Christie NHS Foundation Trust Research Articles

Patient and treatment characteristics of emergency presentations due to immune-mediated toxicities.

6586 Background: The prevalence of immune-mediated toxicities from immune checkpoint inhibitors (ICIs) is well described. However, the characteristics and treatment patterns for patients with emergency presentations due to immune-mediated toxicity are less well known. Methods: This study of all emergency presentations in patients treated with ICIs was performed at The Christie NHS Foundation Trust, Manchester, United Kingdom from May 2018-February 2020. The aims were to describe the patient and treatment characteristics of those diagnosed with an immune-mediated toxicity. Results: In total, 597 patients receiving ICIs had an emergency presentation and 191/597 (32%) were diagnosed with an immune-mediated toxicity. Of these patients, the median age was 64 years and 127/191 (67%) were male. The most common tumour types were melanoma (53%) and lung (22%) and the most common ICI received was ipilimumab + nivolumab combination immunotherapy (42%), followed by pembrolizumab monotherapy (21%) and nivolumab monotherapy (20%). The median number of cycles received was 3 (range 1-54), and 73/191 (38%) previously had ≥ grade 2 immune-mediated toxicity. The most common diagnoses were colitis (38%), hepatitis (15%), and pneumonitis (14%). The majority, 180/191 (94%) received steroids and 52/180 (29%) patients required second-line immunosuppression. The most common second-line immunosuppressants used were mycophenolate mofetil (58%) and infliximab (50%). Eleven patients (22%) required more than one second-line immunosuppressant. Conclusions: The majority of patients with emergency presentations due to immune-mediated toxicity were being treated with combination immunotherapy for melanoma. More than a third of patients had previous ≥ grade 2 immune-mediated toxicity. Over one quarter of patients treated with steroids required second-line immunosuppression. Identifying these characteristics can help inform which patients receiving ICIs seeking medical review need admission to a center with experience in managing immune-mediated toxicity.

Differential response rates in early-phase cancer clinical trials (EPCCT).

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for >6 mos and 7% for >12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response >6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response > 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p<0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small cell lung cancer.

3100 Background: Antibiotic (ABX) use and disruption of the gut microbiome has been demonstrated to reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics in cancer patients. Little is known about the impact of ABX use in patients treated with targeted therapies, such as tyrosine kinase inhibitors (TKI). Methods: Retrospective data analysis was performed on advanced melanoma and non-small cell lung cancer (NSCLC) patients treated with TKIs between January 2015 and April 2017 at The Christie NHS Foundation Trust, UK. Demographics, prior systemic treatment, extent of disease, lactate dehydrogenase level (LDH), presence of brain metastases, performance status, comorbidities, TKI agent and the use of ABX (class, route, duration) were collected. Progression free survival (PFS) and overall survival (OS) were compared between the ABX+ group (defined as patients treated with ABX within 2 weeks of TKI initiation or 6 weeks after) and the ABX – group (patients with no ABX during specified period). Statistical analyses were performed with univariate and multivariable models. Results: In total, 168 patients were included; 89 patients (53%) with advanced NSCLC and 79 patients (47%) with melanoma. Over a third of patients, (57/168, 34%) received ABX in the specified period (ABX+). On univariable analysis, ABX use was associated with shorter PFS (208 days vs 357 days, p = 0.008) and OS (294 days vs 438 days, p = 0.024). Increased age, poorer performance status, and higher LDH were also associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS (HR 1.57, 95% CI 1.05-2.34, p = 0.028) and OS (HR 2.19, 95% CI 1.44-3.32, p = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with worse performance status (HR 3.82, 95% CI 1.18-12.36, p = 0.025). Conclusions: To our knowledge, this is the largest multivariable analysis showing ABX use independently reduces PFS and OS in patients treated with TKIs. It is the first analysis to demonstrate this phenomenon across two distinct tumour sites. The data suggests that ABX use could be an independent predictor of shorter PFS and OS in cancer patients treated with TKIs, and warrants further validation in a larger cohort.

