• An investigation of the radiation dose to staff during cardiac radiological studies.

      Jeans, Steve; Faulkner, K; Love, H; Bardsley, R; Regional Department of Medical Physics and Bioengineering, Christie Hospital and Holt Radium Institute, Withington, Manchester M20 9BX (1985-05)
      Measurements of radiation distributions in the vicinity of the couch were undertaken for a number of projections commonly employed during cardiac radiological studies. Three types of investigations were considered; cardiac catheterisations, pacemaker implants and percutaneous transluminal coronary angioplasties. The radiation dose to staff involved in these procedures was estimated. For each group of staff, the maximum annual workload and the workload which would necessitate an individual becoming a classified radiation worker may be deduced from an expression given in the text.
    • An investigation of the RWPE prostate derived family of cell lines using FTIR spectroscopy.

      Baker, M J; Clarke, C; Démoulin, D; Nicholson, J M; Lyng, F M; Byrne, H J; Hart, C Anthony; Brown, Michael D; Clarke, Noel W; Gardner, Peter; et al. (2010-05-26)
      Interest in developing robust, quicker and easier diagnostic tests for cancer has lead to an increased use of Fourier transform infrared (FTIR) spectroscopy to meet that need. In this study we present the use of different experimental modes of infrared spectroscopy to investigate the RWPE human prostate epithelial cell line family which are derived from the same source but differ in their mode of transformation and their mode of invasive phenotype. Importantly, analysis of the infrared spectra obtained using different experimental modes of infrared spectroscopy produces similar results. The RWPE family of cell lines can be separated into groups based upon the method of cell transformation rather than the resulting invasiveness/aggressiveness of the cell line. The study also demonstrates the possibility of using a genetic algorithm as a possible standardised pre-processing step and raises the important question of the usefulness of cell lines to create a biochemical model of prostate cancer progression.
    • Investigation of the survivorship needs of patients with primary brain tumours and the provision of a health and well-being event.

      Emerson, Julie; Robson, Sara; Molloy, Liz; Smith, Charlotte; McBain, Catherine A; Christie Hospital NHS Foundation Trust, Manchester (2017)
    • Involved site radiation therapy in adult lymphomas: an overview of international lymphoma radiation oncology group guidelines

      Wirth, A; Mikhaeel, NG; Pauline, Aleman BM; Pinnix, CC; Constine, LS; Wilmot, JP; Ricardi, U; Illidge, Timothy M; Eich, HT; Hoppe, BS; et al. (2020)
    • Iodothyronine deiodinase enzyme activities in bone.

      Williams, Allan J; Robson, Helen; Kester, Monique H A; Van Leeuwen, Johannes P T M; Shalet, Stephen M; Visser, Theo J; Williams, Graham R; Molecular Endocrinology Group, Division of Medicine and Medical Research Council (MRC) Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. (2008-07)
      Euthyroid status is essential for normal skeletal development and maintenance of the adult skeleton, but the mechanisms which control supply of thyroid hormone to bone cells are poorly understood. Thyroid hormones enter target cells via monocarboxylate transporter-8 (MCT8), which provides a functional link between thyroid hormone uptake and metabolism in the regulation of T3-action but has not been investigated in bone. Most circulating active thyroid hormone (T3) is derived from outer ring deiodination of thyroxine (T4) mediated by the type 1 deiodinase enzyme (D1). The D2 isozyme regulates intra-cellular T3 supply and determines saturation of the nuclear T3-receptor (TR), whereas a third enzyme (D3) inactivates T4 and T3 to prevent hormone availability and reduce TR-saturation. The aim of this study was to determine whether MCT8 is expressed in the skeleton and whether chondrocytes, osteoblasts and osteoclasts express functional deiodinases. Gene expression was analyzed by RT-PCR and D1, D2 and D3 function by sensitive and highly specific determination of enzyme activities. MCT8 mRNA was expressed in chondrocytes, osteoblasts and osteoclasts at all stages of cell differentiation. D1 activity was undetectable in all cell types, D2 activity was only present in mature osteoblasts whereas D3 activity was evident throughout chondrocyte, osteoblast and osteoclast differentiation in primary cell cultures. These data suggest that T3 availability especially during skeletal development may be limited by D3-mediated catabolism rather than by MCT8 mediated cellular uptake or D2-dependent T3 production.
    • Ionising Radiation (Medical Exposure) Regulations: impact on clinical radiology.

