National Centre for Asbestos-Related Diseases A Strategy Document NCARD Development Group November 2009 Contact: Mr John G Edwards PhD FRCS Glasg.(C/Th) Chair, NCARD Development Group Chair, British Mesothelioma Interest Group Consultant Thoracic Surgeon Northern General Hospital Herries Road Sheffield S5 7AU UNITED KINGDOM Office: 0114 27 14924 Secretary: 0114 22 69279 Fax: 0114 26 10350 e-mail: john.edwards@sth.nhs.uk
Contents NCARD Strategy Document Page 1. Executive Summary 3 2. Introduction 4 3. Asbestos-Related Diseases 6 3.1. Lung Cancer 6 3.2. Asbestosis 6 3.3. Pleural Plaques 6 3.4. Diffuse Pleural Thickening 6 3.5. Mesothelioma 7 3.6. Other non-respiratory asbestos-related cancers 7 3.7. Global Issues 7 4. Mesothelioma Where we are now 8 4.1. Resistance to Current Treatments 9 4.2. Mesothelioma is the least researched top twenty cancer 9 4.3. Mesothelioma Current Clinical Trials in the UK 10 4.4. Current Non-Clinical Research in the UK 11 4.5. Research Funding for Lung Cancer and Mesothelioma 12 4.5.1. Future Research Projects 12 5. NCARD Why and How? 13 5.1. Why NCARD as the Vehicle to Deliver Results? 13 5.2. NCARD Structure and Function 13 5.3. The Economic Case for NCARD 14 5.4. Aims and Objectives of NCARD 14 6. NCARD National Research Strategy 17 6.1. National Mesothelioma Registry and Biobank 17 6.2. Research Themes 18 6.2.1. Epidemiology 18 6.2.2. Staging 18 6.2.3. Clinical Trials 18 6.2.4. Translational Research and Novel Therapies 18 6.2.5. Supportive and Palliative Care 19 6.2.6. Public and Patient Involvement 19 6.3. Research Prioritisation 20 7. Conclusions and Next Steps 21 8. Appendix 8.1. Definition of Terms 22 8.2. Links 23 8.3. NCARD Development Group 24 2
1. Executive Summary NCARD Strategy Document This Strategy Document outlines the rationale, the infrastructure and discusses the research priorities for the proposed National Centre for Asbestos Related Diseases (NCARD) in the United Kingdom. The need for NCARD in raising the profile of and fostering collaboration in appropriate research is presented. Impact of asbestos-related diseases (ARDs) The UK is facing an epidemic of ARDs, particularly malignant mesothelioma Asbestos causes approximately 4,500 deaths per annum in the UK Mesothelioma is amongst the cancers of most rapidly rising incidence Mesothelioma is resistant to current treatments, invariably fatal and has an average survival of less than nine months Lack of Research Research into ARDs has not attracted the focus that the current burden of disease would suggest is required Researchers have not been attracted into the field, because it is easier to prepare and gain a research grant in higher profile diseases Researchers engaged in ARD research have struggled to gain major funding, as track records in ARD research are short As there is insufficient support, there has been a lack continuity of funding for researchers attempting to develop a track record in ARDs The current research funding strategy is not delivering effective treatments at the speed which is required. The need for NCARD The Asbestos Victims Support Groups Forum UK raised a petition of 22,500 signatures for NCARD, which have been delivered to Downing Street. Researchers have developed grant applications for world-class projects and trials which have not yet received funding The United States of America and Australian Governments have dedicated ringfenced funds for research into asbestos-related diseases for similar initiatives to the one proposed in this document The cost of litigation, benefits and healthcare will be reduced significantly by development of effective treatments Making NCARD happen An outcomes focused National Research Strategy has been developed Government support is being enlisted for this funding model Partners have been identified and agreed in principal to provide funding and administrative support Outcomes NCARD will translate research hypotheses into effective therapies NCARD will deliver better value for money than existing frameworks 3
2. Introduction NCARD Strategy Document Michael Clapham MP Chair of the All-Party Parliamentary Group on Occupational Safety and Health The properties of asbestos as a fire-proofing and insulating substance have been recognised for thousands of years. The potential of asbestos as a public health disaster has now been acknowledged for over e century. Yet it still took from 1898 (when HM Chief Inspector of Factories and Workshops first highlighted the dangers to Parliament) until 1999 for the import and use of asbestos finally to be banned in the United Kingdom. We are faced today with an appalling legacy of asbestos related diseases. It can take five decades for diseases such as malignant mesothelioma to develop: we are dealing currently with the burden of those exposed many years ago. Many tens of thousands of people alive in the UK have already been exposed to asbestos and will die from asbestos-related diseases (ARDs). There is an urgent need to research effective treatments for ARDs and for malignant mesothelioma in particular. Mesothelioma