WUTH publication: Refocusing cancer multidisciplinary team meetings in the United Kingdom: comparing urology with other specialties

Citation: Annals of the Royal College of Surgeons of England. 2021, 103(1), 10-17.  Epub 2020 Sep 28
Author: Warner R, Hoinville L, Pottle E, Taylor C, Green J
Abstract: INTRODUCTION: Multidisciplinary team (MDT) meetings have been the gold standard of cancer care in the UK since the 1990s. We aimed to identify the views of urology cancer MDT members in the UK on improving the functioning of meetings and compare them with those of other specialties to manage the increasing demand on healthcare resources and enhance the care of complex cancer cases. 
METHODS: We analysed data from 2 national surveys distributed by Cancer Research UK focusing on the views of 2294 and 1258 MDT members about cancer MDT meetings. 
FINDINGS: Most breast, colorectal, lung and urology cancer MDT members felt meetings could be improved in the following areas: time for meeting preparation in job plans, streamlining of patients, auditing meeting decisions and prioritising complex cases. Most urology respondents (87%) agreed some patients could be managed outside a full MDT discussion, but this was lower for other specialties (lung 78%, breast 75%, colorectal 64%). 
CONCLUSIONS: To facilitate decisions on which patients require discussion in an MDT meeting, factors adding to case complexity across all tumour types were identified, including rare tumour type, cognitive impairment and previous treatment failure. This study confirms that urology MDT members are supportive of changing from reviewing all new cancer diagnoses to discussing complex cases but managing others with a more protocolised pathway. The mechanisms for how to do this and how to ensure the safety of patients require further clarification.

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WUTH publication: The Critical Roles and Mechanisms of Immune Cell Death in Sepsis

Citation: Front Immunol. 2020, 11, 1918

Author: Cheng Z, Abrams ST, Toh J, Wang SS, Wang Z, Yu Q, Yu W, Toh CH, Wang G

Abstract: Sepsis was first described by the ancient Greek physicians over 2000 years ago. The pathophysiology of the disease, however, is still not fully understood and hence the mortality rate is still unacceptably high due to lack of specific therapies. In the last decade, great progress has been made by shifting the focus of research from systemic inflammatory response syndrome (SIRS) to multiple organ dysfunction syndrome (MODS). Sepsis has been re-defined as infection-induced MODS in 2016. How infection leads to MODS is not clear, but what mediates MODS becomes the major topic in understanding the molecular mechanisms and developing specific therapies. Recently, the mechanism of infection-induced extensive immune cell death which releases a large quantity of damage-associated molecular patterns (DAMPs) and their roles in the development of MODS as well as immunosuppression during sepsis have attracted much attention. Growing evidence supports the hypothesis that DAMPs, including high-mobility group box 1 protein (HMGB1), cell-free DNA (cfDNA) and histones as well as neutrophil extracellular traps (NETs), may directly or indirectly contribute significantly to the development of MODS. Here, we provide an overview of the mechanisms and consequences of infection-induced extensive immune cell death during the development of sepsis. We also propose a pivotal pathway from a local infection to eventual sepsis and a potential combined therapeutic strategy for targeting sepsis.

Keywords: sepsis, extensive immune cell death, damage-associated molecular patterns (DAMPs), multiple organ dysfunction syndrome (MODS), extracellular histones, immunosuppression

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CCC publication: Beam characterisation studies of the 62 MeV proton therapy beamline at the Clatterbridge Cancer Centre

Citation: Physica Medica. 2020, 77, 108-20

Author: Yap J. (jacinta.yap@liverpool.ac.uk); Resta-Lopez J.; Schnuerer R.; Welsch C.; Kacperek A.; Jolly S.; Boogert S.

Abstract: The Clatterbridge Cancer Centre (CCC) in the United Kingdom is the world's first hospital proton beam therapy facility, providing treatment for ocular cancers since 1989. A 62 MeV beam of protons is produced by a Scanditronix cyclotron and transported through a passive delivery system. In addition to the long history of clinical use, the facility supports a wide programme of experimental work and as such, an accurate and reliable simulation model of the treatment beamline is highly valuable. However, as the facility has seen several changes to the accelerator and beamline over the years, a comprehensive study of the CCC beam dynamics is needed to firstly examine the beam optics. An extensive analysis was required to overcome facility related constraints to determine fundamental beamline parameters and define an optical lattice written with the Methodical Accelerator Design (MAD-X) and the particle tracking Beam Delivery Simulation (BDSIM) code. An optimised case is presented and simulated results of the optical functions, beam distribution, losses and the transverse rms beam sizes along the beamline are discussed. Corresponding optical and beam information was used in TOPAS to simulate transverse beam profiles and compared to EBT3 film measurements. We provide an overview of the magnetic components, beam transport, cyclotron, beam and treatment related parameters necessary for the development of a present day optical model of the facility. This work represents the first comprehensive study of the CCC facility to date, as a basis to determine input beam parameters to accurately simulate and completely characterise the beamline. Copyright © 2020 Associazione Italiana di Fisica Medica

CCC publication: Proton ocular centers with dedicated fixed low-energy beams: Key concepts for new centers

Citation: Investigative Ophthalmology and Visual Science. 2020, 61(7). (Conference Abstract)