      Walker, Anne; Tuck, J S; North Western Medical Physics, Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2001-07)
    • Ionizing radiation biomarkers in epidemiological studies - an update.

      Hall, J; Jeggo, P; West, Catharine M L; Gomolka, M; Quintens, R; Badie, C; Laurent, O; Aerts, A; Anastasov, N; Azimzadeh, O; et al. (2017)
      Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of <100mSv and dose rates of <10mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles.
    • IPEM Guidelines on the use of MRI for external beam radiotherapy treatment planning

      Speight, R.; Dubec, Michael; Eccles, Cynthia L; Georg, B.; Henry, A.; Herbert, T.; Johnstone, R.; Liney, G.; McCallum, H.; Schmidt, M.; et al. (2021)
      Purpose or Objective The role of MRI to guide external beam radiotherapy (RT) treatment planning is growing. The literature shows significant heterogeneity in the way that MRI for RT is implemented and there is some evidence that this is, in part, due to a lack of consensus in the literature and guidance from professional bodies [1-2]. To combat this, The Institute of Physics and Engineering in Medicine (IPEM) commissioned a working party to produce a guidance document on the use of MRI for RT treatment planning. This guidance has now been published [3] and its key findings will be discussed in this abstract. Materials and Methods The guidelines were produced by a multi-disciplinary party consists of 10 members which first met in February 2018. The guidance is based on the experience of the institutions represented in the IPEM working party, in consultation with other institutions, as well as information taken from the literature. It has multi-disciplinary endorsement from the professional bodies IPEM, Royal College of Radiologists (RCR) and the Society of Radiographers (SCoR). Guidance is only given for MRI acquired for external beam RT treatment planning in a CT-based workflow, i.e. when MRI is acquired and registered to CT with the purpose of aiding delineation of target or organ at risk volumes. MRI use for treatment response assessment, MRI-only RT and other RT treatment types such as brachytherapy, gamma radiosurgery and MR linac are not considered within the scope of this document. Results The guidelines are designed to be a practical document which can benefit all involved disciplines and give advice on introducing an RT workload onto a non-RT-dedicated MR scanner, as well as planning for installation of an MR scanner dedicated for RT (sometimes referred to as an MR-sim). Practical guidance is given on the following, in the context of RT planning: safety; training and education for all staff working in and around an MR scanner; RT patient set-up on an MR scanner; MRI sequence optimisation for RT purposes; commissioning and quality assurance (QA) to be performed on an MR scanner; and MRI to CT registration, including commissioning and QA. Conclusion For the first time a guidance document has been produced on the use of MR in external beam radiotherapy treatment planning. This has been produced by a multidisciplinary team and is endorsed by multiple professional bodies. It is hoped that this document will aid in the safe implementation of MRI for external beam radiotherapy treatment planning both for centres with dedicated MR scanners for radiotherapy and for centres with MR access for radiotherapy on scanners owned by radiology. Furthermore, it is hoped that this document will harmonise how this technology is introduced internationally. [1] - Speight et al. (2019) https://doi.org/10.1088/1361-6560/ab2c7c [2] - Speight et al. (2021) https://doi.org/10.1088/1361-6560/abe9f7 [3] - Speight et al. (2021) https://doi.org/10.1088/1361-6560/abdc30
    • An IPEM international survey of MRI use for external beam RT treatment planning

