• Changes in the Management of Patients having Radical Radiotherapy for Lung Cancer during the First Wave of the COVID-19 Pandemic in the UK.

      Banfill, K; email: kathryn.banfill@manchester.ac.uk; Croxford, W; Fornacon-Wood, I; Wicks, K; Ahmad, S; Britten, A; Carson, C; Dorey, N; Hatton, M; Hiley, C; et al. (2021-10-28)
      In response to the COVID-19 pandemic, guidelines on reduced fractionation for patients treated with curative-intent radiotherapy were published, aimed at reducing the number of hospital attendances and potential exposure of vulnerable patients to minimise the risk of COVID-19 infection. We describe the changes that took place in the management of patients with stage I-III lung cancer from April to October 2020. Lung Radiotherapy during the COVID-19 Pandemic (COVID-RT Lung) is a prospective multicentre UK cohort study. The inclusion criteria were: patients with stage I-III lung cancer referred for and/or treated with radical radiotherapy between 2nd April and 2nd October 2020. Patients who had had a change in their management and those who continued with standard management were included. Data on demographics, COVID-19 diagnosis, diagnostic work-up, radiotherapy and systemic treatment were collected and reported as counts and percentages. Patient characteristics associated with a change in treatment were analysed using multivariable binary logistic regression. In total, 1553 patients were included (median age 72 years, 49% female); 93 (12%) had a change to their diagnostic investigation and 528 (34%) had a change to their treatment from their centre's standard of care as a result of the COVID-19 pandemic. Age ≥70 years, male gender and stage III disease were associated with a change in treatment on multivariable analysis. Patients who had their treatment changed had a median of 15 fractions of radiotherapy compared with a median of 20 fractions in those who did not have their treatment changed. Low rates of COVID-19 infection were seen during or after radiotherapy, with only 21 patients (1.4%) developing the disease. The COVID-19 pandemic resulted in changes to patient treatment in line with national recommendations. The main change was an increase in hypofractionation. Further work is ongoing to analyse the impact of these changes on patient outcomes. [Abstract copyright: Copyright © 2021. Published by Elsevier Ltd.]
    • Development of Randomized Trials in Adults with Medulloblastoma—The Example of EORTC 1634-BTG/NOA-23

      Hau, Peter; orcid: 0000-0003-3894-5053; email: Peter.Hau@ukr.de; Frappaz, Didier; email: Didier.Frappaz@ihope.fr; Hovey, Elizabeth; email: Elizabeth.Hovey@health.nsw.gov.au; McCabe, Martin G.; orcid: 0000-0002-5138-0707; email: Martin.McCabe@manchester.ac.uk; Pajtler, Kristian W.; email: K.Pajtler@kitz-heidelberg.de; Wiestler, Benedikt; orcid: 0000-0002-2963-7772; email: B.Wiestler@tum.de; Seidel, Clemens; email: Clemens.Seidel@medizin.uni-leipzig.de; Combs, Stephanie E.; email: Stephanie.Combs@tum.de; Dirven, Linda; email: L.Dirven@lumc.nl; Klein, Martin; email: M.Klein@amsterdamumc.nl; et al. (MDPI, 2021-07-09)
      Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
    • Early prediction of tumour-response to radiotherapy in NSCLC patients