Author: Mishra K.K.; Daftari I.; Scholey J.; Quivey J.; Kacperek A.; Afshar A.R.; Damato B.; Char D.
Abstract: Purpose : Proton beam treatment for uveal melanoma (UM) has been well established internationally with dedicated ocular beamlines. With the emergence of universal, high-energy, non-fixed beamlines, we share key practices to minimize side effects. Methods : The University of California, San Francisco (UCSF), USA, and the Clatterbridge Cancer Centre (CCC), UK, both have longstanding facilities with dedicated, fixed, low-energy, ocular lines, which produce 67.5 and 60.0 MeV proton beams, respectively (range up to 3 cm). In total 5927 ocular patients, 93% with UM, have been treated. Standard UM dose is 56 Gray Equivalent (GyE) at UCSF and 57.2 GyE at CCC, delivered in 4 fractions. Planning and delivery procedures were analyzed as a bi-institutional effort to communicate key concepts to developing centers. Results : Low-energy dedicated eye beamlines provide critical beam characteristics for normal eye tissue sparing. Both centers offer a very sharp dose fall off (distal ~1 mm and lateral ~1.1-1.6 mm), high dose homogeneity, excellent range precision and short treatment time (~0.5-2 minutes). Analyses confirm that planned doses to critical ocular structures are independent predictors of vision, neovascular glaucoma, and other clinical outcomes (e.g. 28 GyE to macula [P<.0001], optic nerve [P<0.0004], lens [P<.0001], and ciliary body [P<.0001]). A rational tumor/critical structure dose evaluation is used to optimize treatment parameters, i.e. lateral margin, distal range, gaze angle, and aperture shape. New high-energy non-dedicated beam designs, which degrade energy to deliver ocular treatment, may require significant beam adjustment and treatment planning procedures to achieve adequate characteristics. A common dosing regimen for UM is 60 GyE in 4 fractions globally. Unrandomized early retrospective data showed lower local tumor control with 48 GyE (P=0.02). Critical structures including the retina, lacrimal gland, cornea, tear ducts, lids, bony orbit, and limbal stem cells are systematically evaluated to minimize side effects. Eyelid toxicity is minimized by retraction techniques or treatment through closed lids. Conclusions : Experienced proton centers at UCSF and CCC with dedicated, low-energy, fixed eyelines, provide important practical clinical concepts for consideration by new centers to optimize high-energy universal beamline designs, particularly to reduce normal tissue toxicity.

CCC publication: Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma

Citation: BMJ Open. 2020, 10(9), e038892

Author: Lim E. (e.lim@rbht.nhs.uk); Darlison L.; Edwards J.; Elliott D.; Mills N.; Fennell D.A.; Popat S.; Rintoul R.C.; Waller D.; Lau K.; Ali C.; Bille A.; Fuller L.; Ionescu A.; Keni M.; Kirk A.; Koh P.; Mansy T.; Maskell N.A.; Milton R.; Muthukumar D.; Pope T.; Roy A.; Shah R.; Shamash J.; Tasigiannopoulos Z.; Taylor P.; Treece S.; Ashton K.; Harris R.; Joyce K.; Warnes B.; Rogers C.; Stokes E.A.

Abstract: Introduction: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left.

Methods and analysis: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery—(extended) pleurectomy decortication—versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment.

Ethics and dissemination: Research ethics approval was granted by London – Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal.

Trial registration numbers: ISRCTN—ISRCTN44351742 and ClinicalTrials.gov—NCT02040272.

Keywords: oncology, chemotherapy, thoracic surgery, thoracic medicine

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CCC publication: Transoral laser microsurgery and radiotherapy for oropharyngeal squamous cell carcinoma: Equitable survival and enhanced function compared with contemporary standards of care

Citation: European Journal of Surgical Oncology. 2020, 46(11), 2042-49. Epub 2020 Jul 22 (Conference Abstract)

Author: Dalton C.L.; Milinis K.; Ridley P.; Davies K.; Williams R.; Hamilton D.; Wilkie M.D.; Lofthouse M.; Loh C.; Roland N.J.; Tandon S.; Lancaster J.; Jones T.M. (T.M.Jones@liverpool.ac.uk); Houghton D.; Markey A.; Clarke K.; Helliwell T.R.; Triantafyllou A.; Rodrigues J.; Bheemireddy K.; Hanlon R.; Wieshmann H.; Haridass A.; Brammer C.; Husband D.; Shenoy A.; Bekiroglu F.