is a devastating cancer with an appalling prognosis which is resistant to current treatments. We must give hope to current patients and also those future victims, who have knowingly been exposed to asbestos. There remain concerns and debate about the effects of current and future exposure to asbestos in our environment, highlighting the need for better knowledge in this area too. The proposed National Centre for Asbestos Related Diseases (NCARD) aims to address these issues. A virtual centre, facilitating close interaction between the nation s best research groups, NCARD will act as a focal point for funding and coordinating research. This will maximise the use of available funding and bring the hope of effective treatments in the most efficient way possible. Asbestos-related diseases are a man-made problem: essentially all the asbestos used in the UK was imported. Given that the peak of asbestos imports, between the 1950 s and 1970 s, occurred many years after the dangers were recognised, Government has a significant social and moral responsibility for asbestos-related diseases. Asbestos trade continues around the world, particularly in Asia, where the epidemic of suffering will certainly occur. Just as the UK was a leader in asbestos products, NCARD can enable 4
the UK to make a global contribution to research and effective treatments for asbestos diseases. Michael Clapham MP Member of Parliament for Barnsley West and Penistone Chair, All Parliamentary Group on Occupational Safety and Health House of Commons London SW1A 0AA 5
3. Asbestos-Related Diseases Inhalation of asbestos fibres causes several respiratory diseases: Lung Cancer Asbestosis Pleural Plaques Diffuse Pleural Thickening Malignant Mesothelioma Other cancers 3.1 Lung Cancer Lung cancer is the biggest cancer killer in the UK in both men and women. Although cigarette smoking is a major cause, exposure to asbestos is also strongly implicated. Asbestos is known to multiply the cancer-causing effects of cigarette smoking many times and is believed to contribute to 2,000 of the 34,500 deaths annually in the United Kingdom from lung cancer 12. 3.2 Asbestosis Inhalation of significant amounts of asbestos fibres may cause scarring of the lung tissue responsible for gaseous exchange of oxygen and carbon dioxide, resulting in shortness of breath. Asbestosis may contribute to other medical conditions or cause death. In 2007, there were about 700 Disablement Benefit Cases and in 2006 there were 393 deaths where the death certificate mentioned asbestosis: of these 111 had asbestos recorded as the underlying cause of death 3. 3.3 Pleural Plaques Pleural plaques are isolated areas of thickening of the parietal pleura (the inside lining of the chest wall), which may become hard and calcified. Pleural plaques alone rarely cause symptoms, although some patients do experience pain and shortness of breath. They are an indication of exposure to asbestos but evidence is lacking that the presence of pleural plaques increases the risk of malignancy over and above the existing risk as a result of that exposure. Pleural plaques confirm exposure to asbestos and may give rise to anxiety in some individuals 4. 3.4 Diffuse Pleural Thickening This is more widespread thickening of the pleura, which may cause symptoms if it is extensive. Patients with this condition are entitled to apply for Industrial Injuries Disablement Benefit. There were 390 new cases of disablement benefit for diffuse pleural thickening in 2007 and this number is increasing. 1 Health and Safety Executive http://www.hse.gov.uk/statistics/causdis/asbfaq.htm 2 Cancer Research UK http://info.cancerresearchuk.org/cancerstats/mortality/cancerdeaths/?a=5441 3 Health and Safety Executive http://www.hse.gov.uk/statistics/causdis/asbestosis/ 4 Industrial Injuries Advisory Council http://www.iiac.org.uk/pdf/pos_papers/pp23.pdf 6
3.5 Mesothelioma Malignant Mesothelioma is a cancer of the (mesothelial) cells which form the lining of chest (pleural) and abdominal (peritoneal) cavities. Malignant pleural mesothelioma is many times more common than peritoneal mesothelioma, which is also caused by asbestos. Mesothelioma is the 12 th most common cancer killer in men and the cancer of most rapidly increasing incidence in women. There were 2,156 deaths in 2007 5 A peak incidence of 2,500 deaths per year from mesothelioma is expected in about 2,015 The UK has one of the highest rates of mesothelioma in the world Mesothelioma is related to occupational asbestos exposure in about 90% of cases At least 70,000 people already exposed to asbestos in the UK will die from mesothelioma The risks of long-term, low-level exposure to asbestos are poorly understood 3.6 Other non-respiratory asbestos-related cancers Asbestos creates a pro-tumour environment in the body which may contribute to the formation of other cancers. There is sufficient evidence to implicate asbestos in the causation of cancer of the larynx (throat) and ovary. There is some evidence of links between asbestos and colorectal and stomach cancers 6. 3.7 Global Issues The UK has a moral and humane responsibility to work with other global leaders in asbestos issues to ensure the worldwide abolition of asbestos use and to fund improved treatments and care for asbestos victims. There is a rapid rise in the use of asbestos in Asia, with more than 300,000 tons of asbestos imported into India in 2007. 5 http://www.hse.gov.uk/statistics/tables/index.htm#lung 6 http://www.thelancet.com/journals/lanonc/article/piis1470-2045(09)70134-2/fulltext?_eventid=login#tbl1 7