      Amugongo, Lameck Mbangula; orcid: 0000-0001-6468-2643; email: lameckmbangula.amugongo@postgrad.manchester.ac.uk; Osorio, Eliana Vasquez; orcid: 0000-0003-0741-994X; Green, Andrew; orcid: 0000-0002-8297-0953; Cobben, David; van Herk, Marcel; McWilliam, Alan (IOP Publishing, 2021-11-05)
      Abstract: Objective. In this study we developed an automatic method to predict tumour volume and shape in weeks 3 and 4 of radiotherapy (RT), using cone-beam computed tomography (CBCT) scans acquired up to week 2, allowing identification of large tumour changes. Approach. 240 non-small cell lung cancer (NSCLC) patients, treated with 55 Gy in 20 fractions, were collected. CBCTs were rigidly registered to the planning CT. Intensity values were extracted in each voxel of the planning target volume across all CBCT images from days 1, 2, 3, 7 and 14. For each patient and in each voxel, four regression models were fitted to voxel intensity; applying linear, Gaussian, quadratic and cubic methods. These models predicted the intensity value for each voxel in weeks 3 and 4, and the tumour volume found by thresholding. Each model was evaluated by computing the root mean square error in pixel value and structural similarity index metric (SSIM) for all patients. Finally, the sensitivity and specificity to predict a 30% change in volume were calculated for each model. Main results. The linear, Gaussian, quadratic and cubic models achieved a comparable similarity score, the average SSIM for all patients was 0.94, 0.94, 0.90, 0.83 in week 3, respectively. At week 3, a sensitivity of 84%, 53%, 90% and 88%, and specificity of 99%, 100%, 91% and 42% were observed for the linear, Gaussian, quadratic and cubic models respectively. Overall, the linear model performed best at predicting those patients that will benefit from RT adaptation. The linear model identified 21% and 23% of patients in our cohort with more than 30% tumour volume reduction to benefit from treatment adaptation in weeks 3 and 4 respectively. Significance. We have shown that it is feasible to predict the shape and volume of NSCLC tumours from routine CBCTs and effectively identify patients who will respond to treatment early.
    • Early prediction of tumour-response to radiotherapy in NSCLC patients

      Amugongo, Lameck Mbangula; orcid: 0000-0001-6468-2643; email: lameckmbangula.amugongo@postgrad.manchester.ac.uk; Osorio, Eliana Vasquez; orcid: 0000-0003-0741-994X; Green, Andrew; orcid: 0000-0002-8297-0953; Cobben, David; van Herk, Marcel; McWilliam, Alan (IOP Publishing, 2021-11-05)
      Abstract: Objective. In this study we developed an automatic method to predict tumour volume and shape in weeks 3 and 4 of radiotherapy (RT), using cone-beam computed tomography (CBCT) scans acquired up to week 2, allowing identification of large tumour changes. Approach. 240 non-small cell lung cancer (NSCLC) patients, treated with 55 Gy in 20 fractions, were collected. CBCTs were rigidly registered to the planning CT. Intensity values were extracted in each voxel of the planning target volume across all CBCT images from days 1, 2, 3, 7 and 14. For each patient and in each voxel, four regression models were fitted to voxel intensity; applying linear, Gaussian, quadratic and cubic methods. These models predicted the intensity value for each voxel in weeks 3 and 4, and the tumour volume found by thresholding. Each model was evaluated by computing the root mean square error in pixel value and structural similarity index metric (SSIM) for all patients. Finally, the sensitivity and specificity to predict a 30% change in volume were calculated for each model. Main results. The linear, Gaussian, quadratic and cubic models achieved a comparable similarity score, the average SSIM for all patients was 0.94, 0.94, 0.90, 0.83 in week 3, respectively. At week 3, a sensitivity of 84%, 53%, 90% and 88%, and specificity of 99%, 100%, 91% and 42% were observed for the linear, Gaussian, quadratic and cubic models respectively. Overall, the linear model performed best at predicting those patients that will benefit from RT adaptation. The linear model identified 21% and 23% of patients in our cohort with more than 30% tumour volume reduction to benefit from treatment adaptation in weeks 3 and 4 respectively. Significance. We have shown that it is feasible to predict the shape and volume of NSCLC tumours from routine CBCTs and effectively identify patients who will respond to treatment early.
    • Early prediction of tumour-response to radiotherapy in NSCLC patients