Abstract: Introduction: We describe the 5-year oncological and functional outcomes of transoral laser microsurgery, neck dissection (TLM + ND) and adjuvant radiotherapy (PORT) used to treat patients with oropharyngeal carcinoma. The effectiveness of external carotid artery (ECA) ligation in reducing post-operative bleeding, and fibrin glue following ND in reducing wound drainage and length of hospital stay is reported. Material(s) and Method(s): This retrospective case review of consecutive patients undergoing TLM between 2006 and 2017 used the Kaplan-Meier Estimator and Log-Rank Test for univariate, time-to-event analyses, and Cox-Proportionate Hazard modelling for multivariate analysis. Result(s): 264 consecutive patients were included. Mean follow-up was 49.4 months. 219 (82.9%) patients received PORT. Five-year overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) rates were 74.9%, 73.7%, and 86.2%, respectively. Five-year locoregional control was 89.4%. 65.5% of cases were Human papillomavirus associated (HPV+), for whom OS, DFS and DSS was 85.6%, 84.7% and 92.7%, respectively, and demonstrated significantly higher OS (hazard ratio (HR) 0.28, CI 0.16-0.49, p < 0.0001), DFS (HR 0.28, CI 0.17-0.47, p < 0.0001) and DSS (HR 0.2, CI 0.09-0.44, <0.001). Post-operative oropharyngeal bleeding occurred in 23 patients (8.7%), of which 5 were major/severe, in patients without ECA ligation. Fibrin glue significantly reduced neck drain output (p < 0.001), and length of hospital stay (p < 0.001). One-year gastrostomy dependence rate was 2.3%. Conclusion(s): TLM + ND + PORT results in favourable 5-year survival and locoregional control rates, and low feeding tube dependency rates. ECA ligation and fibrin glue appear to reduce major post-operative haemorrhage, wound drainage and length of hospital stay. Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology

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CCC publication: ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer

Citation: Journal of Clinical Oncology. 2020, 38(15). (Conference Abstract)
Author: Ghaneh P.; Palmer D.H.; Cicconi S.; Halloran C.; Psarelli E.E.; Rawcliffe C.L.; Sripadam R.; Mukherjee S.; Wadsley J.; Al-Mukhtar A.; Jiao L.R.; Wasan H.S.; Carter R.; Graham J.S.; Ammad F.; Evans J.; Tjaden C.; Hackert T.; Buchler M.W.; Neoptolemos J.P.
Abstract: Background: Patients with borderline resectable pancreatic cancer have poor survival and low resection rates. Neoadjuvant therapy may improve the outcome for these patients. The aim of this trial was to determine the feasibility and efficacy of a comparison of immediate surgery versus neoadjuvant GEMCAP or FOLFIRINOX or CRT. Method(s): Eligible patients with NCCN defined borderline resectable (following central review of the baseline CT scan) and biopsy proven pancreatic cancer were randomised (stratified by centre) to receive immediate surgery, or neoadjuvant therapy of either 2 cycles of GEMCAP, or 4 cycles of FOLFIRINOX or 50.4Gy capecitabine-based CRT in 28 daily fractions over 5 weeks. Patients were restaged at 4-6 weeks and underwent surgical exploration if still borderline resectable. Resected patients received adjuvant therapy. Follow up was 12 months. There was quality assurance of surgery and CRT. Primary endpoints were recruitment rate and resection rate (R1/R0). Secondary endpoints included overall survival and toxicity. A target of 90 patients was set to determine feasibility and resection rates. Rates will be presented as point estimates and survival compared across treatment arms using a log-rank test. Analyses will be on an ITT basis. Result(s): Between August 2014 and December 2018, 90 patients were randomised with 88 included in the full analysis set (32 immediate surgery, 20 GEMCAP, 20 FOLFIRINOX, 16 CRT). Median age was 63 years, 44% were men. WHO performance status was 0 and 1 in 45% and 55% respectively. Median CA19-9 was 603 kU/L at baseline. 44 (79%) patients completed neoadjuvant therapy. Recruitment rate was 21 patients per year. Resection rate was 62% for immediate surgery and 55% for neoadjuvant therapy (p=0.668). R0 resection rate on resected patients was 15% and 23% respectively (p=0.721). One year survival rate was 40% [95% CI, 26% -62%] for immediate surgery and 77% [95%CI, 66% -89%] for neoadjuvant therapy. Log-rank analysis showed an HR=0.27 [95% CI, 0.13 -0.55]; chi2 (1) = 14.91, P<0.001. 9 out of the 51 neoadjuvant patients included in the safety set reported 12 serious adverse events of grade 3 or above. Conclusion(s): There was no difference in resection rate between arms, however neoadjuvant therapy had a significant survival benefit compared with immediate surgery.

CCC publication: Real-world outcomes of immunerelated adverse events in 2,125 patients managed with immunotherapy: A United Kingdom multicenter series

Citation: Journal of Clinical Oncology. 2020, 38(15). (Conference Abstract) 

Author: Olsson-Brown A.C.; Baxter M.; Dobeson C.; Feeney L.; Lee R.; Maynard A.; Mirza S.; Mughal S.; Parikh S.; Rodgers L.J.; Salawu A.; Shotton R.; Tinsley N.; Zhao S.S.; Jones C.