Collaborating with low- and middle-income countries: Experience from two of the United Kingdom’s comprehensive cancer centers.

e23014 Background: The number of annual global cancer deaths is rising and the majority of this burden, for a multitude of reasons, falls in low- and middle- income countries (LMICs). With the United Nations’ 3rd and 17th Sustainable Development Goals in mind (which include by 2030 “reduce by one third premature mortality from non-communicable diseases” and “partnership for the goals”) a survey was undertaken at the UK’s two largest comprehensive cancer centres to scope individual and team endeavours to work with colleagues in less well-resourced countries. Methods: Employees at the Royal Marsden Foundation Trust (RM) and Institute of Cancer Research (ICR) in London and Surrey, UK and The Christie NHS Foundation Trust (Christie), Manchester were invited to complete a survey to capture collaborative clinical care, research, education and training. Results: Responses were received from 520 multidisciplinary individuals across the 2 centres to two similar questionnaires. A large number had experience of working in some capacity in, or in collaboration with an LMIC. At the RM 14.62% of respondees were currently working with colleagues in LMICs. At The Christie 13.22% of staff had experience of working in LMICs in a supportive capacity. Those currently collaborating with colleagues in LMICs were working in a wide range of countries across Asia, Africa and South America in a range of initiatives spanning clinical care, research, education and training. Of those who answered the survey 64% at The Christie said they’d like to hear more about opportunities to be involved in supporting global health care, and 89% at RM/ICR said they’d be interested in joining a collaborative group working on global oncology initiatives at the institutions. Conclusions: This survey highlights the body of willing, interested individuals keen to work with colleagues in LMICs to improve cancer outcomes. The launch of the UK Global Cancer Network in 2020 will build upon these two surveys with a planned national survey of global health and cancer work undertaken by individuals in 2021.

P90.04 RAS Precision Medicine Trans-Atlantic Partnership: Multi-Centre Pooled Analysis of RAS Pathway Mutations in Advanced NSCLC

The most common histological subtype of non-small cell lung cancer (NSCLC) is adenocarcinoma (50-55% of patients), of which the most common oncogenic driver is KRAS mutation (∼30% internationally). Genetic data has altered the taxonomy of NSCLC over the past 10 years, highlighting subgroups such as EGFR mutation, which have improved prognosis and are susceptible to targeted therapies. Despite its frequency, targeting RAS has historically been limited by pre-clinical and clinical failures. Emerging preclinical/clinical data suggests there is value looking beyond RAS mutation, analysing subtypes- represented by a limited number of variations in its mutational isoforms, codons and alleles. Through international collaboration our partnership aims to extend existing knowledge of RAS precision medicine in NSCLC, evaluating biological, clinical and treatment effects at subtype level. For this analysis, the first 309/384 patients with stage IIIb/IV RAS- and/or NF1-mutant NSCLC were identified from the Christie NHS Foundation Trust and the Gustave Roussy Cancer Centre between August 2008 and July 2020. DNA was extracted from archival FFPE samples, plasma or both to identify mutations using targeted next generation sequencing. Molecular, clinical, pathological and outcome data were collected on all patients and Kaplan-Meier survival analysis was performed to test for survival differences between subtypes based on treatment arms. For clinical characteristics, Mann-Whitney and Fisher’s exact tests were used for statistical comparisons in continuous and dichotomous datasets, respectively. Of 309 patients analysed, 151 patients were from the Christie NHS Foundation Trust and 158 patients from the Gustave Roussy Cancer Centre. Mean age was 63, range 19-92. 30 patients (10%) had stage IIIb disease with the remainder stage IV, 292 patients (94.5%) demonstrated non-squamous histology vs. 16 (5%) squamous vs 1 (0.5%) adenosquamous. Median PD-L1 status across the cohort was 20%. 209 patients (68%) had a mutation identified by tissue analysis, 38 patients (12%) by plasma and 62 (20%) by both. The most common RAS mutation identified was KRAS in 259 patients (84%), followed by NRAS in 13 patients (4%) and HRAS in 7 patients (2%). Amongst the KRAS mutant population, 111 pts (43%) harboured a mutation in G12C, followed by 52 (20%) G12D and 41 (16%) G12V. Codon 61 was most commonly mutated within this subgroup 16/259 (6%). 40 patients (13%) were identified as carrying a mutation in NF1; 35 non-squamous histology, 4 squamous and 1 adenosquamous. Progression free survival following first line chemotherapy plus immunotherapy or immunotherapy alone was variable across KRAS-, NRAS- and NF1-mutant subgroups (8.3 vs. 14.9 vs. 10.2 months; p=0.86). Median PD-L1 status was found to be 63% vs. 100% vs. 79% respectively. Analysis of RAS codon and allelic subgroups, including their therapeutic vulnerabilities beyond immunotherapy, will be presented following further analysis. The RAS precision medicine Trans-Atlantic partnership is designed to evaluate prognostic/predictive value of RAS and NF1 mutations in advanced NSCLC, focusing specifically on signal seeking for therapeutic vulnerabilities in mutant RAS isoforms, codons, and allelic subtypes. Ongoing analysis is planned to expand the dataset and inform the optimal sequence of therapy for subtypes of RAS- and NF1-mutant patients.

