• Cervical cancer and COVID-an assessment of the initial effect of the pandemic and subsequent projection of impact for women in England: A cohort study

      Davies, J. M.; Spencer, A.; Macdonald, S.; Dobson, L.; Haydock, E.; Burton, H.; Angelopoulos, G.; Martin-Hirsch, P.; Wood, N. J.; Thangavelu, A.; et al. (2022)
      Objective To review the effect of the COVID-19 pandemic on the diagnosis of cervical cancer and model the impact on workload over the next 3 years. Design A retrospective, control, cohort study. Setting Six cancer centres in the North of England representing a combined population of 11.5 million. Methods Data were collected retrospectively for all diagnoses of cervical cancer during May–October 2019 (Pre-COVID cohort) and May–October 2020 (COVID cohort). Data were used to generate tools to forecast case numbers for the next 3 years. Main outcome measures Histology, stage, presentation, onset of symptoms, investigation and type of treatment. Patients with recurrent disease were excluded. Results 406 patients were registered across the study periods; 233 in 2019 and 173 in 2020, representing a 25.7% (n = 60) reduction in absolute numbers of diagnoses. This was accounted for by a reduction in the number of low stage cases (104 in 2019 to 77 in 2020). Adding these data to the additional cases associated with a temporary cessation in screening during the pandemic allowed development of forecasts, suggesting that over the next 3 years there would be 586, 228 and 105 extra cases of local, regional and distant disease, respectively, throughout England. Projection tools suggest that increasing surgical capacity by two or three cases per month per centre would eradicate this excess by 12 months and 7 months, respectively. Conclusions There is likely to be a significant increase in cervical cancer cases presenting over the next 3 years. Increased surgical capacity could mitigate this with little increase in morbidity or mortality.
    • Saphenous-sparing ascending video endoscopic inguinal lymph node dissection using a leg approach: surgical technique and perioperative and pathological outcomes

      Fankhauser, Christian D; Lee, Esther W C; Issa, Allaudin; Oliveira, Pedro; Lau, Maurice W; Sangar, Vijay K; Parnham, Arie S; The Christie NHS Foundation Trusts, Manchester, UK. (2022)
    • Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial

      Le Pechoux, C.; Pourel, N.; Barlesi, F.; Lerouge, D.; Antoni, D.; Lamezec, B.; Nestle, U.; Boisselier, P.; Dansin, E.; Paumier, A.; et al. (2022)
      Background In patients with non-small-cell lung cancer (NSCLC), the use of postoperative radiotherapy (PORT) has been controversial since 1998, because of one meta-analysis showing a deleterious effect on survival in patients with pN0 and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many changes have occurred in the management of patients with NSCLC, the role of three-dimensional (3D) conformal PORT warrants further investigation in patients with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT should be part of their standard treatment. Methods Lung ART is an open-label, randomised, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC with complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients aged 18 years or older, with an WHO performance status of 0–2, were recruited from 64 hospitals and cancer centres in five countries (France, UK, Germany, Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the PORT or no PORT (control) groups via a web randomisation system, and minimisation factors were the institution, administration of chemotherapy, number of mediastinal lymph node stations involved, histology, and use of pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30 daily fractions, on five consecutive days a week. Three dimensional conformal radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted in centres with expertise. The primary endpoint was disease-free survival, analysed by intention to treat at 3 years; patients from the PORT group who did not receive radiotherapy and patients from the control group with no follow-up were excluded from the safety analyses. This trial is now closed. This trial is registered with ClinicalTrials.gov number, NCT00410683. Findings Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly staged with 18F-fluorodeoxyglucose (18F-FDG) PET (456 [91%]; 232 (92%) in the PORT group and 224 (90%) in the control group), were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9–7·0). 3-year disease-free survival was 47% (95% CI 40–54) with PORT versus 44% (37–51) without PORT, and the median disease-free survival was 30·5 months (95% CI 24–49) in the PORT group and 22·8 months (17–37) in the control group (hazard ratio 0·86; 95% CI 0·68–1·08; p=0·18). The most common grade 3–4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3–4 cardiopulmonary toxicity was reported in 26 patients (11%) in the PORT group versus 12 (5%) in the control group. Two patients died from pneumonitis, partly related to radiotherapy and infection, and one patient died due to chemotherapy toxicity (sepsis) that was deemed to be treatment-related, all of whom were in the PORT group. Interpretation Lung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using (18F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC. Funding French National Cancer Institute, Programme Hospitalier de Recherche Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK, Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer Research Foundation, Swiss Cancer League.
    • A definitive prognostication system for patients with thoracic malignancies diagnosed with COVID-19: an update from the TERAVOLT registry

