2020 02 28;143:73-80. Epub 2019 Aug 28.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom; Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.

Background And Purpose: Quantitative tumour shape features extracted from radiotherapy planning scans have shown potential as prognostic markers. In this study, we investigated if sphericity of the gross tumour volume (GTV) on planning computed tomography (CT) is an independent predictor of overall survival (OS) in lung cancer patients treated with standard radiotherapy. In the analysis, we considered whether tumour sphericity is correlated with clinical prognostic factors or influenced by the inclusion of lymph nodes in the GTV.

Materials And Methods: Sphericity of single GTV delineation was extracted for 457 lung cancer patients. Relationships between sphericity, and common patient and tumour characteristics were investigated via correlation analysis and multivariate Cox regression to assess prognostic value of GTV sphericity. A subset analysis was performed for 290 nodal stage N0 patients to determine prognostic value of primary tumour sphericity.

Results: Sphericity is correlated with clinical variables: tumour volume, mean lung dose, N stage, and T stage. Sphericity is strongly associated with OS (p < 0.001, hazard ratio (HR) (95% confidence interval (CI)) = 0.13 (0.04-0.41)) in univariate analysis. However, this association did not remain significant in multivariate analysis (p = 0.826, HR (95% CI) = 0.83 (0.16-4.31), and inclusion of sphericity to a clinical model did not improve model performance. In addition, no significant relationship between sphericity and OS was detected in univariate (p = 0.072) or multivariate (p = 0.920) analysis of N0 subset.

Conclusion: Sphericity correlates clearly with clinical prognostic factors, which are often unaccounted for in radiomic studies. Sphericity is also influenced by the presence of nodal involvement within the GTV contour.
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http://dx.doi.org/10.1016/j.radonc.2019.08.003DOI Listing
February 2020

New approaches for effective and safe pelvic radiotherapy in high-risk prostate cancer.

Nat Rev Urol 2019 09 25;16(9):523-538. Epub 2019 Jul 25.

Mount Vernon Cancer Centre, Northwood, UK.

Radical radiotherapy for prostate cancer offers excellent long-term outcomes for patients with high-risk disease. The increased risk of pelvic nodal involvement in this cohort has led to the development of whole-pelvis radiotherapy (WPRT) with a prostate boost. However, the use of WPRT remains controversial. Data are mixed, but advanced radiotherapy techniques enable delivery of increased radiation to pelvic nodes with acceptable levels of toxicity. Contemporary imaging modalities with increased sensitivity for detecting subclinical lymph node disease will facilitate selection of patients most likely to benefit from WPRT. Using such modalities for image guidance of advanced radiotherapy techniques could also permit high-dose delivery to nodes outside the conventional Radiation Therapy Oncology Group volumes, where magnetic resonance lymphography and single-photon-emission CT imaging have mapped a high frequency of microscopic disease. With increased toxicity a concern, an alternative to WPRT would be selective irradiation of target nodal groups most likely to harbour occult disease. New image-based 'big data' mining techniques enable the large-scale comparison of incidental dose distributions of thousands of patients treated in the past. By using novel computing methods and artificial intelligence, high-risk regions can be identified and used to optimize WPRT through refined knowledge of the likely location of subclinical disease.
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http://dx.doi.org/10.1038/s41585-019-0213-3DOI Listing
September 2019

In Regard to Zhang et al.

Int J Radiat Oncol Biol Phys 2019 08;104(5):1179-1180

Division of Molecular and Clinical Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Academic Health Science Centre, Manchester, United Kingdom; Department of Radiation Therapy Related Research, The Christie NHS Foundation Trust, Manchester, United Kingdom.

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http://dx.doi.org/10.1016/j.ijrobp.2019.04.013DOI Listing
August 2019

Organ preservation in bladder cancer: an opportunity for truly personalized treatment.

Nat Rev Urol 2019 09 13;16(9):511-522. Epub 2019 Jun 13.

Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.