      Speight, R.; Tyyger, M.; Schmidt, M. A.; Liney, G. P.; Johnstone, R. I.; Eccles, Cynthia L; Dubec, Michael; George, B.; Henry, A.; Nyholm, T.; et al. (2020)
      Purpose or Objective Despite growing interest in MRI, integration in external beam radiotherapy (EBRT) treatment planning uptake varies globally. In order to understand the current international landscape of MRI in EBRT a survey has been performed in 10 countries. This work reports on differences and common themes identified. Material and Methods A survey was developed covering eight topics: MRI access; MRI use; MRI to CT registration; commissioning/Quality Assurance (QA); safety; workflow/staffing; education; and future applications. The survey was distributed within 10 countries by a ‘local champion’ ensuring it reached all radiotherapy centres. Results The survey had a median response rate of 77% per country (184/442 in total). Response rates in individual countries varied between those with high response rates (≥66% in the UK/Denmark (DK)/Finland (FN)/Sweden (SE)/Netherlands (NL)/Belgium (BE)/New Zealand (NZ)) and those with response rates low enough that results cannot be considered representative of the country (≤35% in Italy (IT)/France (FR)/Australia (AU)). MRI access was varied between countries, with FR and the UK reporting the lowest rates (43% and 69% respectively). In DK/SE >80% of centres reported having dedicated MRI scanners for EBRT, whereas in all other countries <25% reported dedicated scanners for EBRT and were more reliant on collaboration with radiology for MRI access. Anatomical sites receiving MRI for EBRT varies internationally and the most common are shown in table 1. Commissioning and QA of both image registration and MRI scanners varied greatly, as did MRI sequences performed, staffing models and training given to different staff groups. The most common barrier for increasing MRI scans for radiotherapy across all centres (figure 1) was MRI access and a lack of financial reimbursement, except DK/SE where lack of clinical interest/local knowledge was the main barrier. It was reported that within 5 years a median of 29% (range 9-50%, absolute number 57) of centres per country are planning for a new MRI scanner dedicated for EBRT A limited number of sites in NL/DK/SE/FN/AU/BE currently employ MRI-only EBRT planning; over the next 5 years MRIonly EBRT planning is expected to be taken up in >50% of centres in NL/SE/DK/FN but < 35% in UK/NZ/BE/FR/AU/IT. MR-linac technology is being clinically employed in DK/UK/NL and within 5 years expected uptake varies between 63% in DK, 59% in NL and <35% in UK/FN/SE/NZ/BE/AU/IT/FR. Conclusion The current international use of MRI for EBRT has been surveyed in 10 countries. Variations in practice/equipment/QA/staffing models have been identified. These are likely due to differences in funding as well as a lack of consensus or guidelines in the literature. For most countries the lack of MRI access and funding is the limiting factor on the number of patients who benefit from MRI as part of their EBRT treatment planning. Despite these challenges, significant interest remains in increasing MRI-assisted EBRT planning over the next 5 years.
    • An IPEM international survey of MRI use for external beam RT treatment planning