4. Mesothelioma : Where we are now: Of all the asbestos-related diseases, it is in relation to malignant mesothelioma that action needs to be taken most urgently. Its incidence is having a significant impact on society, yet there is a lack of effective treatment, resulting from inadequate funding of research and development of clinical trials. While the Mesothelioma Framework has focused efforts to improve service delivery, improved outcomes are hampered by a lack of evidence for effective treatments. 4.1 Resistance to Current Treatments At present, the majority of patients do not receive any form of active anti-cancer treatment. Without such treatment, outcomes are extremely poor. Current average survival is less than nine months in the UK: this includes patients undergoing aggressive treatment. For those not receiving treatment, the outlook is even worse. Current standard treatment: 4.1.1 Chemotherapy: In February 2007, the National Institute for Health and Clinical Excellence approved the chemotherapy regimen of Pemetrexed (Alimta) and either Cisplatin or Carboplatin for first-time treatment in patients with mesothelioma. Chemotherapy gives symptomatic benefit to only half those who receive it In only one third does shrinkage of tumour occur with chemotherapy The increase in length of life is modest 4.1.2 Radiotherapy: Three inconclusive randomised trials have resulted in 30% of cancer teams ceasing the administration of radiotherapy to drain scars, whereas 70% continue to do so. The widespread distribution of the tumour does not allow effective radiotherapy to the whole extent of the tumour. Radiotherapy cannot be administered to such a large volume at a sufficient dose to control the tumour without causing toxicity to surrounding structures 4.1.3 Surgery: Surgery may be used to obtain biopsy samples to aid diagnosis to improve symptoms. The most common procedure is a to drain fluid from around the lung and eliminate the space with insufflation of talc (Pleurodesis). Some centres perform palliative debulking surgery within the MesoVATS clinical trial (vide infra) to resect all tumour. The roles of surgical resection by extrapleural pneumonectomy or lung-sparing total pleurectomy are being evaluated in the MARS clinical trial (vide infra). However, it is rarely possible to resect all the cancer with a wide and clear margin: even when this is achieved, the disease always recurs 4.1.4 Supportive Care: 8
Given that as few as 30% of patients may receive active anti-cancer management with chemotherapy or surgery, the role of supportive and palliative care is critical in all patients. Control of fluid (by pleurodesis or an indwelling drain) and/or pain are central in the management of all patients at some stage. 4.2 Mesothelioma is the least researched major cancer Randomised Controlled Trials (RCTs) form the fundamental gold standards of evidence based medicine. The following table illustrates the number of citations on the medical literature search engine PubMed limited to randomised controlled trials, with the corresponding annual deaths for the top twenty cancer killers. RCTs citations Annual Deaths Mesothelioma 44 1,928 Pancreas 451 7,238 Multiple myeloma 470 2,477 Malignant Melanoma 628 1,817 Bladder 758 4,734 Brain / central nervous system 824 3,425 Kidney 855 3,580 Cervix 916 1,061 Stomach 1140 5,672 Uterus 1169 1,637 Ovary 1228 4,447 Liver 1517 2,844 Prostate 1574 10,000 Non-Hodgkin Lymphoma 1791 4,451 Leukaemia 2421 4,317 Colorectal 2772 16,092 Lung 2817 33,465 Oral 2828 1,722 Oesophagus 3120 7,419 Breast 4845 12,509 4.2.1 How helpful have been the RCTs for Mesothelioma Treatment? The 44 citations for mesothelioma relate to the 9 published RCTs. Three trials have established a standard chemotherapy regime A fourth suggested that chemotherapy might be better delivered soon after diagnosis rather than later on Radiotherapy may be administered to biopsy sites in an attempt to reduce the growth of painful tumours in the skin. Three trials have investigated this, but with no firm conclusions as to its merit 9