      Whisenant, J. G.; Baena, J.; Cortellini, A.; Huang, L. C.; Lo Russo, G.; Porcu, L.; Wong, S. K.; Bestvina, C. M.; Hellmann, M. D.; Roca, E.; et al. (2022)
      Background: Patients with thoracic malignancies are at increased risk for mortality from 4 Coronavirus disease 2019 (COVID-19) and large number of intertwined prognostic variables have 5 been identified so far. 6 Methods: Capitalizing data from the TERAVOLT registry, a global study created with the aim of 7 describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering 8 approach, a fast-backward step-down selection procedure and a tree-based model to screen and 9 optimize a broad panel of demographics, clinical COVID-19 and cancer characteristics. 10 Results: As of April 15, 2021, 1491 consecutive evaluable patients from 18 countries were 11 included in the analysis. With a mean observation period of 42 days, 361 events were reported 12 with an all-cause case fatality rate of 24.2%. The clustering procedure screened approximately 13 73 covariates in 13 clusters. A further multivariable logistic regression for the association between 14 clusters and death was performed, resulting in five clusters significantly associated with the 15 outcome. The fast-backward step-down selection then identified seven major determinants of 16 death ECOG-PS (OR 2.47 1.87-3.26), neutrophil count (OR 2.46 1.76-3.44), serum procalcitonin 17 (OR 2.37 1.64-3.43), development of pneumonia (OR 1.95 1.48-2.58), c-reactive protein (CRP) 18 (OR 1.90 1.43-2.51), tumor stage at COVID-19 diagnosis (OR 1.97 1.46-2.66) and age (OR 1.71 19 1.29-2.26). The ROC analysis for death of the selected model confirmed its diagnostic ability 20 (AUC 0.78; 95%CI: 0.75 – 0.81). The nomogram was able to classify the COVID-19 mortality in 21 an interval ranging from 8% to 90% and the tree-based model recognized ECOG-PS, neutrophil 22 count and CRP as the major determinants of prognosis. 23 Conclusion: From 73 variables analyzed, seven major determinants of death have been 24 identified. Poor ECOG-PS demonstrated the strongest association with poor outcome from 25 COVID-19. With our analysis we provide clinicians with a definitive prognostication system to help 26 determine the risk of mortality for patients with thoracic malignancies and COVID-19.
    • Early Therapeutic Interventions for Newly Diagnosed Glioblastoma: Rationale and Review of the Literature

      Waqar, M.; Trifiletti, D. M.; McBain, C.; O'Connor, J.; Coope, D. J.; Akkari, L.; Quinones-Hinojosa, A.; Borst, G. R.; Department of Academic Neurological Surgery, Geoffrey Jefferson Brain Research Centre, Salford Royal Foundation Trust, Manchester, UK. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health and Manchester Cancer Research Centre, University of Manchester, Manchester, UK. Department of Radiation Oncology, Mayo Clinic Florida, 4500 San Pablo Road S, Mayo 1N, Jacksonville, FL, 32224, USA. Department of Neurological Surgery, Mayo Clinic, Jacksonville, FL, USA. Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Dept 58, Floor 2a, Room 21-2-13, Wilmslow Road, Manchester, M20 4BX, UK. Division of Tumour Biology and Immunology, The Netherlands Cancer Institute, Oncode Institute, Amsterdam, The Netherlands. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health and Manchester Cancer Research Centre, University of Manchester, Manchester, UK. Gerben.Borst@nhs.net. Department of Radiotherapy Related Research, The Christie NHS Foundation Trust, Dept 58, Floor 2a, Room 21-2-13, Wilmslow Road, Manchester, M20 4BX, UK. Gerben.Borst@nhs.net. (2022)
      Purpose of Review Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically. Recent Findings Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and several radiotherapy techniques. We critically appraise and compare these strategies in terms of their efficacy, toxicity, challenges and potential to prolong survival. Finally, we discuss the most promising strategies that could benefit future glioblastoma patients. Summary There is biological rationale to suggest that early interventions could improve the outcome of glioblastoma patients and they should be investigated in future trials.
    • The development of a decision aid to support Hodgkin lymphoma survivors considering lung cancer screening