      Speight, R.; Tyyger, M.; Schmidt, M. A.; Liney, G. P.; Johnstone, R. I.; Eccles, Cynthia L; Dubec, Michael; George, B.; Henry, A.; Nyholm, T.; et al. (2020)
      Purpose or Objective Despite growing interest in MRI, integration in external beam radiotherapy (EBRT) treatment planning uptake varies globally. In order to understand the current international landscape of MRI in EBRT a survey has been performed in 10 countries. This work reports on differences and common themes identified. Material and Methods A survey was developed covering eight topics: MRI access; MRI use; MRI to CT registration; commissioning/Quality Assurance (QA); safety; workflow/staffing; education; and future applications. The survey was distributed within 10 countries by a ‘local champion’ ensuring it reached all radiotherapy centres. Results The survey had a median response rate of 77% per country (184/442 in total). Response rates in individual countries varied between those with high response rates (≥66% in the UK/Denmark (DK)/Finland (FN)/Sweden (SE)/Netherlands (NL)/Belgium (BE)/New Zealand (NZ)) and those with response rates low enough that results cannot be considered representative of the country (≤35% in Italy (IT)/France (FR)/Australia (AU)). MRI access was varied between countries, with FR and the UK reporting the lowest rates (43% and 69% respectively). In DK/SE >80% of centres reported having dedicated MRI scanners for EBRT, whereas in all other countries <25% reported dedicated scanners for EBRT and were more reliant on collaboration with radiology for MRI access. Anatomical sites receiving MRI for EBRT varies internationally and the most common are shown in table 1. Commissioning and QA of both image registration and MRI scanners varied greatly, as did MRI sequences performed, staffing models and training given to different staff groups. The most common barrier for increasing MRI scans for radiotherapy across all centres (figure 1) was MRI access and a lack of financial reimbursement, except DK/SE where lack of clinical interest/local knowledge was the main barrier. It was reported that within 5 years a median of 29% (range 9-50%, absolute number 57) of centres per country are planning for a new MRI scanner dedicated for EBRT A limited number of sites in NL/DK/SE/FN/AU/BE currently employ MRI-only EBRT planning; over the next 5 years MRIonly EBRT planning is expected to be taken up in >50% of centres in NL/SE/DK/FN but < 35% in UK/NZ/BE/FR/AU/IT. MR-linac technology is being clinically employed in DK/UK/NL and within 5 years expected uptake varies between 63% in DK, 59% in NL and <35% in UK/FN/SE/NZ/BE/AU/IT/FR. Conclusion The current international use of MRI for EBRT has been surveyed in 10 countries. Variations in practice/equipment/QA/staffing models have been identified. These are likely due to differences in funding as well as a lack of consensus or guidelines in the literature. For most countries the lack of MRI access and funding is the limiting factor on the number of patients who benefit from MRI as part of their EBRT treatment planning. Despite these challenges, significant interest remains in increasing MRI-assisted EBRT planning over the next 5 years.
    • IPEM topical report 1: guidance on implementing flattening filter free (FFF) radiotherapy.

      Budgell, Geoff J; Brown, K; Cashmore, J; Duane, S; Frame, J; Hardy, Mark; Paynter, D; Thomas, R; Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Wilmslow Road, Manchester (2016-12-07)
      Flattening filter free (FFF) beams are now commonly available with new standard linear accelerators. These beams have recognised clinical advantages in certain circumstances, most notably the reduced beam-on times for high dose per fraction stereotactic treatments. Therefore FFF techniques are quickly being introduced into clinical use. The purpose of this report is to provide practical implementation advice and references for centres implementing FFF beams clinically. In particular UK-specific guidance is given for reference dosimetry and radiation protection.
    • IPEM topical report: a 2018 IPEM survey of MRI use for external beam radiotherapy treatment planning in the UK