Abstract PR-11: Developing an agnostic risk prediction model for acute kidney injury in cancer patients using a machine learning algorithm from blood results data

Abstract Acute Kidney Injury (AKI) is a common complication in hospital inpatients with the annual number of excess inpatient deaths associated with AKI in England estimated to be above 40,000 and the annual cost of AKI-related inpatient care around £1.02 billion. Oncology patients are a known high risk population for developing AKI. The prevalence of AKI in oncology populations is 7.5 to 9.5%, with AKI incidence associated with lower remission rates and higher mortality. To reduce the impact of this condition in cancer patients we aimed to create a model to predict AKI events before occurrence allowing intervention and prevention strategies to be put in place. We trained a Random Forest Model on 597,403 blood test results from 48,865 patients undergoing cancer treatment at The Christie NHS Foundation Trust, Manchester, UK between January 2017 and 3rd May 2020, to identify AKI events upcoming in the next 30 days. From this model, risk levels of very low, low, medium, high and very high were assigned to the risk of an upcoming AKI event. We tested the model and risk assessment through a prospective analysis on patients’ blood tests results collected between 1st June 2020 to 31st August 2020. The trained model gave an area under the receiver operating characteristic curve (ROC AUC) of 88.1% (95% confidence interval 87.8% - 88.3%) when assessing predictions per blood test for AKI occurrences within 30 days. Assigning risk levels and testing the model through prospective validation across the period 1st June to the 31st August identified 61.2% of AKI occurrences with a risk alert of `Medium' or higher, identifying 73.8% of patients with AKI event before at least one AKI occurrence. Our results demonstrate the exciting potential for using routinely collected blood test data to assign AKI risk levels allowing early intervention and preventative strategies to be put in place. Citation Format: Lauren A. Scanlon, Jorge Barrusio, Alexander Garbett. Developing an agnostic risk prediction model for acute kidney injury in cancer patients using a machine learning algorithm from blood results data [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PR-11.

Evaluation of GATE-RTion (GATE/Geant4) Monte Carlo simulation settings for proton pencil beam scanning quality assurance.