      Broadbent, R.; Seale, T.; Armitage, C. J.; Linton, K.; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. rachel.broadbent-2@postgrad.manchester.ac.uk. NIHR Greater Manchester Patient Safety Translational Research Centre, University of Manchester, Manchester, UK. rachel.broadbent-2@postgrad.manchester.ac.uk. The Christie NHS Foundation Trust, Manchester, UK. rachel.broadbent-2@postgrad.manchester.ac.uk. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. NIHR Greater Manchester Patient Safety Translational Research Centre, University of Manchester, Manchester, UK. Division of Psychology and Mental Health, Manchester Centre for Health Psychology, University of Manchester, Manchester, UK. Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK. Manchester Cancer Research Centre, Wilmslow Road, Manchester, M20 4QL, UK. (2022)
      Background: Decisions aids (DA) can support patients to make informed decisions about screening tests. This study describes the development and initial evaluation of a lung cancer screening (LCS) DA targeted towards survivors of Hodgkin lymphoma (HL). Methods: A prototype decision aid booklet was developed and subsequently reviewed by a steering group who provided feedback. Revisions were made to produce the DA tested in this study. HL survivors were recruited to an online survey and/or focus groups. Lymphoma practitioners were invited to an interview study. In the online survey, decisional confict scales and knowledge scales were completed before and after accessing the DA. The focus groups and interviews explored acceptability and comprehensibility and the decisional needs of stakeholders. Focus groups and interviews were audio recorded. The framework method was used to analyse qualitative data. Results: 38 HL survivors completed the online survey. Following exposure to the DA, knowledge of LCS and risk factors and decisional confict scores (total score and subscale scores) improved signifcantly. 11 HL survivors took part in two focus groups (n=5 and n=6) and 11 practitioners were interviewed. Focus group and interview results: The language, format and length were considered acceptable. Both groups felt the DA was balanced and presented a choice. Icon arrays were felt to aid comprehension of absolute risk values and for some survivors, they reduced afective risk perceptions. Among survivors, the impact of radiation risk on decision making varied according to gender and screening interval, whilst practitioners did not anticipate it to be a major concern for patients. Both groups expressed that a screening ofer could mitigate anxiety about lung cancer risk. As anticipated by practitioners, survivors expressed a desire to seek advice from their clinical team. Practitioners thought the DA would meet their informational needs regarding LCS when supporting survivors. Conclusions: The DA is considered acceptable by HL survivors and practitioners. The DA reduces decisional confict and improves knowledge in HL survivors, suggesting that it would support HL survivors to make informed decisions when considering LCS in a future clinical trial.
    • Inter-organisational collaboration enabling care delivery in a specialist cancer surgery provider network: A qualitative study