      Speight, R; Schmidt, M; Liney, G; Johnstone, R; Eccles, Cynthia L; Dubec, Michael; George, B; Henry, A; McCallum, H; Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds (2019)
      INTRODUCTION/BACKGROUND:The benefits of integrating MRI into the radiotherapy pathway are well published, however there is little consensus in guidance on how to commission or implement its use. With a view to developing consensus guidelines for the use of MRI in external beam radiotherapy (EBRT) treatment planning in the UK, an audit was undertaken by an Institute of Physics and Engineering in Medicine (IPEM) working-party to assess the current landscape of MRI use in EBRT in the UK. METHODS: A multi-disciplinary working-party developed a survey to understand current practice using MRI for EBRT treatment planning; investigate how MRI is currently used and managed; and identify knowledge gaps . The survey was distributed electronically to radiotherapy service managers and physics leads in 71 UK radiotherapy (RT) departments (all NHS and private groups). RESULTS:The survey response rate was 87% overall, with 89% of NHS and 75% of private centres responding. All responding centres include EBRT in some RT pathways: 94% using Picture Archiving and Communication System (PACs) images potentially acquired without any input from RT departments, and 69% had some form of MRI access for planning EBRT. Most centres reporting direct access use a radiology scanner within the same hospital in dedicated (26%) or non-dedicated (52%) RT scanning sessions. Only two centres reported having dedicated RT MRI scanners in the UK, lower than reported in other countrieS Six percent of radiotherapy patients in England (data not available for other UK countries) have MRI as part of their treatment, which again is lower than reported elsewhere. Although a substantial number of centres acquire MRI scans for treatment planning purposes, most centres acquire less than five patient scans per month for each treatment site. Commissioning and quality assurance of both image registration and MRI scanners was found to be variable across theUK In addition, staffing models and training given to different staff groups varied considerably across the UK, reflecting the current lack of national guidelines CONCLUSION: The primary barriers reported to MRI implementation in EBRT planning included costs (Eg., lack of a national tariff for planning MRI), lack of MRI access and/or capacity within hospitals. Despite these challenges, significant interest remains in increasing MRI-assisted EBRT planning over the next five years.
    • IPEM topical report: an evidence and risk assessment based analysis of the efficacy of quality assurance tests on fluoroscopy units - part I; dosimetry and safety

      Worrall, M; Shaw, Daniel; Baker, C; Charnock, P; Fazakerley, J; Honey, I; Iball, GR; Koutalonis, M; Price, M; Renaud, C; et al. (2019)
      This work aims to assess the efficacy of x-ray quality assurance tests undertaken on fluoroscopy units in the UK. Information was gathered on the results of dosimetry and safety tests recommended by the reports of the Institute of Physics and Engineering in Medicine, and those additionally undertaken by medical physics departments. The assessment of efficacy considers the frequency with which a test result breaches the remedial level or other relevant threshold where applicable. The third quartile of those results exceeding the remedial level or threshold is used to estimate the severity of such a breach in terms of potential impact on patient dose and image quality. A risk assessment approach is then used to recommend to what degree, if any, the test should be included in an on-going test regimen.&amp;#13; Data was analysed from 468 testing sessions to 336 unique fluoroscopy units throughout the UK. Across all tests, the rate with which the remedial level was exceeded varied from 0 - 29.5%, with severity ranging from little or none to major degradation to image quality or significant increase on population dose. Where possible, the data has also been used to produce representative ranges for the results of dosimetric tests. These could be useful as an up to date comparator for those sites considering the purchase of or commissioning new equipment.&amp;#13; Overall the results indicate a wide range for the efficacy of those tests undertaken at present; this can be used to review local test protocols and to inform future changes to national guidance in the UK. The results also highlight some tests where measurement technique varies significantly throughout the UK, making any valid comparison difficult. This may indicate a need for further guidance on how best to undertake these tests.
    • IPEM Topical Report: An evidence and risk assessment based analysis of the efficacy of quality assurance tests on fluoroscopy units part II; image quality

      Shaw, Daniel; Worrall, M.; Baker, C.; Charnock, P.; Fazakerley, J.; Honey, I.; Iball, G. R.; Koutalonis, M.; Price, M.; Renaud, C.; et al. (2020)
      This work aims to assess the efficacy of x-ray quality assurance tests undertaken on fluoroscopy units in the UK. Information was gathered on the results of image quality tests recommended by the reports of the Institute of Physics and Engineering in Medicine, and those additionally undertaken by medical physics departments. The assessment of efficacy considers the frequency with which a test result breaches the remedial level or other relevant threshold where applicable. The third quartile of those results exceeding the remedial level or threshold is used to estimate the severity of such a breach in terms of potential impact on patient dose and image quality. A risk assessment approach is then used to recommend to what degree, if any, the test should be included in an on-going test regimen. Data was analysed from 469 testing sessions to 337 unique fluoroscopy units throughout the UK. Across all tests, the rate with which the remedial level was exceeded varied from 0 10.6%, with severity ranging from little or none to major degradation to image quality or significant increase on population dose. Where possible, the data has also been used to produce representative ranges for the results of image quality tests. These could be useful as an up to date comparator for those sites considering the purchase of or commissioning new equipment. Overall the results indicate a wide range for the efficacy of those tests undertaken at present; this can be used to review local test protocols and to inform future changes to national guidance in the UK. The results also highlight some tests where measurement technique varies significantly throughout the UK, making any valid comparison difficult. This may indicate a need for further guidance on how best to undertake these tests.
    • IPEM topical report: guidance on the use of MRI for external beam radiotherapy treatment planning