Radical treatment of many solid tumours has moved from surgery to multimodal organ preservation strategies combining systemic and local treatments. Trimodality bladder-preserving treatment (TMT) comprises maximal transurethral resection of the bladder tumour followed by radiotherapy and concurrent radiosensitizing treatment, thereby sparing the urinary bladder. From the patient's perspective, the choice of maintaining quality of life without a negative effect on the chances of cure and long-term survival is attractive. In muscle-invasive bladder cancer (MIBC), the evidence shows comparable clinical outcomes between patients undergoing radical cystectomy and TMT. Despite this evidence, many patients continue to be offered radical surgery as the standard-of-care treatment. Improvements in radiotherapy techniques with adaptive radiotherapy and advances in imaging translate to increases in the accuracy of treatment delivery and reductions in long-term toxicities. With the advent of novel biomarkers promising improved prediction of treatment response, stratification of patients for different treatments on the basis of tumour biology could soon be a reality. The future of oncological treatment lies in personalized medicine with the combination of technological and biological advances leading to truly bespoke management for patients with MIBC.
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http://dx.doi.org/10.1038/s41585-019-0199-xDOI Listing
September 2019

Influence of tumour laterality on patient survival in non-small cell lung cancer after radiotherapy.

Radiother Oncol 2019 08 9;137:71-76. Epub 2019 May 9.

Division Clinical Cancer Science, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, UK; Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Manchester, UK; NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, UK.

Background: Lung cancer survival after radiotherapy remains poor and greater knowledge of normal tissue risk factors is needed to further optimise treatments. In this work, we investigate tumour laterality in a large cohort of patients treated with curative-intent radiotherapy, including the effect of dose on the right and left lungs.

Methods: 1101 NSCLC patients were included in the analysis, treated with 55 Gy in 20 fractions. Tumour laterality was determined by comparing the centre of mass of the tumour volume with the centre of mass of the lung. Right and left lungs were segmented from the whole lung contour and the mean dose to each volume calculated. Laterality and mean lung doses were included in multi-variable cox-regression survival models.

Results: 1026 patients were eligible for inclusion; 579 right-sided and 447 left-sided tumours were identified. All tumour and patient characteristics were balanced with laterality. The multi-variable models were controlled for known clinical factors: tumour volume (p < 0.001), age (p < 0.001), performance status (p < 0.05) and nodal stage (p < 0.01). Multi-variable analysis showed laterality to be highly significant (p < 0.01) with right-sided tumours showing worse overall survival than left-sided tumours (15 versus 18 months). The right lung mean dose was found to be significant (p = 0.03) for overall survival but the left lung mean dose was not (p = 0.78).

Conclusion: Our study showed that right-sided lung tumours show worse overall survival for NSCLC treated with curative-intent radiotherapy. Results suggest that the effect of laterality is through a difference in dose-response for individual lungs, with the larger, right lung, having the greater impact on survival.
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http://dx.doi.org/10.1016/j.radonc.2019.04.022DOI Listing
August 2019

Does magnetic resonance imaging improve soft tissue sarcoma contouring for radiotherapy?

BJR Open 2019 13;1(1):20180022. Epub 2019 May 13.

Department of Clinical Oncology, The Christie NHS Foundation Trust, 550 Wilmslow Road, Withington, Manchester, United Kingdom.

Objective: Soft tissue sarcomas (STS) are a rare, heterogeneous tumour group. Radiotherapy improves local control. CT is used to plan radiotherapy, but has poor soft tissue definition. MRI has superior soft tissue definition. Contour variation amongst oncologists is an important factor in treatment failure. This study is the first to directly compare STS tumour contouring using CT MRI.

Methods: Planning CT and weighted MR images of eight patients with STS were distributed to four oncologists. Gross tumour volume was contoured on both imaging modalities using in-house software. Images were recontoured 6 weeks later. The mean distance to agreement (DTA), standard deviation of the DTA, dice similarity coefficient (DSC) and contour volume were calculated for each oncologist and compared to a median contour volume. Results for CT and MRI were compared using a pairwise Student's -test.