Abstract: Background: Immune-related adverse events (irAE) are a recognised complication of immune checkpoint inhibitor (ICI) therapy. Previous characterisation of irAEs has been limited to clinical trial or registry populations and small case series. Here we present a multi-centre, granular, real-world analysis of the prevalence and outcomes of irAEs experienced by patients managed within a single comprehensive public health service. Method(s): A multi-centre retrospective analysis of 2125 consecutive patients treated with ICIs was undertaken across 12 centres. All patients were managed within the UK National Health Service outside of a trial setting between June 2016 and September 2018. Patients received either ICI monotherapy (MT) or combination therapy (CT). Data were collected using a standardised, prepiloted, collection tool. IrAEs >= grade 2 or endocrinopathies of any grade were considered clinically significant and recorded as per the Common Terminology Criteria for Adverse Events (V5) (CTCAE). Descriptive statistics were employed using Stata v15 (College Station, TX). Result(s): Patients received alphaPD-1 (1757; 82%), combination alphaPD-1/alphaCTLA-4 (285, 13%), alphaCTLA-4 (51; 2%) and alphaPD-L1 (31; 1%) immunotherapy for malignant melanoma (961), non-small cell lung cancer (788) or renal cell carcinoma (335). The median age was 66 (MT) and 57 (CT). Clinically significant irAEs occurred in 732 (34%) individuals; 28% (524) on MT and 73% (208) on CT. Colitis (206,10%), thyroiditis (194, 9%), hepatitis (142, 7%) and dermatitis (126, 6%) were most commonly observed. Grade 1 endocrinopathies occurred in 20% (173) of cases. Grade 2 irAEs occurred in 43% (359), grade 3 31% (269) and grade 4 6% (51). The were 3 (0.4%) cases of grade 5 irAE; pneumonitis (2) and hepatitis, all following alphaPD-1 MT. 93% (680) required corticosteroids with 64% (490) requiring systemic corticosteroids and 11% (80) steroid sparing immunosuppression. 16% (336) of patients had pre-existing autoimmune disease of whom 40% (136) experienced irAEs. IrAEs led to admission in 42% (308) of cases, accounting for 2996 bed days. Length of stay was 7 days (1-67; IQR 4-13). Higher dependency care was required in 0.7% (15) of cases. Colitis (35%, 107) and hepatitis (25%, 77) accounted for the most admissions. Pneumonitis accounted for 3% (66) of irAEs but 12% of admissions. Conclusion(s): One third of patients experienced a clinically-significant irAE resulting in significant morbidity and admission burden highlighting the need for effective management strategies to optimise patient outcomes.

CCC publication: ARISTOTLE: A phase III trial comparing concurrent capecitabine with capecitabine and irinotecan (Ir) chemoradiation as preoperative treatment for MRIdefined locally advanced rectal cancer (LARC)

Citation: Journal of Clinical Oncology. 2020, 38(15). (Conference Abstract)

Author: Sebag-Montefiore D.; Adams R.; Gollins S.; Samuel L.M.; Glynne-Jones R.; Harte R.; West N.; Quirke P.; Myint A.S.; Bach S.P.; Parsons P.; Falk S.; Dhadda A.S.; Misra V.; Brown N.; Brown G.; Harrison M.; White L.; Duggan M.; Lopes A.

Abstract: Background: Phase II studies reported high pathological complete response (pCR) rates and acceptable toxicity using irinotecan and fluoropyrimidine chemoradiation in LARC (ISRCTN:09351447). Method(s): This phase III, multicentre, open-label trial funded by Cancer Research UK, randomly assigned (1:1) patients with MRI defined LARC threatening or involving resection margins without metastases, to pre-operative radiotherapy (RT) 45Gy/25 fractions combined with either capecitabine 900mg/m2 (CRT) or 650 mg/m2 bd weekdays with Irinotecan iv once-weekly 60mg/m2 weeks 1-4 (IrCRT). The primary endpoint is disease-free survival (DFS). Secondary endpoints include treatment compliance, safety and pCR. Result(s): 75 UK sites randomised 564 eligible patients from Oct/11 to July/18; 284 to CRT and 280 to IrCRT. 370 (66%) male; median age 61 years (range:29-83). Staging in both arms was similar: mrT3 (432/564(77%), mrT4 (89/564(16%); mrCRM involved (275/564(49%); threatened <=1mm (215/564(38%). Compared with CRT, IrCRT patients were less likely to receive 45Gy RT (207/276(75%) vs 251/283(89%), p < 0.001) or receive >=90% capecitabine dose in 188/276(68%) vs 253/283(89.4%)p < 0.001). A total of 204/276(74%) received >=90% irinotecan dose. The grade 3-4 gastrointestinal adverse event rate was 21%(58/276) with IrCRT and 12%(34/283) with CRT (p = 0.004). Patients receiving IrCRT had significantly more diarrhoea 38/276(13.8%) vs 10/283(3.5%)p < 0.001) and neutropenia 27/276(9.8%) vs 3/283 (1.1%) p < 0.001). Two CRT and three IrCRT patients experienced a treatment related death. 237/276(86%) IrCRT and 241/283(85%) CRT patients had surgery. The median time from end of RT to surgery(10.6 weeks), the surgical procedure APE 262/478(55%), AR 189/478(40%), Hartmann's 10/478(2%); and the surgical complications(any event) 38%(181/478) were similar in both arms. The pCR rate is available in > 95% patients and is 20.2% (46/228) for IrCRTvs.17.4%(40/230) for CRT (p = 0.45), A > 84% CRM-ve resection rate is similar in both arms. Conclusion(s): For patients with MRI defined high risk LARC low rates of CRM involvement were observed in both arms reflecting high quality multidisciplinary care. The addition of irinotecan did not significantly improve the pCR rate, was associated with a decrease in the RT and capecitabine compliance and a higher rate of adverse events. Surgical procedure or complications were unaffected. Longer follow-up is required to assess DFS and translational data.