Two trials have examined novel therapies: a vaccine designed to boost the antitumour effects of the immune system was not effective and photodynamic laser therapy was shown to be of no additional value after surgical resection. These trials have provided useful insights into treatment, but have yet to provide patients with significant benefits. 4.3 Mesothelioma Current Clinical Trials in the UK The UK has a good reputation within the International Mesothelioma Interest Group for the commitment to generate clinical trials. Three of the nine published RCTs were performed in the UK. The two current surgical RCTs are the only such trials being undertaken worldwide. There are several aspects to the UK healthcare and research systems which will enable the UK to continue to lead in clinical trials in mesothelioma, as long as investment is forthcoming: There is a large potential study population, given the high incidence in comparison to other countries There is an enthusiastic body of clinical researchers, who are active in thoracic oncology trials The growing number of Specialist-Mesothelioma Multi-Disciplinary Teams promoted by the Mesothelioma Framework are effective in encouraging recruitment to clinical trials 4.3.1 Chemotherapy and Novel Agents: MS-02: This trial follows on from the success of the British MS-01 chemotherapy trial, which helped establish the place for chemotherapy in mesothelioma. MS-02 has gained funding from Cancer Research-UK to randomise patients receiving the novel agent vorinostat, or placebo, in addition to pemetrexed / cisplatin chemotherapy. The trial is not yet open to recruitment. EORTC 08052: Patients in the UK are also eligible for entry into the European clinical trial EORTC 08052, a Phase II study of bortezomib (VELCADE) in the treatment of mesothelioma. ADI-PEG 20: A Randomised Stratified Phase II Multicentre Clinical Trial of Singleagent ADI-PEG 20 (Pegylated Arginine Deiminase) in patients with Malignant Pleural Mesothelioma. This study funded by Cancer Research UK is investigating a novel drug to kill mesothelioma cancer cells whilst leaving normal cells intact. There are several early phase studies open to patients with mesothelioma. Phase I studies investigating the toxicity of new drugs given to patients with solid tumours are carried out across the country in cancer research centres. The portfolio is ever changing. 4.3.2 Radiotherapy: The value of irradiating drain scars has been questioned by the investigators of the Prophylactic Irradiation of Tracts (PIT) Trial, who are seeking funding for the study. New radical radiotherapy techniques, such as Intensity Modulated Radiotherapy (IMRT) and Tomotherapy, are not being investigated within study protocols in the UK, although they are elsewhere. 4.3.3 Surgery: 10
The Mesothelioma and Radical Surgery (MARS) Trial, funded by Cancer Research-UK and the June Hancock Mesothelioma Research Fund, has completed recruitment to a feasibility study. This randomised 54 patients to an extensive surgical resection (extrapleural pneumonectomy), or no surgery. Results are awaited and will inform the set-up of a larger study (MARS-2), work which is on-going. MesoVATS, funded by the BUPA Foundation, is a randomised trial investigating the role of palliative debulking surgery by Video-Assisted Thoracoscopic Surgery (VATS). This procedure may have benefits in terms of quality of life and survival over the standard of talc pleurodesis to expand the lung and prevent reaccumulation of fluid. 4.3.4 Supportive Care: INPIC: A survey of the practice of cordotomy for chronic pain resulting from mesothelioma is being funded by the National Cancer Research Institute Lung Cancer Supportive and Palliative Care research initiative grant scheme. TIME2: (The Second Therapeutic Intervention in Malignant Effusion Trial) This randomised trial is investigating the differences between the use of indwelling pleural catheters versus talc pleurodesis for malignant pleural effusion (including patients with mesothelioma). The study is funded by the British Lung Foundation. 4.3.5 Epidemiology: The Mesothelioma and Lung Cancer Study (MALCS) is a population based case-control study of mesothelioma and lung cancer in relation to occupation in British men and women. This study is funded by the Health and Safety Executive and aims to assess the risks of different occupations in relation to lung fibre burden. 4.4 Current Non-Clinical Research in the UK Non-clinical research involves the development in the laboratory of potential new treatments. It is essential to test the mechanisms of disease and the applicability of some treatments in the laboratory. The majority of current non-clinical research is funded by specific research charities. The June Hancock Mesothelioma Research Fund and the Mick Knighton Mesothelioma Research Fund have, over the last ten years, raised between them approximately 1.25 million. These Funds have financed several relatively small research projects around the country. Cancer Research UK is providing full funding for one Senior Clinician Scientist and part-funding for a second. Current Laboratory Research ADI-PEG 20 London CR-UK Apoptosis Belfast CR-UK (part funded) Immunology Cardiff JHMRF Chemotherapy mechanisms Newcastle MKMRF Stem Cells London MKMRF Cyclo-oxygenase-2 Hull Yorkshire Cancer Research 4.5 Research Funding for Lung Cancer and Mesothelioma 11