      Speight, R.; Dubec, Michael; Eccles, Cynthia L; George, B.; Henry, A.; Herbert, T.; Johnstone, R.; Liney, G. P.; McCallum, H. M.; Schmidt, M. A.; et al. (2021)
      This document gives guidance for multidisciplinary teams within institutions setting up and using an MRI-guided radiotherapy (RT) treatment planning service. It has been written by a multidisciplinary working group from the Institute of Physics and Engineering in Medicine (IPEM). Guidance has come from the experience of the institutions represented in the IPEM working group, in consultation with other institutions, as well as information taken from the literature. Guidance is only given for MRI acquired for external beam RT treatment planning in a CT-based workflow, i.e. when MRI is acquired and registered to CT with the purpose of aiding delineation of target or organ at risk volumes. MRI-only RT and other RT treatment types such as brachytherapy and gamma radiosurgery are not considered in scope here, although some of the major themes discussed are relevant. The aim was to produce guidance that will be useful for institutions who are setting up and using a dedicated MR scanner for RT (referred to as an MR-sim) and those who will have limited time on an MR scanner potentially managed outside of the RT department, often by radiology. Although not specifically covered in this document, there is an increase in the use of hybrid MRI-linac systems worldwide and brief comments are included to highlight any crossover with the early implementation of this technology. In this document, advice is given on introducing an RT workload onto a non-RT-dedicated MR scanner, as well as planning for installation of an MR scanner dedicated for RT. Next, practical guidance is given on the following, in the context of RT planning: training and education for all staff working in and around an MR scanner; RT patient set-up on an MR scanner; MRI sequence optimisation for RT purposes; commissioning and quality assurance (QA) to be performed on an MR scanner; and MRI to CT registration, including commissioning and QA.
    • IPEM topical report: results of a 2020 UK survey for the use of online treatment monitoring solutions for IMRT/VMAT

      Stevens, S. W.; Moloney, S.; Bangiri, A.; Blackmore, A.; Hart, C.; Holmes-Smith, W.; Pooler, Alistair; Rixham, P.; Doolan, P. J.; Department of Medical Physics, London Clinic, London, (2021)
      Numerous commercial technologies for online treatment monitoring (OTM) in radiotherapy (RT) are currently available including electronic portal imaging device (EPID) in vivo dosimetry (IVD), transmission detectors and log files analysis. Despite this, in the UK there exists limited guidance on how to implement and commission a system for clinical use or information about the resources required to set up and maintain a service. A Radiotherapy Special Interest Group (RTSIG) working party, established by Institute of Physics and Engineering in Medicine (IPEM) was formed with a view to reassess the current practice for OTM in the UK and an aim to develop consensus guidelines for the implementation of a system. A survey distributed to Heads of Medical Physics at 71 UK RT departments investigated: availability of OTM in the UK; estimates of workload; clinical implementation; methods of analysis; quality assurance; and opinions on future directions. The survey achieved a 76% response rate and demonstrated that OTM is widely supported in the UK, with 87% of respondents indicating all patients should undergo OTM. EPID IVD (EIVD) was the most popular form of OTM. An active EIVD service was reported by 37% of respondents, with 84% believing it was the optimal solution. This demonstrates a steady increase in adoption since 2012. Other forms of OTM were in use but they had only been adopted by a minority of centres. Financial barriers and the increase of staff workload continue to hinder wider implementation in other centres. Device automation and integration is a key factor for successful future adoption and requires support between treatment machine and OTM manufacturers. The survey has provided an updated analysis on the use of OTM methods across the UK. Future guidance is recommended on commissioning, adoption of local tolerances and root-cause analysis strategies to assist departments intending to implement OTM.
    • Ipilimumab (IPI) alone or in combination with anti-PD-1 (IPI+PD1) in patients (pts) with metastatic melanoma (MM) resistant to PD1 monotherapy