Geant4 is a multi-purpose Monte Carlo simulation tool for modeling particle transport in matter. It provides a wide range of settings, which the user may optimize for their specific application. This study investigates GATE/Geant4 parameter settings for proton pencil beam scanning therapy. GATE8.1/Geant4.10.3.p03 (matching the versions used in GATE-RTion1.0) simulations were performed with a set of prebuilt Geant4 physics lists (QGSP_BIC, QGSP_BIC_EMY, QGSP_BIC_EMZ, QGSP_BIC_HP_EMZ), using 0.1mm-10mm as production cuts on secondary particles (electrons, photons, positrons) and varying the maximum step size of protons (0.1mm, 1mm, none). The results of the simulations were compared to measurement data taken during clinical patient specific quality assurance at The Christie NHS Foundation Trust pencil beam scanning proton therapy facility. Additionally, the influence of simulation settings was quantified in a realistic patient anatomy based on computer tomography (CT) scans. When comparing the different physics lists, only the results (ranges in water) obtained with QGSP_BIC (G4EMStandardPhysics_Option0) depend on the maximum step size. There is clinically negligible difference in the target region when using High Precision neutron models (HP) for dose calculations. The EMZ electromagnetic constructor provides a closer agreement (within 0.35mm) to measured beam sizes in air, but yields up to 20% longer execution times compared to the EMY electromagnetic constructor (maximum beam size difference 0.79mm). The impact of this on patient-specific quality assurance simulations is clinically negligible, with a 97% average 2%/2mm gamma pass rate for both physics lists. However, when considering the CT-based patient model, dose deviations up to 2.4% are observed. Production cuts do not substantially influence dosimetric results in solid water, but lead to dose differences of up to 4.1% in the patient CT. Small (compared to voxel size) production cuts increase execution times by factors of 5 (solid water) and 2 (patient CT). Taking both efficiency and dose accuracy into account and considering voxel sizes with 2mm linear size, the authors recommend the following Geant4 settings to simulate patient specific quality assurance measurements: No step limiter on proton tracks; production cuts of 1mm for electrons, photons and positrons (in the phantom and range-shifter) and 10mm (world); best agreement to measurement data was found for QGSP_BIC_EMZ reference physics list at the cost of 20% increased execution times compared to QGSP_BIC_EMY. For simulations considering the patient CT model, the following settings are recommended: No step limiter on proton tracks; production cuts of 1mm for electrons, photons and positrons (phantom/range-shifter) and 10mm (world) if the goal is to achieve sufficient dosimetric accuracy to ensure that a plan is clinically safe; or 0.1mm (phantom/range-shifter) and 1mm (world) if higher dosimetric accuracy is needed (increasing execution times by a factor of 2); most accurate results expected for QGSP_BIC_EMZ reference physics list, at the cost of 10-20% increased execution times compared to QGSP_BIC_EMY.