In 2007, the National Cancer Institute Lung Cancer Strategic Planning Group published a report regarding lung cancer research (including mesothelioma) 7. It found that, despite lung cancer accounting for 22% of cancer deaths, only 3.9% of cancer research spending was directed to lung cancer. Of 67 Lung Cancer research projects registered in the 2005 Cancer Research Database, there was only one mesothelioma project 8. In proportion to the number of deaths, research spending for lung cancer (including mesothelioma) is by far the least: for mesothelioma it is arguably even less than for lung cancer. 4.5.1 Future Research Projects There are several research groups around the country wishing to conduct research in asbestos-related diseases, but who are working towards or have not yet been successful in grant applications. Many of these are to fund Research Training Fellowships: it is important to be able to provide subsequent ongoing support for researchers to develop a career in ARD research. For example, the following projects were not successful for the June 2009 round of applications for the Mick Knighton Research Fellowship, for research in ARDs: A Comparative Proteomic Evaluation of Serum and Pleural Markers in Patients with Mesothelioma MESO-2 TRANS: Micro-RNA regulation of clinical drug resistance in MM The Relevance of Endoplasmic Reticulum Stress Signalling to MM South West Area Mesothelioma and Pemetrexed (SWAMP) Trial Ex-vivo Modelling of Intrapleural Immunotherapy in Mesothelioma Overcoming Resistance to Tyrosine Inhibitors in Mesothelioma The Role of TNF-α Inducible Novel Transcriptional Gene (TNT) in Mesothelioma Cell Tumorigenesis A Novel Self-Management Programme for Individuals with Mesothelioma Can It Improve Quality of Life? A Phase II clinical trial to study the effects of the Trovax anti-cancer vaccine Two Phase III randomised controlled trials are in set-up and are seeking funding at the current time: PIT (Prophylactic Irradiation of Tracts) seeks to determine whether the practice of administering radiotherapy to tube sites is worthwhile. MARS-2 (Mesothelioma And Radical Surgery-2) will build on the successful feasibility study of MARS in examining complete surgical resection of tumour by lung-sparing Total Pleurectomy. The protocol is currently being finalised before funding will be sought In addition, the Mesothelioma UK Nurse Action Team have prepared and submitted five grant applications to various funding bodies over the last 18 months, but remain unsuccessful in securing funding. 5. NCARD Why and How? 7 Lung Cancer Strategic Planning Group Report 2006, NCRI http://www.ncri.org.uk/includes/publications/reports/lcreport.pdf 8 Analysis of the National Cancer Research Portfolio 2002-2006, NCRI http://www.ncri.org.uk/includes/publications/reports/analysisreport08.pdf 12
5.1 Why NCARD as the Vehicle to Deliver Results? The existing research frameworks (NIHR/MRC/Research Charities) could offer much with individual initiatives, but the channelling of efforts through NCARD in a co-ordinated approach has added value. The organisation of NCARD will provide a collaborative national network and link to similar organisations around the world, facilitating the sharing of information and knowledge Clinicians and academics working in partnership to build research capacity nationally across the NHS and internationally, in a difficult to research disease NCARD will provide the umbrella under which a National Research Strategy will be co-ordinated and delivered. NCARD will prevent any duplication of functions connected to research exercise and offer better value for money compared to disparate projects The badge of NCARD is extremely important to patients and carers: o Government and industry financial support for NCARD will enable the public to see that asbestos related diseases are being taken seriously o Private benefactors can contribute to major research projects in a transparent way o Other benefactors may be more willing to support the NCARD as an independent agency o NCARD will provide a focal point and raise the public profile of ARDs 5.2 NCARD Structure and Function NCARD will be a collaborative organisation of research groups, a virtual centre rather than a team based at a particular research location. Management Team Strategy Board Scientific Advisory Committee Who? Director of NCARD Operational Manager UK based expert-body National and international experts What? Communications Funding Strategy Co-ordination of activities Accountable to NCARD funders Liaison with research agencies Develop Research Strategy Peer review of grant applications Oversee Research Strategy 13