CCC publication: Key Clinical Concepts from Multi-Institutional Experience with Dedicated Fixed Low-Energy Proton Ocular Beamlines

Citation: International Journal of Radiation Oncology Biology Physics. 2020, 108(3) (Conference Abstract)

Author: Mishra K.K.; Daftari I.K.; Quivey J.M.; Kacperek A.; Afshar A.R.; Scholey J.; Damato B.; Char D.H.

Abstract: Purpose/Objective(s): Proton beam treatment for ocular tumors has been well established with dedicated eye beamlines internationally. Given the emergence of universal, high-energy, non-fixed beamline options, we share key practices for uveal melanoma (UM) treatment planning and delivery. We focus particularly on practical clinical and physics concepts to minimize important ocular side effects. Materials/Methods: Practices were studied from two well-established international dedicated proton ocular institutions with very longstanding facilities, both using fixed, low-energy, ocular beamlines to treat eye tumors only. Since the 1970s and 1980s until now, the respective cyclotrons produce 67.5 and 60.0 MeV proton beams (range up to 3 cm). In total 5927 ocular patients, 93% with UM, have been treated. Standard UM dose is 56 Gray Equivalent (GyE) and 57.2 GyE, respectively, delivered in 4 fractions. Planning and delivery procedures were analyzed as a bi-institutional effort to communicate key concepts to newer developing proton centers. Result(s): Normal eye tissue sparing is related to critical beam characteristics provided in the setting of low-energy dedicated eye beamlines. Both centers offer a very sharp dose fall off (distal ~1 mm and lateral ~1.1-1.6 mm), high dose homogeneity, excellent range precision and short treatment time (~0.5-2 minutes). Planned doses to critical ocular structures are independent predictors of ocular complications such as vision loss and neovascular glaucoma, including the following parameters: 28 GyE to macula [P<.0001], optic nerve [P<0.0004], lens [P<.0001], and ciliary body [P<.0001]. A systematic tumor/critical structure dose evaluation is used to optimize treatment parameters, i.e. lateral margin, distal range, gaze angle, and aperture shape. New high-energy non-dedicated beam designs, which degrade energy to deliver ocular treatment, may require significant beam adjustment and treatment planning procedures to achieve adequate characteristics. Regarding UM dose, a common regimen is 60 GyE in 4 fractions globally. Unrandomized early retrospective data shows lower local tumor control with 48 GyE (P = 0.02). Critical structures including the retina, lacrimal gland, cornea, tear ducts, lids, bony orbit, and limbal stem cells are methodically evaluated to minimize side effects. Eyelid toxicity is reduced by institutional retraction techniques or treatment through closed lids. Conclusion(s): Experienced international specialty proton ocular centers with dedicated, low-energy, fixed eyelines, provide important practical concepts for consideration by developing centers to optimize high-energy universal beamline designs for eye treatments. As new centers with different beam designs emerge globally, key clinical and treatment planning/delivery practices will need to be applied, particularly to reduce potential normal tissue toxicity for ocular patients.

CCC publication: FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy

Citation: Int J Mol Sci. 2020, 21(18), E6492

Author: Hughes JR, Parsons JL

Abstract: FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy.

CCC publication: 838P TRIOC-A randomised phase II trial to examine MVA-5T4 vaccine in patients with relapsed asymptomatic epithelial ovarian, fallopian tube or primary peritoneal cancer,

Citation: Annals of Oncology. 2020, 31(Sup 4), S629
Author: A. Michael, W. Wilson, R. Harrop, I. McNeish, R. Lord, D. Blount, A.R. Clamp, M. Feeney, L. Farrelly, L. Hanna, R. Kristeleit, S. Nicum, A. Walther, O. Pressey, A. Hackshaw, J.A. Ledermann,

CCC publication: A multicentre randomised phase III trial comparing pembrolizumab vs single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial,

Citation: Annals of Oncology. 2020, 31(12), 1734-45

Author: S. Popat, A. Curioni-Fontecedro, U. Dafni, R. Shah, M. O’Brien, A. Pope, P. Fisher, J. Spicer, A. Roy, D. Gilligan, O. Gautschi, E. Nadal, W.D. Janthur, R. López Castro, R. García Campelo, S. Rusakiewicz, I. Letovanec, V. Polydoropoulou, H. Roschitzki-Voser, B. Ruepp, A. Gasca-Ruchti, S. Peters, R. Stahel,

Abstract: Background. Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterized by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity. Patients and methods. PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200mg/Q3W) vs institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0-1 and unselected for PD-L1 status. At progression, patients randomised to chemotherapy were allowed to crossover to pembrolizumab. The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary endpoints were overall survival (OS), investigator assessed (IA)-PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses. Results. Between September 2017 and August 2018, 144 patients were randomised, (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20/02/2019, median follow-up of 11.8 months (IQR: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected (HR=1.06, 95%CI:0.73-1.53; p=0.76), and median BICR-PFS (95% CI) for pembrolizumab was 2.5(2.1-4.2), compared with 3.4(2.2-4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95%CI:13%-33%), over chemotherapy (6%,95%CI:2%-14%; p=0.004). Forty-five patients (63%) assigned to chemotherapy, received pembrolizumab at progression. With follow-up to 21 August 2019 [17.5 months: 14.8-19.7)], no difference in OS was detected between groups (HR=1.12,95%CI:0.74-1.69; p=0.59), even after adjusting for cross-over. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS. Conclusion. This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy. Keywords: Malignant pleural mesothelioma; Pembrolizumab; Immune-checkpoint inhibition; Randomized clinical trial