      Vindrola-Padros, C.; Ramsay, A. I. G.; Black, G.; Barod, R.; Hines, J.; Mughal, M.; Shackley, D.; Fulop, N. J.; Senior Research Fellow, Department of Targeted Intervention, University College London, London, UK. Senior Research Fellow, Department of Applied Health Research, University College London, London, UK. Principal Research Fellow, Department of Applied Health Research, 4919University College London, London, UK. Consultant Urological Surgeon, Specialist Centre for Kidney Cancer, 4965Royal Free London NHS Foundation Trust, London, UK. Consultant Urological Surgeon and London Cancer Urology Pathway Board Director, Department of Urology, 8964University College London Hospitals NHS Foundation Trust, London, UK. Consultant General & Upper Gastrointestinal Surgeon, 8964University College London Hospitals NHS Foundation Trust, London, UK. Medical Director, Greater Manchester Cancer and Manchester Academic Health Science Centre, Christie NHS Foundation Trust, Manchester, UK. Professor of Health Care Organisation and Management, Department of Applied Health Research, University College London, London, UK. (2022)
      Objective To explore the processes, challenges and strategies used to govern and maintain inter-organisational collaboration between professionals in a provider network in London, United Kingdom, which implemented major system change focused on the centralisation of specialist cancer surgery. Methods We used a qualitative design involving interviews with stakeholders (n = 117), non-participant observations (n = 163) and documentary analysis (n = 100). We drew on an existing model of collaboration in healthcare organisations and expanded this framework by applying it to the analysis of collaboration in the context of major system change. Results Network provider organisations established shared goals, maintained central figures who could create and sustain collaboration, and promoted distributed forms of leadership. Still, organisations continued to encounter barriers or challenges in relation to developing opportunities for mutual acquaintanceship across all professional groups; the active sharing of knowledge, expertise and good practice across the network; the fostering of trust; and creation of information exchange infrastructures fit for collaborative purposes. Conclusion Collaborative relationships changed over time, becoming stronger post-implementation in some areas, but continued to be negotiated where resistance to the centralisation remained. Future research should explore the sustainability of these relationships and further unpack how hierarchies and power relationships shape inter-organisational collaboration.
    • Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer

      Spigel, D. R.; Faivre-Finn, C.; Gray, J. E.; Vicente, D.; Planchard, D.; Paz-Ares, L.; Vansteenkiste, J. F.; Garassino, M. C.; Hui, R.; Quantin, X.; et al. (2022)
      PURPOSE The phase III PACIFIC trial compared durvalumab with placebo in patients with unresectable, stage III non–small-cell lung cancer and no disease progression after concurrent chemoradiotherapy. Consolidation durvalumab was associated with significant improvements in the primary end points of overall survival (OS; stratified hazard ratio [HR], 0.68; 95% CI, 0.53 to 0.87; P = .00251) and progression-free survival (PFS [blinded independent central review; RECIST v1.1]; stratified HR, 0.52; 95% CI, 0.42 to 0.65; P < .0001), with manageable safety. We report updated, exploratory analyses of survival, approximately 5 years after the last patient was randomly assigned. METHODS Patients with WHO performance status 0 or 1 (any tumor programmed cell death-ligand 1 status) were randomly assigned (2:1) to durvalumab (10 mg/kg intravenously; administered once every 2 weeks for 12 months) or placebo, stratified by age, sex, and smoking history. Time-to-event end point analyses were performed using stratified log-rank tests. Medians and landmark survival rates were estimated using the Kaplan-Meier method. RESULTS Seven hundred and nine of 713 randomly assigned patients received durvalumab (473 of 476) or placebo (236 of 237). As of January 11, 2021 (median follow-up, 34.2 months [all patients]; 61.6 months [censored patients]), updated OS (stratified HR, 0.72; 95% CI, 0.59 to 0.89; median, 47.5 v 29.1 months) and PFS (stratified HR, 0.55; 95% CI, 0.45 to 0.68; median, 16.9 v 5.6 months) remained consistent with the primary analyses. Estimated 5-year rates (95% CI) for durvalumab and placebo were 42.9% (38.2 to 47.4) versus 33.4% (27.3 to 39.6) for OS and 33.1% (28.0 to 38.2) versus 19.0% (13.6 to 25.2) for PFS. CONCLUSION These updated analyses demonstrate robust and sustained OS and durable PFS benefit with durvalumab after chemoradiotherapy. An estimated 42.9% of patients randomly assigned to durvalumab remain alive at 5 years and 33.1% of patients randomly assigned to durvalumab remain alive and free of disease progression, establishing a new benchmark for standard of care in this setting.
    • Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma

      Dummer, R.; Long, G. V.; Robert, C.; Tawbi, H. A.; Flaherty, K. T.; Ascierto, P. A.; Nathan, P. D.; Rutkowski, P.; Leonov, O.; Dutriaux, C.; et al. (2022)
      PURPOSE Preclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma. METHODS Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age $ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692). RESULTS At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placeboDabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P 5 .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade $ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm. CONCLUSION The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
    • Regulation of bone mass in endocrine diseases including diabetes

      Higham, C.; Abrahamsen, B.; Christie Hospital NHS Foundation Trust, Manchester, UK; University of Manchester, Manchester, UK. Electronic address: claire.higham2@nhs.net. Open Patient Data Exploratory Network, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Medicine, Holbæk Hospital, Holbæk, Denmark; NDORMS, University of Oxford, Oxford, UK. Electronic address: b.abrahamsen@physician.dk. (2022)
      Hormonal regulation plays a key role in determining bone mass in humans. Both skeletal growth and bone loss in health and disease is critically controlled by endocrine factors and low bone mass is a feature of both excess and deficiency of a broad range of hormones. This article explores the impact of diabetes and thyroid, parathyroid, sex steroid and growth hormone disorders on bone mass and fracture risk. Evidence for current management strategies is provided along with suggested practice points and gaps in knowledge for future research.
    • Determining the influence of different linking patterns on the stability of students' score adjustments produced using Video-based Examiner Score Comparison and Adjustment (VESCA)

      Yeates, P.; McCray, G.; Moult, A.; Cope, N.; Fuller, R.; McKinley, R.; School of Medicine, David Weatherall Building, Keele University, Keele, Staffordshire, ST5 5BG, UK. p.yeates@keele.ac.uk. Fairfield General Hospital, Northern Care Alliance NHS Foundation Trust, Rochdale Old Road, Bury, BL9 7TD, Lancashire, UK. p.yeates@keele.ac.uk. School of Medicine, David Weatherall Building, Keele University, Keele, Staffordshire, ST5 5BG, UK. Christie Education, Christie Hospitals NHS Foundation Trust, Wilmslow Rd, Manchester, M20 4BX, UK. (2022)
      Background Ensuring equivalence of examiners’ judgements across different groups of examiners is a priority for large scale performance assessments in clinical education, both to enhance fairness and reassure the public. This study extends insight into an innovation called Video-based Examiner Score Comparison and Adjustment (VESCA) which uses video scoring to link otherwise unlinked groups of examiners. This linkage enables comparison of the influence of different examiner-groups within a common frame of reference and provision of adjusted “fair” scores to students. Whilst this innovation promises substantial benefit to quality assurance of distributed Objective Structured Clinical Exams (OSCEs), questions remain about how the resulting score adjustments might be influenced by the specific parameters used to operationalise VESCA. Research questions, How similar are estimates of students’ score adjustments when the model is run with either: fewer comparison videos per participating examiner?; reduced numbers of participating examiners? Methods Using secondary analysis of recent research which used VESCA to compare scoring tendencies of different examiner groups, we made numerous copies of the original data then selectively deleted video scores to reduce the number of 1/ linking videos per examiner (4 versus several permutations of 3,2,or 1 videos) or 2/examiner participation rates (all participating examiners (76%) versus several permutations of 70%, 60% or 50% participation). After analysing all resulting datasets with Many Facet Rasch Modelling (MFRM) we calculated students’ score adjustments for each dataset and compared these with score adjustments in the original data using Spearman’s correlations. Results Students’ score adjustments derived form 3 videos per examiner correlated highly with score adjustments derived from 4 linking videos (median Rho = 0.93,IQR0.90–0.95,p < 0.001), with 2 (median Rho 0.85,IQR0.81–0.87,p < 0.001) and 1 linking videos (median Rho = 0.52(IQR0.46–0.64,p < 0.001) producing progressively smaller correlations. Score adjustments were similar for 76% participating examiners and 70% (median Rho = 0.97,IQR0.95–0.98,p < 0.001), and 60% (median Rho = 0.95,IQR0.94–0.98,p < 0.001) participation, but were lower and more variable for 50% examiner participation (median Rho = 0.78,IQR0.65–0.83, some ns). Conclusions Whilst VESCA showed some sensitivity to the examined parameters, modest reductions in examiner participation rates or video numbers produced highly similar results. Employing VESCA in distributed or national exams could enhance quality assurance or exam fairness.
    • Improved pyrexia-related outcomes associated with an adapted pyrexia adverse event management algorithm in patients treated with adjuvant dabrafenib plus trametinib: Primary results of COMBI-APlus