5.3 The Economic Case for NCARD There is a paradox regarding the economics of asbestos-related diseases Government, industry and insurers do not want to fund the immense costs of treatment, benefits and litigation Patients would much rather have improved survival and quality of life than the money Researchers have plenty of ideas but not enough funding A tiny proportion of the money going into litigation, benefits and healthcare will make a huge difference to research, providing hope, improved service and more and effective treatments for mesothelioma. The progress made by research coordinated and funded by NCARD will allow the development of effective treatments for mesothelioma. In time this will help relieve the huge financial burden on the taxpayer of ARDs, in the form of social security benefits and healthcare costs, on the insurance industry, with a lesser requirement for civil litigation settlements. 5.4 Aims and Objectives of NCARD Focal point for acquisition of research funding Directory of researchers and research Develop research strategy National collaboration Governance of research funding International collaboration Information Support the best research and attract high quality researchers Delivery of a National Research Strategy Rapid results in the translation of research hypotheses to the delivery of effective therapies 14
5.4.1 To Provide a Focal Point for Multi-Source Funding To achieve significantly more money for ARD research. To bring together multiple potential sources of funding: o Government directly and through its medical research agencies o Industry and Trade Unions o Insurance industry o Legal profession o The public o Private benefactors o Research charities Funds for NCARD have been received and/or pledged from several of these sources. Amalgamating funds from different sources will enable the funding of more ambitious projects, which are difficult to achieve at present with current funding streams and to establish centres of excellence to carry out longer-term projects or programs. 5.4.2 To Provide Governance of Research Funding Scientific Peer Review Panel of international experts in asbestos-related diseases Strategic Board A co-ordinating office and management team Alliance with research agencies (NIHR, MRC, NCRI, Cancer Research-UK etc.) Close collaboration with patient groups and charities 5.4.3 To Develop and Deliver a National Research Strategy To formulate important questions to which answers can be delivered To draw on the strengths of established UK research groups Support the best UK research in asbestos related diseases and attract high quality researchers Support new researchers into the field by the provision of Research Training Fellowships Develop continuity for the future for programmes demonstrating merit Deliver rapid results in the translation of research hypotheses to effective therapies 5.4.5 To Forge National and International Collaborations To facilitate national and international collaboration between UK and international groups in a global network To engage in FP7 and similar European research initiatives Proposed international collaborators include: The Australian National Centre for Asbestos Related Diseases The United States Mesothelioma Applied Research Foundation (MARF) International Mesothelioma Interest Group (IMIG) International Association for the Study of Lung Cancer European Thoracic Oncology Platform 15
International links would facilitate: Collaboration in basic science research The sharing of Biobank samples and registry data Collaborations in clinical research would increase the power of clinical trials Access to a wider range of clinical trials for patients 16
6. NCARD National Research Strategy 6.1 National Mesothelioma Registry and Biobank INFORMATION Demographics Exposure Clinical information Management BIOBAN K Tumour Blood Fluid National Mesothelioma Registry LuCADA National Cancer Intelligence Network IASLC / IMIG Mesothelioma Staging Project Foundation for Audit and Research: Epidemiology Clinical Translational 6.1.1 National Mesothelioma Registry Central to the functions of NCARD Local Multidisciplinary Teams (MDTs) will register patients Core Information and Management Data Tracking process and outcome Act as the data entry system for the existing national audit projects (LUCADA, NCIN) Estimated costs for Information and Audit 250,000-300,000 p.a. 6.1.2 National Mesothelioma Biobank Held locally, central registration and co-ordination Allied to national surgical centres for tissue acquisition Available to all NCARD researchers for study Collect, process, store and distribute tissue, fluid and blood samples Support the development of a live cell-line collection Pre-diagnosis, pre-treatment, post-treatment and follow-up Approx 300 patients per year Estimated costs for Biobank 100,000 p.a. 17
6.2 Research Themes 6.2.1 Epidemiology National Mesothelioma Registry provides the foundation for UK Epidemiological research Expansion of size and scope of the current MALCS study to all patients Document exposure to asbestos occupational, domestic, environmental Investigate changing patterns in exposure 6.2.2 Staging The International Association for the Study of Lung Cancer (IASLC) and International Mesothelioma Interest Group (IMIG) have commissioned a Mesothelioma Staging Project (MSP), which is projected to run until 2016. Data from the National Mesothelioma Registry submitted to the IASLC MSP Datasets developed for the MSP will be incorporated into the National Mesothelioma Registry 6.2.3 Clinical Trials Adequate and prompt funding for clinical trials is essential to allow development of effective treatments