CCC publication: 1670O Prospective data of first 1,797 hospitalised patients with cancer and COVID-19 derived from the COVID-19 Clinical Information Network and international Severe Acute Respiratory and emerging Infections Consortium, WHO Coronavirus Clinical Characterisation Consortium

Citation: Annals of Oncology. 2020, 31(Sup4), S992

Author: C. Palmieri, L. Turtle, A. Docherty, E. Harrison, T. Drake, B. Greenhalf, P.J. Openshaw, J.K. Baillie, M.G. Semple,

Abstract: Background. The SARS-CoV-2 pandemic in the UK triggered a national characterisation protocol and information on co-morbidities including malignant neoplasm is recorded. A lack of prospective data regarding cancer patients with COVID-19 hampers the development of an evidence based approach in this population. The Clinical Characterisation Protocol-CANCER-UK is a UK multi-disciplinary project aimed at characterising the presentation and course of COVID-19 in cancer patients with the aim of informing practice.

Methods. The international Severe Acute Respiratory and emerging Infections Consortium (ISARIC)-4C COVID-19 Clinical Information Network (CO-CIN) collects data on hospital inpatients with proven/high likelihood of COVID-19. Data was collected in 166 UK sites using a questionnaire adopted by the WHO. Data on patients with malignant neoplasm was extracted from the main dataset. We chose a priori to restrict any analysis of outcome to patients who were admitted more than 14 days before data extraction (13th May 2020).

Results. As of 13th May 2020 1797 of 16160 participants had malignant neoplasm (8.6% of all cases). Age<50 62 (3.5%), 50-60 378 (21%), 70-79 558 (31%), 80+ 1002 (42%). Male 1147 (64%); Female 645 (36%). Commonest comorbidities chromic pulmonary disease (22%), chronic kidney disease (21%), uncomplicated diabetes (19%) and dementia (14%). Outcomes 35% discharged alive, 30% care ongoing & 35% died. Admiited to ICU: 150 cases (25% discharged alive,31% care ongoing & 45% died). Receiving invasive ventiation: 67 cases (18% discharged alive, 25% care ongoing:25% & 57% died). HR mortality for malignancy (adjusted for age, sex, other comorbidity): 1.13 (1.02-1.24, p=0.017). Data on presentation will be presented.

Conclusions. Europe’s largest prospective COVID-19 dataset demonstrates that cancer is independently associated with mortality in patients admitted with COVID-19. Data collection is on-going and updated data will be presented including a comparison of cancer vs. non-cancer cohort with regard to presentation, comorbidity and otucomes.

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CCC publication: 1703P UK Coronavirus Cancer Monitoring Project (UKCCMP): A national reporting network for real time data of the COVID-19 pandemic

Citation: Annals of Oncology. 2020, 31, S1004

Author: A.C. Olsson-Brown, D.J. Hughes, K. Purshouse, L. Lee, V.W. Cheng, A.J.X. Lee, E. Protheroe, A. Smith, H. Curley, R. Arnold, J-B. Cazier, J. D'Costa, C. Palles, N. Campton, C. Varnai, S. Sivakumar, R. Kerr, G. Middleton,

Abstract: Background. The COVID-19 pandemic required a rapid response and need for real-world data in cancer patients. The nationwide, real-time coordinated UKCCMP reporting network provided an immediate solution.

Methods. The ability to set up an interdisciplinary multi-organisational team quickly, covering expert knowledge from clinical, legal, statistical, and computer science was essential. The technical infra-structure allows clinician-led anonymised data entry and rapid dissemination of results with a clinical (RedCap) database as core. However the development of a national cancer reporting network was crucial for the viability of the project. From its inception in March 2020 the reporting network was established via 4 iterative phases.

Results. Within the first 4 weeks, >50 centres were involved with coverage throughout the UK. Expansion has continued with >70 centres within 6 weeks reporting over 1200 COVID positive cancer patients. This was achieved through a 4-phase approach: phase 1 - Outline: This involved project protocol development where key data and timelines were confirmed by a small project team followed by whole-team sign-off. phase 2 - Engagement: This involved identification and engagement of existing groups to establish an initial network. Professional body endorsement led to increased recognition and utilisation of their membership networks. Finally regional leads were identified. phase 3 - Invitation: The third phase involved the distribution of a formal invite letter via identified networks. Project specific email and standard mailing lists were created to enhance network identity and communication. phase 4 - Consolidation: Early development of an interactive project website and focus on communication via social media with varied content consolidated interest and led to further extension.

Conclusions. Real-time reporting of real world data can be achieved with clearly defined project phases, standardised documentation and an iterative recruitment process. The COVID-19 pandemic necessitated a rapid response, proving that similar reporting networks can be set up quickly and robustly to react to the evidence-based needs of the oncology community in the drive for implementation of change.