      Atkinson, V.; Robert, C.; Grob, J. J.; Gogas, H.; Dutriaux, C.; Demidov, L.; Gupta, A.; Menzies, A. M.; Ryll, B.; Miranda, F.; et al. (2022)
      Background COMBI-AD demonstrated long-term benefit of adjuvant dabrafenib plus trametinib in patients with resected stage III BRAF V600E/K–mutant melanoma; however, 9% of patients permanently discontinued therapy due to pyrexia. COMBI-APlus evaluated whether an adapted pyrexia management algorithm reduces high-grade pyrexia and pyrexia-related adverse outcomes. Methods COMBI-APlus is an open-label, phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K–mutant melanoma treated with up to 12 months of adjuvant dabrafenib plus trametinib. Both drugs were interrupted for pyrexia (temperature ≥38°C) or the occurrence of pyrexia syndrome for suspected recurrent pyrexia. Treatment was restarted at the same dose once patients were symptom free for ≥24 h. The primary endpoint was the composite rate of grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent discontinuation due to pyrexia versus historical COMBI-AD control (20.0%; 95% confidence interval [CI], 16.3%–24.1%). Results At data cutoff (5 October 2020), COMBI-APlus met its primary endpoint of significant improvement in the composite rate of pyrexia (8.0% [95% CI, 5.9%–10.6%]), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalisation due to pyrexia, and 2.4% for discontinuation due to pyrexia. Estimated 12-month relapse-free survival was 91.8% (95% CI, 89.0%–93.9%). The most common adverse events were consistent with those in COMBI-AD, and 14.7% of patients permanently discontinued treatment due to adverse events. Conclusions The adapted pyrexia management algorithm appears to reduce the incidence of severe pyrexia outcomes, enables patients to manage pyrexia at home, and helps patients remain on treatment.
    • Lung Cancer in the United Kingdom

      Navani, N.; Baldwin, D. R.; Edwards, J. G.; Evison, M.; McDonald, F.; Nicholson, A. G.; Fenemore, J.; Sage, E. K.; Popat, S.; Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom; Department of Thoracic Medicine, University College London Hospital, London, United Kingdom. Electronic address: n.navani@ucl.ac.uk. Department of Thoracic Medicine, University College London Hospital, London, United Kingdom; Respiratory Medicine Unit, Nottingham University Hospitals, Nottingham, United Kingdom. Department of Cardiothoracic Surgery, Northern General Hospital, Sheffield Teaching Hospitals National Health Service (NHS) Foundation Trust, Sheffield, United Kingdom. Lung Cancer & Thoracic Surgery Directorate, Wythenshawe Hospital, Manchester University National Health Service (NHS) Foundation Trust, Manchester, United Kingdom. Lung Unit, Royal Marsden Hospital, London, United Kingdom; Division of Radiotherapy & Imaging, The Institute of Cancer Research, London, United Kingdom. Department of Histopathology, Royal Brompton and Harefield Hospitals, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, London, United Kingdom; Genomics and Environmental Medicine Section, National Heart and Lung Institute, Imperial College, London, United Kingdom. The Lung Cancer Team, The Christie Hospital, Manchester, United Kingdom; Lung Cancer Nurses UK, Solihull, United Kingdom. Department of Respiratory Medicine, Raigmore Hospital, National Health Service (NHS) Highland and Centre for Rural Health, University of Aberdeen, Aberdeen, United Kingdom. Lung Unit, Royal Marsden Hospital, London, United Kingdom; Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom. (2022)
    • Postoperative Radiation Therapy Should Not Be Used for the Therapy of Stage III-N2 NSCLC