NCARD will enable rapid funding of clinical trials There are two clinical trials that are currently seeking funding: o Prophylactic Irradiation of Tracts (PIT) trial o Mesothelioma and Radical Surgery-2 (MARS-2) In addition, trials of novel therapies are being designed: o Trials of anti-growth factor agents o Trials of anti-cancer vaccines 6.2.4 Translational Research and Novel Therapies The failure of conventional treatments (surgery, radiotherapy, chemotherapy) to find a cure has led to efforts around the world to investigate novel therapies Novel therapies are being investigated on a small scale in the UK at present, although there are several promising research projects in the UK underway These include o Immunotherapy Modifying the immune system to fight and eliminate cancer cells, with the use of agents to boost immune responses, or vaccines o Inhibitors of Angiogenesis Preventing blood vessel growth to supply the needs of the tumour o Inhibitors of Growth Factors Blocking tumour stimulation by growth factors and hormones o Apoptosis Induction of programmed cell death in cancer cells o Gene Therapy Uptake of genes into tumour cells to activate chemotherapy drugs or induce cell death o Chemotherapy mechanisms drugs to reverse resistance to or improve activity of chemotherapy agents All the researchers would benefit from access to new funds to allow them to increase their efforts and bring new treatments from the bench to the bedside. 18
6.2.5 Supportive and Palliative Care Holistic Needs Assessment of Patients and Carers o Large scale prospective study of the holistic needs of patients and carers To include: symptoms / impact / expectations psychosocial / financial / spiritual needs Recruit for up to 3 years, run for up to 5 years Estimated cost 400,000 o Investigation of psychological burden in patients and carers o Evaluation of care in last 48 hours of life o Study of grief after death o Evaluation of Asbestos Victims Support Groups Survey of Preferences of Care o Interventions, services, place of care o Analgesics o Practice in specialist centres/hospices Recruit 200 patients Run for 2 years Estimated cost 100,000 (in conjunction with Holistic Needs) Associated clinical trials would include: o standard management +/- early specialist supportive care o Methadone vs. ketamine o opioid +/- specific drugs (pregabalin, clonazepam, duloxetine, lamotrigine) Biomarkers and Genomics of Symptoms and Distress in Mesothelioma o To include pain, fatigue, psychological distress Could be run in parallel with lung cancer studies Recruit 200 patients Estimated cost 200,000 o Influence of cytokines/biomarkers on pain / fatigue / psychological symptoms o Influence of polymorphisms of pain receptor / cytokine genes o Influence of CyP450, ABCB1 etc on response to Management Patient Self-Management of Symptoms and Psychological Distress o To include pain, dyspnoea, nutrition, fatigue, anxiety and depression o Estimated cost 50,000 per symptom 6.2.6 Public and Patient Involvement A National Consumer Research Panel to Co-ordinate patient and carer involvement on all aspects of research into asbestos-related diseases, especially mesothelioma Advisory capacity to NCARD Estimated cost 10-20,000 per annum 6.3 Research Prioritisation 19
Core Foundation Funding is required to establish NCARD. Funding of the National Research Strategy will depend on competitive grant applications and the guidance of the expert Strategy Board. As projects and programmes develop, there will be the need for Sustainability Funding. The figures below are estimations of the minimum amount to deliver anticipated targets. 6.3.1 Foundation Funding To enable the foundation of NCARD and establish infrastructure Appointment of Director (2 sessions) and Manager (FT) Office Costs, communications, website National Mesothelioma Registry and Biobank Annual research conference National Consumer Research Panel 500k p.a. 6.3.2 Strategy Funding Essential priority areas of work within each Research Theme: fund the best projects NCARD Strategy Board to decide the priority areas according to available funds and the National Research Strategy. The specific topics will be decided by the NCARD Strategy Board, in conjunction with the Scientific Advisory Board, being open to ideas and competitive proposals from the research groups. Initial Strategy Funding could go towards the Research Themes as follows: Epidemiology Demographic studies based on National Mesothelioma Registry 100k p.a. Staging 100k p.a. Collection, validation and submission of data to the Mesothelioma Staging Project Clinical Trials 1 million initially Ensure the trials currently seeking funding and under development are funded Translational Research Support the studies currently applying for funding 1 million initially Supportive and Palliative Care 1 million initially Initial studies of Holistic Needs Assessments, survey of preferences of care, clinical trials; biomarkers and genomics study 6.3.3 Sustainable Funding Sustainable funding for promising research Follow-up promising research Build up the research networks' portfolios of studies Support new research ideas or themes as they emerge. 500k to 1million p.a. 20