Results: When comparing MRI to CT, tumour volumes were significantly smaller, with a difference of 21.4 cm across all patients ( = 0.008). There was not a statistically significant difference in the mean distance to agreement or dice similarity coefficient, but the standard deviation of the DTA showed a statistically significant improvement ( = 0.04). For intraobserver variation, there was no statistically significant improvement using MRI CT.

Conclusion: Oncologists contour smaller tumour volumes using MRI, with reduced interobserver variation. Improving the reliability and consistency of contouring is needed for improved quality assurance.

Advances In Knowledge: With further experience, the use of MRI in STS radiotherapy planning may reduce variation between oncologists and contribute to improved local control and reduced treatment toxicities.
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http://dx.doi.org/10.1259/bjro.20180022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592468PMC
May 2019

Post-treatment lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with radical radiotherapy.

Radiother Oncol 2019 06 20;135:115-119. Epub 2019 Mar 20.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK.

Introduction: Post-treatment lymphocytopaenia is a recognized complication of thoracic radiotherapy likely due to irradiation of a large volume of circulatory blood. We hypothesize that post-treatment absolute lymphocyte count (ALC) is associated with integral body dose and overall survival (OS) in lung cancer patients treated with radical radiotherapy.

Materials And Methods: Data on clinicopathological variables, dosimetric parameters, and pre and post-treatment blood counts were collected retrospectively in 217 lung cancer patients (131 with non-small cell lung cancer and 86 with small cell lung cancer) treated with radical radiotherapy. Induction chemotherapy followed by radiotherapy and concurrent chemoradiotherapy were delivered in 89 (42%) and 99 (47%) patients respectively. Multiple stepwise regression analysis was performed separately for ALC and absolute neutrophil count (ANC) to derive a model for prediction of post-treatment count and multivariate analysis was performed for OS using a Cox regression model.

Results: There was a significant decline in post-treatment counts for both ANC and ALC (p < 0.001). Multiple stepwise linear regression analysis confirmed pre-treatment ALC, body integral dose and use of concurrent chemotherapy as significant predictors of post-treatment ALC (R = 0.33, F(4,212) = 26.6 p < 0.001). Pre-treatment ANC, integral heart dose and number of fractions were significant predictors of post-treatment ANC (R = 0.18, F(3,213) = 16.38 p < 0.001). Low post-treatment ALC, high pre-treatment ANC, high planning target volume integral dose and lower number of fractions were predictive of inferior OS.

Conclusions: There is a negative correlation between integral body dose and post-treatment ALC which is an adverse prognostic factor in lung cancer patients treated with radical radiotherapy.
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http://dx.doi.org/10.1016/j.radonc.2019.03.008DOI Listing
June 2019

Quantitative evaluation of 4D Cone beam CT scans with reduced scan time in lung cancer patients.

Radiother Oncol 2019 07 11;136:64-70. Epub 2019 Apr 11.

Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.

Purpose: Image guided radiotherapy (IGRT) based on respiration correlated cone-beam CT (4D-CBCT) provides accurate tumour localisation in lung cancer patients by taking into account respiratory motion when deriving setup correction. However, 4D-CBCT scan times are typically longer than for acquisition of 3D-CBCT scans, e.g. 4 min. This work aims to quantitatively evaluate the effect of reduced scan times on 4D-CBCT image quality and registration accuracy in lung cancer patients.

Methods And Materials: Scan times down to 1 min were simulated by retaining only projection images corresponding to every second, third or fourth respiratory cycle in forty-four 4D-CBCTs from 15 lung cancer patients. In addition twenty 2-minute scans were acquired for 12 lung cancer patients. Image quality was quantified by assessing registration accuracy in the shorter scan times, comparing to the 4-minute scan registration result where available as reference.

Results: Use of 2-minute scans had little impact on registration accuracy or ability to detect tumour motion: automatic registration accuracy was within 2 mm in 6/8 scans analysed with 2-minute acquisitions, and 96.6% of registration discrepancies were within 2 mm for the simulated scans. When the scan time simulated was below 2 min, automatic registration results still agreed within 2 mm for 84.7% of scans, however visual image quality was considerably degraded.