      Faivre-Finn, C.; Edwards, J. G.; Hatton, M.; The Christie NHS Foundation Trust, Manchester, United Kingdom; Department of Radiotherapy Related Research, University of Manchester, Manchester, United Kingdom. Electronic address: corinne.finn@nhs.net. Sheffield Teaching Hospital NHS Foundation Trust, Northern General Hospital, Sheffield, United Kingdom. Department of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom. (2022)
    • White Paper on the Value of Time Savings for Patients and Healthcare Providers of Breast Cancer Therapy: The Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection as an Example COMMENT

      Jackisch, C.; Manevy, F.; Frank, S.; Roberts, N.; Shafrin, J.; AGO-B and Sana Klinikum Offenbach GmbH, Offenbach, Germany (2022)
      Health technology assessments and value frameworks are becoming increasingly important for clinical decision-making. Most of these frameworks, however, focus on value to payers rather than patients and healthcare providers and may ignore other sources of economic value such as patient and physician time cost, impact on productivity, and direct health system costs. This article focusses on fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in the treatment of HER2-positive breast cancer. We review relevant clinical evidence, examine data on time and resource use of the subcutaneous administration of trastuzumab compared with intravenous treatment and how it can be extrapolated to PH FDC SC, and discuss the value PH FDC SC can bring to patients and healthcare providers. We will also provide our own experiences of PH FDC SC from the healthcare (oncologist, healthcare economist, pharmacist) and patient point of view. The data, combined with our personal experiences, suggest that switching from intravenous pertuzumab and trastuzumab to PH FDC SC could reduce non-drug costs for healthcare providers treating patients with HER2-positive breast cancer through time savings and other economic benefits. Furthermore, PH FDC SC could also save patient time given its shorter administration and post-injection observation time versus intravenous infusions, potentially resulting in reduced productivity loss. These benefits could be applied to other subcutaneous formulations, either currently available or in development.
    • Response to winter pressures in acute services: analysis from the Winter Society for Acute Medicine Benchmarking Audit

      Atkin, C.; Knight, T.; Subbe, C.; Holland, M.; Cooksley, T.; Lasserson, D.; Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2GW, UK (2022)
      Background There is increased demand for urgent and acute services during the winter months, placing pressure on acute medicine services caring for emergency medical admissions. Hospital services adopt measures aiming to compensate for the effects of this increased pressure. This study aimed to describe the measures adopted by acute medicine services to address service pressures during winter. Methods A survey of acute hospitals was conducted during the Society for Acute Medicine Benchmarking Audit, a national day-of-care audit, on 30th January 2020. Survey questions were derived from national guidance. Acute medicine services at 93 hospitals in the United Kingdom completed the survey, evaluating service measures implemented to mitigate increased demand, as well as markers of increased pressure on services. Results All acute internal medicine services had undertaken measures to prepare for increased demand, however there was marked variation in the combination of measures adopted. 81.7% of hospitals had expanded the number of medical inpatient beds available. 80.4% had added extra clinical staff. The specialty of the physicians assigned to provide care for extra inpatient beds varied. A quarter of units had reduced beds available for providing Same Day Emergency Care on the day of the survey. Patients had been waiting in corridors within the emergency medicine department in 56.3% of units. Conclusion Winter pressure places considerable demand on acute services, and impacts the delivery of care. Although increased pressure on acute hospital services during winter is widely recognised, there is considerable variation in the approach to planning for these periods of increased demand.
    • Curing a Malignant Climate

      Chuter, R.; Lowe, G.; Dickinson, N.; The Christie NHS Foundation Trust, Manchester, UK (2022)
    • SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study