7. Conclusions and Next Steps The Development Group believe that there is a strong case for the establishment of NCARD: There is a significant need to increase research and funding in the UK into ARDs There is the need to develop more effective treatments for malignant mesothelioma, in particular Those exposed to asbestos wish to see the establishment of NCARD as a separate new initiative which they can support Multiple funding partners are willing to combine efforts Research groups are actively seeking collaborations, but require specific infrastructure to work together effectively NCARD will promote and facilitate research and trials both nationally and internationally The next steps are to: Create the NCARD office, manager and website with the funding received Establish the NCARD Strategy Board, with the first meeting to be held in Q1 of 2010 Confirm membership of the Scientific Advisory Committee Sign management and continuing funding agreements with partner organisations Receive formal Government support for NCARD Realise pledges of financial support from partner organisations Publish the initial call for grant applications 21
Appendix NCARD Strategy Document Definitions of Terms Pleural cavity Pleura Mesothelial cells Pleural Effusion Pleurectomy VATS The lung is only attached to the body by its hilum (root). All around each lung lies its respective pleural cavity, which is a potential space containing a few mls of pleural fluid The pleural cavity is lined by a layer of tissue called the pleura, which covers the inside surface of the chest wall, the diaphragm, the surface of the lung and the mediastinum (the major structures in the centre of the chest) The pleura is composed of a single cell cobblestone layer of mesothelial cells, supported by tougher fibrous tissue The accumulation of fluid in the pleural space, sometimes several litres, causing compromise of lung function and shortness of breath The peeling away of the pleural membrane, to improve chest wall or lung dynamics Video-Assisted Thoracoscopic Surgery, the keyhole surgery of the chest using telescopes and cameras, with images visualised on a screen Extrapleural pneumonectomy (EPP) A major operation to remove the entire pleura and lung within, also removing and reconstructing the diaphragm and pericardium (sac containing the heart) Total Pleurectomy MARS EORTC A similar operation to EPP, removing all the pleural tumour with the diaphragm and pericardium, but preserving the lung by peeling the tumour off its surface The Mesothelioma And Radical Surgery trial, a randomised controlled trial investigating the role of EPP European Organisation for the Research and Treatment of Cancer, a major European cancer trials organisation 22
Links NCARD Strategy Document Mesothelioma UK http://www.mesothelioma.uk.com June Hancock Mesothelioma Research Fund http://www.junehancockfund.org/ Mick Knighton Mesothelioma Research Fund http://www.mickknightonmesorf.org/ Asbestos Victims Support Groups Forum UK http://www.asbestosforum.org/ Cancer Research UK http://www.cancerresearchuk.org/ Medical Research Council http://www.mrc.ac.uk British Lung Foundation http://www.lunguk.org National Cancer Intelligence Network http://www.ncin.org.uk/ National Lung Cancer Audit Database (LUCADA) http://www.ic.nhs.uk/services/national-clinical-audit-support-programmencasp/cancer/lung International Mesothelioma Interest Group http://www.imig.org International Association for the Study of Lung Cancer http://www.iaslc.org/ Mesothelioma Applied Research Foundation http://www.curemeso.org US National Mesothelioma Virtual Bank http://www.mesotissue.org/ Australian National Centre for Asbestos Related Diseases http://www.ncard.org.au European Thoracic Oncology Platform http://www.etop.ch/ 23
NCARD Development Group NCARD Strategy Document The following have participated in the NCARD Development Group: Mr John G Edwards Michael Clapham MP Chair NCARD Development Group Chair, British Mesothelioma Interest Group Consultant Thoracic Surgeon, Northern General Hospital, Sheffield Chair, All Party Parliamentary Group on Occupational Safety and Health Dr Jeremy Steele Dr Mick Peake Liz Darlison Chair, Mesothelioma UK Consultant Medical Oncologist, St Bartholomew s Hospital, London Clinical Lead, UK Lung Cancer Coalition Consultant Chest Physician, Glenfield Hospital, Leicester Nurse Consultant, Mesothelioma UK, Leicester Adrian Budgen Trustee, June Hancock Mesothelioma Research Fund Dr Kate Hill Anthony Whitston Research Fellow, University of Leeds & Trustee, June Hancock Mesothelioma Research Fund Chair, Asbestos Victims Support Groups Forum Dr Dean Fennell Senior Lecturer in Medical Oncology Queens University, Belfast Dr Peter Szlosarek Senior Lecturer in Medical Oncology University College, London Dr Zsuzanna Tabi Senior Lecturer in Oncology, Cardiff University Prof Bruce Robinson Director, National Centre for Asbestos Related Diseases Perth, Western Australia 24