FOLFOX as Second-Line Chemotherapy for Advanced Biliary Tract Cancer

Background: Advanced biliary tract cancer (ABC) has a poor prognosis for which cisplatin-gemcitabine is the reference first-line chemotherapy. No robust evidence is available for second-line chemotherapy. Methods: Patients with ABC who progressed on first-line cisplatin-gemcitabine were randomised to active symptom control (ASC) and oxaliplatin and 5-fluorouracil (FOLFOX) or ASC alone. The primary end-point was overall survival (OS); recruitment of 162 patients was required, to deliver 148 events (hypothesised hazard ratio (HR) 0.63; 80% power; 5% two-sided alpha). Secondary end-points included progression-free survival (PFS) and response rate (ASC+FOLFOX arm only). Results: A total of 162 patients were randomised (81 in each arm) between 27-Mar-2014 and 04-Jan-2018). The median age was 65 years (range 26-84); 80 (49%) were male and the primary tumour sites were intrahepatic cholangiocarcinoma (CCA) 72 (44%), extrahepatic CCA 45 (28%), gallbladder 34 (21%) and ampullary cancer 11 (7%). After 150 OS events, the adjusted HR was 0.69 (95%CI-0.50-0.97; p=0.031; ASC+FOLFOX vs ASC). Median OS (months (m)), 6m and 12m OS-rate (%) were 6.2m, 50.6% and 25.9% for the ASC+FOLFOX and 5.3m, 35.5%, 11.4% for the ASC arm, respectively. The median PFS was 4.0 months (95%-CI 3.2-5.0); the response rate was 5% and the disease control rate 33%. Grade 3-5 adverse events were reported in 56 (69%) and 42 (52%) patients in the ASC+FOLFOX and ASC arm, respectively, including two chemotherapy-related deaths. Conclusion: FOLFOX improved OS after progression to cisplatin-gemcitabine with a clinically-meaningful increase in 6m and 12m OS rate. FOLFOX should become standard-of-care in second-line for ABC. Trial Registration: NCT01926236, EudraCT: 2013-001812-30. Funding Statement: The study was sponsored by The Christie NHS Foundation Trust. The ABC-6 study was funded by Cancer Research UK (CRUK/13/004), StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity) and The Christie Charity. The Cholangiocarcinoma Foundation provided funding translational research. Dr Angela Lamarca received funding from ESMO (European Society for Medical Oncology), SEOM (Sociedad Espanola de Oncologia Medica) and Conquer Cancer Foundation (Young Investigator Award) fellowship programs and from The Christie Charity. Declaration of Interests: Dr Angela Lamarca received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen and Incyte; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche; she is also a member of the Knowledge Network and NETConnect Initiatives funded by Ipsen. Prof Daniel H Palmer declares research grants from AstraZeneca, Bayer, BMS, Nucana, Sirtex; and Consulting or Advisory roles for AstraZeneca, Bayer, BMS, Eisai, MSD, Servier, Roche. Harpreet Singh Wasan declares no conflict of interest associated to this work. Dr Paul J Ross declares research grants from research grants from Sanofi, Bayer; Consulting or Advisory roles for Bayer, BMS, Eisai, Sirtex, Roche; speaker fees from Amgen, Roche, Servier; Travel grants from Bayer, Roche, Servier. Dr Yuk Ting Ma declares speaker honoraria and advisory roles for Bayer, Eisai and Roche. Dr Arvind Arora declares no conflict of interest. Dr Stephen Flak declares no conflict of interest. Dr Roopinder Gilmore declares no conflict of interest. Prof Jon Wadsley declares research grants from AstraZeneca and Sanofi-Genzyme and Consulting or Advisory roles for Lilly, AstraZeneca, Sanofi Genyme, Eisai, AAA, Roche, Novartis, Ipsen. Dr Kinnari Patel declares no conflict of interest. Alan Anthony declares no conflict of interest. Prof Anthony Maraveyas declares research grants from Pfizer, BMS and Bayer. Speaker fees from BMS. Bayer Ipsen, EUSA Pharma, Daiichi Sankyo and Pfizer and advisory roles for Bayer ,BMS, Leo, Pfizer, Merck and Ipsen. Dr Tim Iveson declares no conflict of interest. Dr Justin S Walters received educational support for travel and conference attendance from Mylan and Ipsen, and speaker honoraria from Mylan. Dr Claire Hobbs declares no conflict of interest. Safia Barber declares no conflict of interest. David Ryder declares no conflict of interest. Prof John Ramage declares research grants, speaker fees and advisory roles for Ipsen, Novartis and AAA. Linda M Davies declares no conflict of interest. Prof John Bridgewater declares Consulting or Advisory role for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD oncology, Merck Serono, Servier and BMS. Prof Juan W Valle declares Consulting or Advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, PierisPharmaceuticals, QED and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited Ipsen Novartis Nucana; and Travel Grants from Celgene and Nucana. Ethics Approval Statement: The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study protocol was approved by a research ethics committee and all patients were required to provide written informed consent.

Automated Monte-Carlo re-calculation of proton therapy plans using Geant4/Gate: implementation and comparison to plan-specific quality assurance measurements.

Software re-calculation of proton pencil beam scanning plans provides a method of verifying treatment planning system (TPS) dose calculations prior to patient treatment. This study describes the implementation of AutoMC, a Geant4 v10.3.3/Gate v8.1 (Gate-RTion v1.0)-based Monte-Carlo (MC) system for automated plan re-calculation, and presents verification results for 153 patients (730 fields) planned within year one of the proton service at The Christie NHS Foundation Trust. A MC beam model for a Varian ProBeam delivery system with four range-shifter options (none, 2 cm, 3 cm, 5 cm) was derived from beam commissioning data and implemented in AutoMC. MC and TPS (Varian Eclipse v13.7) calculations of 730 fields in solid-water were compared to physical plan-specific quality assurance (PSQA) measurements acquired using a PTW Octavius 1500XDR array and PTW 31021 Semiflex 3D ion chamber. TPS and MC showed good agreement with array measurements, evaluated using γ analyses at 3%, 3 mm with a 10% lower dose threshold:>94% of fields calculated by the TPS and >99% of fields calculated by MC had γ ≤ 1 for>95% of measurement points within the plane. TPS and MC also showed good agreement with chamber measurements of absolute dose, with systematic differences of <1.5% for all range-shifter options. Reliable independent verification of the TPS dose calculation is a valuable complement to physical PSQA and may facilitate reduction of the physical PSQA workload alongside a thorough delivery system quality assurance programme. A Gate/Geant4-based MC system is thoroughly validated against an extensive physical PSQA dataset for 730 clinical fields, showing that clinical implementation of MC for PSQA is feasible.