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CCC publication: 611O Abiraterone acetate plus prednisolone for hormone-naïve prostate cancer (PCa): Long-term results from metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476),

Citation: Annals of Oncology. 2020, 31(Sup4), S509

Author: N. James, H. Rush, N. Clarke, G. Attard, A. Cook, D. Dearnaley, S. Gillessen, A. Hoyle, R. Jones, R. Millman, A. Birtle, S. Chowdhury, J. Gale, Z. Malik, J. O'Sullivan, C. Pezaro, D. Sheehan, J. Tanguay, M.K. Parmar, M.R. Sydes,

CCC publication: PIVOTALboost: A phase III randomised controlled trial of prostate and pelvis versus prostate alone radiotherapy with or without prostate boost (CRUK/16/018)

Citation: Clinical and Translational Radiation Oncology. 2020, 25, 22-8

Author: Isabel Syndikus, Clare Cruickshank, John Staffurth, Alison Tree, Ann Henry, Olivia Naismith, Helen Mayles, Nicola Snelson, Shama Hassan, Stephanie Brown, Nuria Porta, Clare Griffin, Emma Hall,

WUTH publication: Non-anaemic iron deficiency should be investigated with the same priority as iron deficiency anaemia in fast track colorectal clinics-retrospective cohort study

Citation: Journal of Gastrointestinal oncology. 2020, 11(4), 609-615 

Author: Majeed T, Solomon J, Ali RS, Chitsabesan P

Abstract: Background:  Since year 2000 the diagnostic criterion for fast track (FT) referrals for patients with suspected colorectal cancer (CRC) is used in the UK. Iron deficiency anaemia (IDA) is one of the diagnostic criteria. There is a strong evidence in the literature which suggests that Iron deficiency (ID) alone has a strong relationship with CRC. Non-anaemic Iron deficiency (NAID) and all other types of anaemia are investigated outside the scope of FT clinics. We postulated that patients with ID regardless of degree of anaemia have an increased risk of CRC. By confirming this hypothesis, we can broaden the scope of the diagnostic criterion for referral that can help to increase diagnostic yield of FT CRC services. 

Methods:  A retrospective observational cohort study was conducted from a dedicated data for FT clinics from 2016-2018. Association between CRC and different forms of anaemia, Iron deficiency alone and bowel symptoms was determined. 

Results:  Patients with iron deficiency (low MCV, MCH and ferritin) regardless of degree of anaemia were found more likely to have CRC. Factors like age, gender, family history and bowel symptoms (except abdominal mass) showed a very weak association with CRC in patients with ID. 

Conclusions:  ID without anaemia has a strong relationship with CRC and should be investigated with the same priority as IDA is investigated. 

Keywords:  Iron deficiency anaemia; colorectal cancer (CRC); colorectal surgery; department of health diagnostic criterion; fast track clinics; iron deficiency; iron deficiency without anaemia; two weeks wait.

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WUTH publication: Comparative effectiveness of ustekinumab or vedolizumab after one year in 130 patients with anti-TNF-refractory Crohn's disease

Citation: Alimentary pharmacology and therapeutics. 2020, 52(8), 1341-52
Author: Townsend T, Razanskaite V, Dodd S, Storey D, Michail S, Morgan J, Davies M, Penman D, Watters C, Swaminathan M, Sabine J, Chapman A, Smith PJ, Flanagan PK, Reilly I, Bodger K, Subramanian S
Abstract: Background:  Anti-tumour necrosis factor (TNF) agents are effective in Crohn's disease but some patients lose response and require alternative biologic therapy. There are few data on comparative effectiveness of vedolizumab and ustekinumab in this setting.
Aim:  To compare the effectiveness of ustekinumab and vedolizumab in anti-TNF-refractory Crohn's disease over 12 months.
Methods:  Patients commencing ustekinumab or vedolizumab for anti-TNF-refractory Crohn's disease with minimum follow-up of 12 months were included. The primary outcome measure was the difference in steroid-free remission rates at end of induction (2 months) and at 12 months. We also assessed rates of clinical response and remission, treatment persistence, surgery and adverse events in both groups. We performed logistic regression analysis to assess factors associated with steroid-free remission and clinical response and remission.
Results:  We included 85 patients commencing vedolizumab and 45 commencing ustekinumab. In an unadjusted model, rates of steroid-free and clinical remission were significantly higher among ustekinumab-treated patients. After adjusting for confounders, steroid-free remission was higher among ustekinumab-treated patients at 2 months (odds ratio, OR 2.79, 95% confidence interval, CI 1.06-7.39, P = 0.038) and 12 months (OR 2.01, 95% CI 0.89-4.56, P = 0.095). More patients treated with ustekinumab remained on therapy at the end of 12 months (84.4% vs 61.5%, P = 0.007).
Conclusions:  Ustekinumab appeared more effective in treating anti-TNF-refractory Crohn's disease and more patients persisted with therapy. 

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WUTH publication: Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score

Citation: BMC Geriatrics. 2020, 20(1), 346

Author: Danjuma MI, Almasri H, Alshokri S, Khir FK, Elmalik A, Battikh NG, Abdallah IMH, Elshafei M, Fatima H, Mohamed MFH, Maghoub Y, Hussain T, Kamal I, Anwer Z, Bidmos MA, Elzouki AN

Abstract: Background: Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI.

Methods: We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes.

Results: The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively.

Conclusion: We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

Keywords: Avoidability; preventability; DILI; LAAT; elderly patients.

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WUTH publication: The Central Role and Possible Mechanisms of Bacterial DNAs in Sepsis Development

Citation: Mediators of Inflammation. 2020 Aug 31;2020:7418342. eCollection 2020.