      Ritzmann, T. A.; Chapman, R. J.; Kilday, J. P.; Thorp, N.; Modena, P.; Dineen, R. A.; Macarthur, D.; Mallucci, C.; Jaspan, T.; Pajtler, K. W.; et al. (2022)
      Background SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) of non-metastatic intracranial ependymoma in children aged 3–21 years treated with a staged management strategy. A further aim was to assess the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide, and cyclophosphamide (VEC). We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers. Methods Seventy-four participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation, 1q, hTERT, ReLA, Tenascin-C, H3K27me3, and pAKT status were evaluated. Results Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (P = .003, HR = 2.6, 95% confidence interval (CI) 1.4–5.1). Grade 3 tumours were associated with worse OS (P = .005, HR = 2.8, 95%CI 1.3–5.8). 1q gain and hTERT expression were associated with poorer EFS (P = .003, HR = 2.70, 95%CI 1.49–6.10 and P = .014, HR = 5.8, 95%CI 1.2–28) and H3K27me3 loss with worse OS (P = .003, HR = 4.6, 95%CI 1.5–13.2). Methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, best chemotherapy RR was 65.5% (19/29, 95%CI 45.7–82.1), exceeding the prespecified 45%. Conclusions Participants with totally resected ependymoma had the best outcomes. RR of STR to VEC exceeded the pre-specified efficacy criterion. However, cases of inaccurate stratification highlighted the need for rapid central review. 1q gain, H3K27me3 loss, and hTERT expression were all associated with poorer survival outcomes.
    • Women's health behaviour change after receiving breast cancer risk estimates with tailored screening and prevention recommendations

      Rainey, L.; van der Waal, D.; Donnelly, L. S.; Southworth, J.; French, D. P.; Evans, D. G.; Broeders, M. J. M.; Radboud Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. linda.rainey@radboudumc.nl. Dutch Expert Centre for Screening, PO Box 6873, 6503 GJ, Nijmegen, The Netherlands. Centre for Mental Health and Safety, University of Manchester, Manchester, M13 9PL, England. Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK. Manchester Centre for Health Psychology, School of Health Sciences, University of Manchester, Coupland Street, Manchester, M13 9PL, UK. Genomic Medicine, Division of Evolution and Genomic Sciences, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK. The Christie NHS Foundation Trust, Withington, Manchester, M20 4BX, UK. Radboud Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. (2022)
      Background The Predicting Risk of Cancer at Screening (PROCAS) study provided women who were eligible for breast cancer screening in Greater Manchester (United Kingdom) with their 10-year risk of breast cancer, i.e., low (≤1.5%), average (1.5–4.99%), moderate (5.-7.99%) or high (≥8%). The aim of this study is to explore which factors were associated with women’s uptake of screening and prevention recommendations. Additionally, we evaluated women’s organisational preferences regarding tailored screening. Methods A total of 325 women with a self-reported low (n = 60), average (n = 125), moderate (n = 80), or high (n = 60) risk completed a two-part web-based survey. The first part contained questions about personal characteristics. For the second part women were asked about uptake of early detection and preventive behaviours after breast cancer risk communication. Additional questions were posed to explore preferences regarding the organisation of risk-stratified screening and prevention. We performed exploratory univariable and multivariable regression analyses to assess which factors were associated with uptake of primary and secondary breast cancer preventive behaviours, stratified by breast cancer risk. Organisational preferences are presented using descriptive statistics. Results Self-reported breast cancer risk predicted uptake of (a) supplemental screening and breast self-examination, (b) risk-reducing medication and (c) preventive lifestyle behaviours. Further predictors were (a) having a first degree relative with breast cancer, (b) higher age, and (c) higher body mass index (BMI). Women’s organisational preferences for tailored screening emphasised a desire for more intensive screening for women at increased risk by further shortening the screening interval and moving the starting age forward. Conclusions Breast cancer risk communication predicts the uptake of key tailored primary and secondary preventive behaviours. Effective communication of breast cancer risk information is essential to optimise the population-wide impact of tailored screening.