Technical Note: GATE-RTion: a GATE/Geant4 release for clinical applications in scanned ion beam therapy.

GATE-RTion is a validated version of GATE for clinical use in the field of light ion beam therapy. This paper describes the GATE-RTion project and illustrates its potential through clinical applications developed in three European centers delivering scanned proton and carbon ion treatments. GATE-RTion is a collaborative framework provided by the OpenGATE collaboration. It contains a validated GATE release based on a specific Geant4 version, a set of tools to integrate GATE into a clinical environment and a network for clinical users. Three applications are presented: Proton radiography at the Centre Antoine Lacassagne (Nice, France); Independent dose calculation for proton therapy at the Christie NHS Foundation Trust (Manchester, UK); Independent dose calculation for protons and carbon ions at the MedAustron Ion Therapy center (Wiener Neustadt, Austria). GATE-RTion builds the bridge between researchers and clinical users from the OpenGATE collaboration in the field of Light Ion Beam Therapy. The applications presented in three European facilities using three completely different machines (three different vendors, cyclotron- and synchrotron-based systems, protons, and carbon ions) demonstrate the relevance and versatility of this project.

Systemic anti-cancer therapy delivery in the home: a service model.

The Christie NHS Foundation Trust is a leader in adapting patient care in response to treatment advances and new patient-centred care/efficiency initiatives. Due to extended waiting times in cancer clinics, The Christie developed an at-home treatment service to help reduce the pressure on clinics and improve patient experience. This article provides a detailed examination of the requirements necessary to successfully develop a home service for the delivery of systemic anticancer treatment. The authors discuss the criteria used to identify suitable at-home treatments, as well as necessary resources and equipment. The success of the Christie at Home service was examined using a patient survey to assess the standard of this care. Details are given regarding the challenges of implementing a homecare service and potential future challenges. As an example, systemic treatment with eribulin as a 'Christie at Home' therapy demonstrates the practicalities of introduction of new therapies in a homecare service.

Tackling antimicrobial resistance in cancer patients at the Christie NHS Foundation Trust

Tackling antimicrobial resistance in cancer patients at the Christie NHS Foundation Trust

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

An introduction to proton beam therapy.

Radiotherapy is a highly effective anti-cancer treatment commonly used alongside systemic therapies and surgery to achieve long-term cancer-free survival. Conventional radiotherapy uses photon beams to deliver a high dose of radiation to the tumour volume to eradicate cancer cells. This has to be offset against the irradiation of surrounding normal tissues, as increasing this dose causes more treatment-related toxicity. In August 2018, the NHS's first high energy proton beam therapy centre opened at The Christie NHS Foundation Trust in Manchester. A second NHS centre is scheduled to open in 2020 at the University College London Hospitals NHS Trust. Proton beam therapy may offer dosimetric advantages compared to conventional radiotherapy as a result of its characteristic dose deposition - proton beams deliver a comparatively higher proportion of their dose to the target volume relative to normal tissues, without significant exit doses when compared to conventional photon therapy. Therefore proton beam therapy may be indicated for certain tumours situated next to critical organs or in the paediatric population where quality of life and the reduction of secondary effects from radiation are particularly significant. The indications for proton beam therapy and patient outcomes after treatment will be carefully monitored and evaluated in order to provide a robust evidence base for its use.

P6238International cardiovascular disease risk calculators do not identify high risk in young hodgkin lymphoma survivors