      Da Silva, I. P.; Ahmed, T.; Lo, S.; Reijers, I. L. M.; Weppler, A.; Warner, A. B.; Patrinely, J. R.; Serra-Bellver, Patricio; Lebbe, C.; Mangana, J.; et al. (2020)
      Background: PD1 induces long-term responses in approximately 30% of MM pts, however 2/3 are resistant (innate or acquired) and will require further treatment. A subset of these pts will benefit from IPI or IPI+PD1, but these pts are yet to be identified. We sought to determine; i) response rate (RR) and survival to IPI+/-PD1 after PD1 progression, and ii) clinical predictors of response and survival to IPI+/-PD1. Methods: MM pts resistant to PD1 and then treated with IPI+/-PD1 were studied. Demographics, disease characteristics and baseline blood parameters were examined. Univariate, multivariate and backward elimination technique analyses were performed to create predictive models of response and overall survival (OS). Results: Of 330 MM pts resistant to PD1 (median time to prog 2.9 months [0.5 – 42.3], 12% adjuvant, 88% metastatic; 70% innate, 30% acquired), 161 (49%) had subsequent IPI and 169 (51%) had IPI+PD1. Characteristics at start of IPI+/-PD1 were similar in IPI vs IPI+PD1 groups (stage M1D 27% vs 34%; elevated LDH 38% vs 40%), except IPI group had more ECOG ?1 (60% vs 34%) and less BRAF mutation (mut) (21% vs 37%). Median follow-up from start of IPI+/-PD1 was 22.3 months (19.8 - 25.8); RR was 22%, higher in IPI+PD1 (31%) vs IPI (12%) (p < 0.01). PFS and OS at 1 year were 20% and 48%, respectively; better with IPI+PD1 (27%/57%) vs IPI (13%/38%) (p < 0.01). PD1 setting (adjuvant/metastatic) and response did not impact response to IPI+/-PD1. Most pts progressing on adjuvant PD1 had IPI+PD1 (88%) and RR was 33%. Neither the interval between PD1 and IPI+/-PD1 nor use of other drugs affected response to IPI+/-PD1. RR was similar in BRAF WT (23%) vs BRAF mut (RR 21%) pts. In BRAF WT pts, RR was higher with IPI+PD1 vs IPI (38% vs 9%, p < 0.01), while RR was similar with IPI (24%) or IPI+PD1 (19%) in BRAF mut pts. One third of BRAF mut pts had BRAF inhibitors (BRAFi) prior to IPI+/-PD1 and lower RR (13%) vs those without BRAFi (RR = 25%, p > 0.05). High grade (?G3) toxicity (tox) was similar with IPI+PD1 (30%) or IPI (34%, p = 0.48), and was not associated with response. Stage III/M1A/M1B, normal LDH and treatment with IPI+PD1 were the best predictors of response (AUC = 0.69). These factors, in addition to sex (male), ECOG PS = 0, BRAF mut, progressed/recurred > 3 months on PD1, and absence of bone mets were the best predictors of longer OS (AUC = 0.74). Conclusions: In pts resistant to PD1, IPI+PD1 has higher RR, longer survival, yet similar high grade tox than IPI alone. Predictive models of response & survival will help select pts for IPI+/-PD1 after progressing on PD1.
    • Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study