      Amugongo, Lameck Mbangula; orcid: 0000-0001-6468-2643; email: lameckmbangula.amugongo@postgrad.manchester.ac.uk; Osorio, Eliana Vasquez; orcid: 0000-0003-0741-994X; Green, Andrew; orcid: 0000-0002-8297-0953; Cobben, David; van Herk, Marcel; McWilliam, Alan (IOP Publishing, 2021-11-05)
      Abstract: Objective. In this study we developed an automatic method to predict tumour volume and shape in weeks 3 and 4 of radiotherapy (RT), using cone-beam computed tomography (CBCT) scans acquired up to week 2, allowing identification of large tumour changes. Approach. 240 non-small cell lung cancer (NSCLC) patients, treated with 55 Gy in 20 fractions, were collected. CBCTs were rigidly registered to the planning CT. Intensity values were extracted in each voxel of the planning target volume across all CBCT images from days 1, 2, 3, 7 and 14. For each patient and in each voxel, four regression models were fitted to voxel intensity; applying linear, Gaussian, quadratic and cubic methods. These models predicted the intensity value for each voxel in weeks 3 and 4, and the tumour volume found by thresholding. Each model was evaluated by computing the root mean square error in pixel value and structural similarity index metric (SSIM) for all patients. Finally, the sensitivity and specificity to predict a 30% change in volume were calculated for each model. Main results. The linear, Gaussian, quadratic and cubic models achieved a comparable similarity score, the average SSIM for all patients was 0.94, 0.94, 0.90, 0.83 in week 3, respectively. At week 3, a sensitivity of 84%, 53%, 90% and 88%, and specificity of 99%, 100%, 91% and 42% were observed for the linear, Gaussian, quadratic and cubic models respectively. Overall, the linear model performed best at predicting those patients that will benefit from RT adaptation. The linear model identified 21% and 23% of patients in our cohort with more than 30% tumour volume reduction to benefit from treatment adaptation in weeks 3 and 4 respectively. Significance. We have shown that it is feasible to predict the shape and volume of NSCLC tumours from routine CBCTs and effectively identify patients who will respond to treatment early.
    • Impact of hypoxia on cervical cancer outcomes.

      Datta, Anubhav; orcid: 0000-0002-5234-2315; email: anubhav.datta@manchester.ac.uk; West, Catharine; O'Connor, James P B; Choudhury, Ananya; Hoskin, Peter (2021-09-30)
      The annual global incidence of cervical cancer is approximately 604 000 cases/342 000 deaths, making it the fourth most common cancer in women. Cervical cancer is a major healthcare problem in low and middle income countries where 85% of new cases and deaths occur. Secondary prevention measures have reduced incidence and mortality in developed countries over the past 30 years, but cervical cancer remains a major cause of cancer deaths in women. For women who present with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO 2018) stages IB3 or upwards, chemoradiation is the established treatment. Despite high rates of local control, overall survival is less than 50%, largely due to distant relapse. Reducing the health burden of cervical cancer requires greater individualization of treatment, identifying those at risk of relapse and progression for modified or intensified treatment. Hypoxia is a well known feature of solid tumors and an established therapeutic target. Low tumorous oxygenation increases the risk of local invasion, metastasis and treatment failure. While meta-analyses show benefit, many individual trials targeting hypoxia failed in part due to not selecting patients most likely to benefit. This review summarizes the available hypoxia-targeted strategies and identifies further research and new treatment paradigms needed to improve patient outcomes. The applications and limitations of hypoxia biomarkers for treatment selection and response monitoring are discussed. Finally, areas of greatest unmet clinical need are identified to measure and target hypoxia and therefore improve cervical cancer outcomes. [Abstract copyright: © IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Neoadjuvant therapy or upfront surgery in advanced endometrial cancer: a systematic review protocol.