Abstract Background Cardiotoxic therapy causes significant morbidity and mortality in patients (pts) treated for Hodgkin lymphoma (HL). Cardiovascular (CVS) risk calculators do not include cancer therapy despite epidemiological data demonstrating increased risk. We have assessed modifiable CVS risk factors and predicted risk of CVS disease in a cohort of HL survivors. Hypothesis Cardiovascular risk calculators will not identify high risk in young HL survivors. Methods Pts now aged ≤50 treated with doxorubicin and/or radiotherapy (RT) to cardiac tissue for HL &gt;5 years ago were identified. Telephone review of CVS risk factors was offered to pts taking statins or already diagnosed with cerebrovascular or CVS disease. Remaining pts were offered clinical review to assess BMI, blood pressure, cholesterol and HbA1c. Carotid-radial pulse wave velocity (PWV) was measured if available. CVS risk was predicted using international risk calculators (European SCORE, QRISK3, Framingham). Results 160 eligible pts were identified. Median age was 43 years (26–50) and 52% were female. Median time since treatment was 182 months (61–367). Pts received doxorubicin (n=150), with RT (n=97) or RT alone (n=10). Pts were excluded from study due to severe medical condition (n=8), recurrence (n=1), relocation (n=3) or death (n=1). Data were gathered at clinical review (n=70) or telephone review (n=26). Existing cardiovascular diagnoses included hypertension (n=5), transient ischaemic attack (n=2), valvular disease (n=3), heart failure (n=1), atrial fibrillation (n=2), complete heart block (n=1) and coronary artery disease (n=1). At clinical review 51% pts had 3 or more modifiable risk factors with a median of 3 (0–5) per pt. Total cholesterol was &gt;5.0 mmol/L in 58% of patients with a median of 5.2 mmol/L (3.2–8.6). Median systolic blood pressure was 125.5 mmHg (103–164). Median body mass index was 26.3 kg/m-2 (18.6–56.1) with 60% of patients classed as overweight or obese.Advice was offered to all smokers (9%), pts that drank alcohol above UK recommended levels (20%) or exercised below the recommended amount (60%). Risk calculators classified 1.4% (QRISK3) and 10% (Framingham) of pts at high risk of CVS disease and 0% (European SCORE) at high risk of CVS mortality. Pulse wave velocity measured in 34 pts was elevated (&gt;8 m/s) in 76% of cases with a median 10.2 m/s (2.3–16.8). Conclusions Numerous modifiable CVS risk factors were identified in an HL survivor population known from epidemiological studies to be at high risk of CVS morbidity/mortality. None of the CVS risk calculators identified this high risk. Intriguing data indicate PWV may represent an accessible early indicator of CVS dysfunction. These data prompt comprehensive assessment and management of CVS risk factors in cancer survivors and review of the use of risk calculators in this population. Acknowledgement/Funding The Christie NHS Foundation Trust

Outcomes in patients ≥ 80years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy.

Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan-Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80years. Of patients < 80 and ≥ 80years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients ≥ 80years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80years. Of patients ≥ 80years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07months (95% CI 8.89-11.08) and 10.10months (95% CI 6.30-12.30) in patients < 80 and ≥ 80years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.

Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study.

PURPOSESomatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients.PATIENTS AND METHODSWe extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom).RESULTSWe recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively.CONCLUSIONThe GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

PF765 RESULTS OF AUTOLOGOUS STEM CELL TRANSPLANT (ASCT) IN PATIENTS ABOVE THE AGE OF 70 ARE COMPARABLE TO THE RESULTS IN YOUNGER PATIENTS