      Pires da Silva, I.; Ahmed, T.; Reijers, I. L. M.; Weppler, A. M.; Betof Warner, A.; Patrinely, J. R.; Serra-Bellver, Patricio; Allayous, C.; Mangana, J.; Nguyen, K.; et al. (2021)
      Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET-CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5-30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7-34·8]) than with ipilimumab monotherapy (8·8 months [6·1-11·3]; hazard ratio [HR] 0·50, 95% CI 0·38-0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6-3·6]) than with ipilimumab (2·6 months [2·4-2·9]; HR 0·69, 95% CI 0·55-0·87; p=0·0019). Similar proportions of patients reported grade 3-5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3-5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3-5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma.
    • Ipilimumab and nivolumab (I plus N) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world review in North West of England, United Kingdom

      Allison, Jennifer; Griffiths, R.; Waddell, Thomas K; Pillai, Manon; Christie NHS Foundation Trust, Manchester, United Kingdom (2021)
      Background: Ipilimumab and Nivolumab (I+N) is now an established first line option for patients with advanced RCC of intermediate (I) or poor (P) IMDC risk score. In this retrospective review, we review our experience of this combination in two cancer centres in North West England with a focus on immune related adverse events (irAEs) and their impact on the patient pathway. Methods: Treatment naïve mRCC patients starting I+N between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), the management of irAEs and early survival observations. Results: A total of 69 patients were identified. Median age was 60yr (19-82yr), 77% had clear cell histology. The IMDC risk was 72% I and 28% P. Median follow-up was 11.0 mo (1-22mo). ORR was 45% (CR 9%, PR 36%, SD 28%, PD 23%, NE 4%) Median time to first response was 2.9mo. (1.8- 15.5mo). 10% of patients experienced pseudoprogression. Median PFS and OS are not yet reached with 86% of patients still alive at the time of data cut-off. The majority (75%) of patients completed all 4 doses of I+N. Of the 10% receiving less than 4 doses due to toxicity, 14% continued on single agent N. Overall, 15% discontinued therapy due to toxicity and 28% experienced at least one treatment delay. Any grade irAEs were seen in 74% of patients (G3 35%) with no treatment related deaths. The commonest irAEs were: rash/pruritis 39%; endocrinopathies 30%(G3 7%); diarrhoea 29% (G3 14%); hepatitis 22% (G3 6%); and nephritis 3% (G3 3%). Of the patients developing irAEs, 71% received steroids with 16% requiring additional immunosuppression including infliximab (6%) and mycophenolate mofetil (8%). A third of all patients required admission for irAE management with a total of 37 inpatient episodes across the cohort with a median length of 7 days (1-24). 7% of patients proceeded to surgery for either primary or metastatic disease, which contributed to ongoing disease response in these patients. At the time of data cut-off, 45% of patients were no longer on treatment due to PD (29%), toxicity (15%) or unrelated death (1%). Of those who stopped due to toxicity, 50% subsequently progressed with a median time to progression of 4mo (3-6 mo) and 50% remain on active surveillance with a median follow-up of 7.5mo (1-10). 62% of patients with PD received second line treatment; most frequently, cabozantinib (83%). Conclusions: Our experience of I+N shows comparable efficacy and toxicity profiles to available reports. irAEs requiring intervention are frequent and may be associated with prolonged hospital admission, and patients should be counselled appropriately. Data within mirrors published reports of ongoing responses in a subset of patients who stop treatment due to toxicity and also suggests a possible role for resection of residual or metastatic disease in disease control. Updated survival data will be presented
    • Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients.

      Ahmad, S; Qian, W; Ellis, S; Mason, Elaine; Khattak, M; Gupta, A; Shaw, H; Quinton, A; Kovarikova, J; Thillai, K; et al. (2015-10)
      Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.