      McCarthy, Amy; Balfour, Katharine; El Sayed, Iman; Edmondson, Richard; Wan, Yee-Loi Louise; orcid: 0000-0003-1441-6050; email: louise.wan@manchester.ac.uk (2021-11-11)
      There is no consensus on the optimal treatment strategy for people with advanced endometrial cancer. Neoadjuvant therapies such as chemotherapy and radiotherapy have been employed to try to reduce the morbidity of surgery, improve its feasibility and/or improve functional performance in people considered unfit for primary surgery. The objective of this review is to assess whether neoadjuvant chemotherapy or radiotherapy improves health outcomes in people with advanced endometrial cancer when compared with upfront surgery. This review will consider both randomised and non-randomised studies that compare health outcomes associated with the neoadjuvant therapy and upfront surgery in advanced endometrial cancer. Potential studies for inclusion will be collated from electronic searches of OVID Medline, Embase, international trial registries and conference abstract lists. Data collection and extraction will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodological quality of the studies will be assessed using the Risk of Bias 2 and Risk of Bias in Non-randomised Studies of Interventions tools. If appropriate, we will perform a meta-analysis and provide summary statistics for each outcome. Ethics approval was not required for this study. Once complete, we will publish our findings in peer-reviewed publications, via conference presentations and to update relevant practice guidelines. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Resurgence of a Nation’s Radiation Science Driven by Its Nuclear Industry Needs

      Leay, Laura; email: laura.leay@outlook.com; Baidak, Aliaksandr; email: aliaksandr.baidak@manchester.ac.uk; Anderson, Christopher; orcid: 0000-0003-4452-4378; email: christopher.anderson-3@postgrad.manchester.ac.uk; Chan, Choen May; email: ChoenMay.Chan@jacobs.com; Daubney, Aaron; email: aaron.daubney@sellafieldsites.com; Donoclift, Thomas; email: Thomas.Donoclift@glasgow.ac.uk; Draper, Gemma; email: gemma.draper@stfc.ac.uk; Edge, Ruth; orcid: 0000-0002-9144-041X; email: ruth.edge@manchester.ac.uk; Hobbs, Jeff; email: jeff.w.hobbs@sellafieldsites.com; Jones, Luke; email: Luke.Jones@uknnl.com; et al. (MDPI, 2021-11-23)
      This article describes the radiation facilities and associated sample preparation, management, and analysis equipment currently in place at the Dalton Cumbrian Facility, a facility which opened in 2011 to support the UK’s nuclear industry. Examples of measurements performed using these facilities are presented to illustrate their versatility and the breadth of research they make possible. Results are presented from research which furthers our understanding of radiation damage to polymeric materials, radiolytic yield of gaseous products in situations relevant to nuclear materials, radiation chemistry in light water reactor cooling systems, material chemistry relevant to immobilization of nuclear waste, and radiation-induced corrosion of fuel cladding elements. Applications of radiation chemistry relevant to health care are also described. Research concerning the mechanisms of radioprotection by dietary carotenoids is reported. An ongoing open-labware project to develop a suite of modular sample handling components suited to radiation research is described, as is the development of a new neutron source able to provide directional beams of neutrons.
    • The Effects of Ionising and Non-Ionising Electromagnetic Radiation on Extracellular Matrix Proteins

      Tuieng, Ren Jie; orcid: 0000-0001-9019-7342; email: renjie.tuieng@postgrad.manchester.ac.uk; Cartmell, Sarah H.; orcid: 0000-0001-6864-0846; email: sarah.cartmell@manchester.ac.uk; Kirwan, Cliona C.; email: cliona.kirwan@manchester.ac.uk; Sherratt, Michael J.; orcid: 0000-0003-4759-6617; email: michael.j.sherratt@manchester.ac.uk (MDPI, 2021-11-05)
      Exposure to sub-lethal doses of ionising and non-ionising electromagnetic radiation can impact human health and well-being as a consequence of, for example, the side effects of radiotherapy (therapeutic X-ray exposure) and accelerated skin ageing (chronic exposure to ultraviolet radiation: UVR). Whilst attention has focused primarily on the interaction of electromagnetic radiation with cells and cellular components, radiation-induced damage to long-lived extracellular matrix (ECM) proteins has the potential to profoundly affect tissue structure, composition and function. This review focuses on the current understanding of the biological effects of ionising and non-ionising radiation on the ECM of breast stroma and skin dermis, respectively. Although there is some experimental evidence for radiation-induced damage to ECM proteins, compared with the well-characterised impact of radiation exposure on cell biology, the structural, functional, and ultimately clinical consequences of ECM irradiation remain poorly defined.