Conclusion: A 4D-CBCT acquisition time of 2 min produces scans of sufficient image quality for IGRT in most lung cancer patients, as demonstrated quantitatively by assessing the impact on automatic registration accuracy in simulated and real acquisitions.
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http://dx.doi.org/10.1016/j.radonc.2019.03.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598855PMC
July 2019

Changes in prostate apparent diffusion coefficient values during radiotherapy after neoadjuvant hormones.

Ther Adv Urol 2018 Dec 11;10(12):359-364. Epub 2018 Oct 11.

The Christie NHS Foundation Trust, Manchester, UK.

Background: Changes in prostate cancer apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (MRI) provide a noninvasive method for assessing radiotherapy response. This may be attenuated by neoadjuvant hormone therapy (NA-HT). We investigate ADC values measured before, during and after external beam radiotherapy (EBRT) following NA-HT.

Methods: Patients with ⩾T2c biopsy-proven prostate cancer receiving 3 months of NA-HT plus definitive radiotherapy were prospectively identified. All underwent ADC-MRI scans in the week before EBRT, in the third week of EBRT and 8 weeks after its completion. Imaging was performed at 1.5 T. The tumour, peripheral zone (PZ) and central zone (CZ) of the prostate gland were identified and median ADC calculated for each region and time point.

Results: Between September and December 2014, 15 patients were enrolled (median age 68.3, range 57-78) with a median Gleason score of 7 (6-9) and prostate-specific antigen (PSA) at diagnosis 14 (3-197) ng/ml. Median period of NA-HT prior to first imaging was 96 days (69-115). All patients completed treatment. Median follow up was 25 months (7-34), with one patient relapsing in this time. Thirteen patients completed all imaging as intended, one withdrew after one scan and another missed the final imaging. PZ and CZ could not be identified in one patient. Median tumour ADC before, during and post radiotherapy was 1.24 × 10 mm/s (interquartile range 0.16 × 10 mm/s), 1.31 × 10 mm/s (0.22 × 10 mm/s), then 1.32 × 10 mm/s (0.13 × 10 mm/s) respectively ( > 0.05). There was no significant difference between median tumour and PZ or CZ ADC at any point. Gleason score did not correlate with ADC values.

Conclusions: Differences in ADC parameters of normal and malignant tissue during EBRT appear attenuated by prior NA-HT. The use of changes in ADC as a predictive tool in this group may have limited utility.
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http://dx.doi.org/10.1177/1756287218798748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295782PMC
December 2018

Comparison of intensity modulated radiotherapy plan optimisation methods for a 1.5 T MR-Linac.

J Appl Clin Med Phys 2019 Jan 29;20(1):43-49. Epub 2018 Oct 29.

Christie Medical Physics and Engineering (CMPE), The Christie NHS Foundation Trust, Manchester, UK.

Purpose: For the 1.5 T Elekta MR-Linac it is essential that the optimisation of a treatment plan accounts for the electron return effect on the planned dose distribution. The ability of two algorithms for the first stage fluence optimisation, pencil beam (PB) and Monte Carlo (MC), to produce acceptable plan quality was investigated. Optimisation time for each algorithm was also compared.

Methods: Ten head and neck patients, ten lung patients and five prostate patients were selected from the clinical archive. These were retrospectively planned using a research version of Monaco with both the PB and MC algorithms for the fluence optimisation stage. After full optimisation DVH parameters, optimisation time and the number of Monitor Units (MU) as a measure of plan complexity were extracted.

Results: There were no clinically significant differences between any of the DVH parameters studied or the total number of MUs between using PB or MC for stage 1 optimisation across the three patient groups. However, planning time increased by a factor of ten using MC algorithms for stage 1.

Conclusion: The use of MC calculations compared to PB, for stage 1 fluence optimisation, results in increased planning time without clinical improvement in plan quality or reduction in complexity and is therefore not necessary.
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http://dx.doi.org/10.1002/acm2.12475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333134PMC
January 2019