Author: Cheng Z, Abrams ST, Austin J, Toh J, Wang SS, Wang Z, Yu Q, Yu W, Toh CH, Wang G

Abstract: The pathological roles of bacterial DNA have been documented many decades ago. Bacterial DNAs are different from mammalian DNAs; the latter are heavily methylated. Mammalian cells have sensors such as TLR-9 to sense the DNAs with nonmethylated CpGs and distinguish them from host DNAs with methylated CpGs. Further investigation has identified many other types of DNA sensors distributed in a variety of cellular compartments. These sensors not only sense foreign DNAs, including bacterial and viral DNAs, but also sense damaged DNAs from the host cells. The major downstream signalling pathways includeTLR-9-MyD88-IKKa-IRF-7/NF-κB pathways to increase IFN/proinflammatory cytokine production, STING-TBK1-IRF3 pathway to increase IFN-beta, and AIM2-ASC-caspas-1 pathway to release IL-1beta. The major outcome is to activate host immune response by inducing cytokine production. In this review, we focus on the roles and potential mechanisms of DNA sensors and downstream pathways in sepsis. Although bacterial DNAs play important roles in sepsis development, bacterial DNAs alone are unable to cause severe disease nor lead to death. Priming animals with bacterial DNAs facilitate other pathological factors, such as LPS and other virulent factors, to induce severe disease and lethality. We also discuss compartmental distribution of DNA sensors and pathological significance as well as the transport of extracellular DNAs into cells. Understanding the roles of DNA sensors and signal pathways will pave the way for novel therapeutic strategies in many diseases, particularly in sepsis.

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WUTH publication: An audit of process and outcome for emergency colectomy in England and Wales

Citation: Colorectal Disease. 2020 Sep 16. Online ahead of print.

Author: Burns EM, Poulton T, Deputy M, Pinkney T, Guy R

Abstract: Aim: To describe process and outcome for patients undergoing emergency colectomy for colitis in England and Wales.

Methods: National Emergency Laparotomy Audit (NELA) is a national audit including patients undergoing emergency laparotomy and laparoscopic resectional procedures. Adult patients under 65 years oldwho underwent emergency subtotal colectomy or panproctocolectomy for colitis between 2013-2016 were analysed.

Results: In total 1204 patients were included. Although approximately a third of patients underwent a colectomy within five days of admission [37% (440/1204)], 32% (383/1204) were admitted for more than ten days prior to surgery. Colorectal surgeons were present at operation in 72% (869/1204) of cases and consultant surgeons attended 94%(1137/1204) of procedures.Laparoscopy was attempted in 32%(390/1204) of operations with wide institutional variation in its use (0-100% of cases). The overall 30-day inpatient mortality was 2.9%(35/1204). On multivariableregression analysis, age>55 [odds ratio(OR) 3.59(1.05-12.21), p=0.041], female gender [OR 2.88(1.27-6.52), p=0.011], and ASA of 5 [OR 37.43 (2.72-514.52), p=0.007] were associated with increased mortality.

Conclusion: There is a consultant-driven service that is largely delivered by specialist Colorectal surgeons. Laparoscopy rates were high although there was wide variation in use across institutions. Preoperative delays were evident and further work is necessary to determine the underlying reasons forthese.

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WUTH publication: Tax-otsubo': stress cardiomyopathy following an encounter with the Inland Revenue

Citation: BMJ Case Reports. 2020, 13(1), e232225
Author: Roach MW, Currie P
Abstract: An 89-year-old man developed chest pain and palpitations shortly after finishing a stressful 40 min phone call to HM Revenue and Customs. After admission to the emergency department, he had a cardiovascular collapse followed soon after by a cardiac arrest due to ventricular fibrillation (VF). The troponin T was elevated and his ECG showed extensive deep T wave inversion with prolongation of the QT interval. A portable hand-held ultrasound device (VScan; GE Healthcare) was used to demonstrate classical apical ballooning of the left ventricular apex indicating a diagnosis of takotsubo stress cardiomyopathy. Shortly following admission to the cardiac care unit, he had a further episode of VF, which was successfully defibrillated. A coronary angiogram was performed, which was normal. He was treated with a short course of benzodiazepines. He was discharged after 8 days without any neurological deficit. His echocardiogram subsequently showed complete resolution of the abnormalities of the left ventricular function.

Keywords: arrhythmias; clinical diagnostic tests; heart failure.

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WUTH publication: Reply to "Fluoroscopy during coccygectomy for rectal cancer"

Citation: Techniques in colproctology. 2020 Aug 29 Online ahead of print
Author: Simpson G, Marks T, Blacker S, Smith D, Walsh C

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WUTH publication: Legacy of COVID-19 - the opportunity to enhance surgical services for patients with colorectal disease

Citation: Colorectal Disease. 2020 Aug 28. Online ahead of print
Author: Arulampalam T, Bhangu A, Brown SR, Clark SK, Din F, Harji D, Knowles CH, McNamara D, Moug SJ, Smart N, Tierney G, Torkington J, Walsh C, Watson A, Fearnhead NS
Abstract: The COVID-19 crisis has undoubtedly taken a toll on the care of patients with colorectal disease. Elective services, be that face to face contact, endoscopy or operating all but ceased during the pandemic.

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