Background:High dose chemotherapy and autologous stem cell transplant is an important therapeutic procedure for select solid tumours and haematological malignancies providing chance of durable remission following induction therapy and in some patient potential cure. Increasing numbers of patients above the age of 70 are offered high dose chemotherapy and Auto‐PBSCT. This retrospective analysis compares the outcomes, morbidity and mortality of Auto‐PBSCT in patients above the age of 70 to those in the age group of 65‐69.Aims:To evaluate the results of ASCT in patients with lymphoma or myeloma who were above the age of 70 yrs to the reults in matched group in the age group of 65 to 70 yr. with the aim to compare engraftment data, morbidity, mortality and overall survival.Methods:Retrospective evaluation using case notes, electonic patient records and haematology database.Results:We analysed 54 patients, ages 70 and over, and 56 patients, ages between 65 and 69 years, who received AutoPSCT from 1990 to 2018 in Haematology and Transplant Unit, The Christie NHS Foundation Trust, Manchester, UK. Median age was 71yr(70–75) and 67yr(65–69). Male to female ratio are 38:16 (&gt;70yr) and 41:15 (65–69). The two indications for transplants are Myeloma and lymphoma. The proportions are similar for both age groups, Myeloma:Lymphoma 37(68.5%):17(31.5%) in &gt;70yrs and 40(71.4%):16(28.6%) in 65–69yr The numbers of patients undergoing second Auto‐PBSCT are 9(17%) in &gt;70yr and 11(20%) in 65–69yrs. The follow up period was 2 years (43d‐14.1years) in &gt;70yrs and 4 years (41d‐16.3years) in the 65–69yrs. Median time to neutrophil engraftment (ANC&gt;0.5) was 12 days(9–19days) and 12 days(9–21days). Median platelet recovery (&gt;25) was 21days(10–195days) and 29 days (10–694 days). Median hospitalisation was 27 days (14–91days) and 21days (14–60days). In terms of morbidity during transplant, patients needing intensive or high dependency care was 8 (15%) in &gt;70yr and 5(9%) in 65–69yrs). Patients requiring readmission post discharge was 14(26%) in &gt;70yrs and 9 (16%) in younger age group.here was no difference in treatment related mortality and less than 3% in both groups.Summary/Conclusion:It is feasible to offer ASCT to patients above the age of 70 yr. Patient selection is crucial and should be based not only on the objective organ function evaluation but also the subjective assessment of transplant physician about appropriateness to undergo the ASCT therapy. The decision should be based on the individualised risk benefit ratio, risk of morbidity and expected survival benefit.image

Intravenous versus subcutaneous trastuzumab: an economic and patient perspective.

Since 2005, when the first patients outside of a clinical trial were treated with trastuzumab at The Christie NHS Foundation Trust, a nurse-led service has been developed to facilitate and support a safe treatment pathway for patients. There have been significant developments in the number of patients treated, the mode of administration of the drug and patient choice regarding the location of treatment delivery. This article focuses on the change from intravenous to subcutaneous administration, considering patient experience and choice, particularly in light of the advent of biosimilar drugs, which will necessitate a return to the intravenous route. The relative costs of intravenous and subcutaneous administration are illustrated and the results of a patient survey presented, indicating a strong preference for subcutaneous trastuzumab.

956P - A phase Ib and randomised phase II trial of pazopanib with or without fosbretabulin in advanced recurrent ovarian cancer

Background: Prospective trials have validated angiogenesis as a treatment target in ovarian cancer although improvements in PFS have been modest. One potential strategy to improve efficacy is to combine anti-vascular agents. Fosbretabulin (F) is an intravenous vascular disrupting agent and pazopanib (P) is an oral VEGFR tyrosine kinase inhibitor. Methods: A multi-centre Phase 1b(P1b)/randomised phase 2 (RP2) trial that recruited women with recurrent epithelial ovarian cancer and a platinum-free interval of 3-12 months. Any Bevacizumab had been received ≥6 months prior to recruitment. Phase 1b dose levels ranged from F = 54mg/m2 d1,8,15q28d + P = 600mg/day (F54+P600) up to F = 60mg/m2 d1,8,15q28d + P = 800mg/day. In RP2 participants received either RP2D or P = 800mg/day (P800). Primary outcome in P1b was safety plus RP2D and in RP2 was RECIST PFS. Results: 12 and 21 patients were recruited to P1b & RP2 respectively. The RP2D was F54+P600. In the RP2 median PFS was 7.6 months (95%CI 4.1-not estimated) in F54+P600 group vs. 3.7 months (95%CI 1.0-8.1) in P800 group (HR 0.30, 95%CI 0.08-1.03, P = 0.06). Four patients who received F+P (2 in P1b and 2 in RP2) developed acute hypertension plus reversible secondary cardiac toxicity. The occurrence of cardiac toxicity resulted in premature discontinuation of the trial. Data on circulating biomarkers of angiogenesis collected in in P1b & RP2 will also be presented. Conclusions: F54+P600 appeared effective but was associated with reversible secondary cardiac toxicity that with better hypertension control might have been avoided. Clinical trial identification: EudraCT: 2013-005471-40. Legal entity responsible for the study: The Christie NHS Foundation Trust. Funding: Novartis & Mateon Therapeutics. Disclosure: G.J.S. Rustin: Advisory board: Mateon, Roche, AstraZeneca in past 3 years, only Roche in past year. All other authors have declared no conflicts of interest.