November 2009 National Centre for Asbestos Disease. Strategy Document by NCARD Development Group.
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
1. Executive Summary
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 ring-fenced 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
2. Introduction
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 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,
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 .
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 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 .
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.
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 12th most common cancer killer in men and the cancer of most rapidly increasing incidence in women. There were 2,156 deaths in 2007
• 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 .
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.
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:
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
• Two trials have examined novel therapies: a vaccine designed to boost the anti-tumour 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 Single-agent 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:
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
In 2007, the National Cancer Institute Lung Cancer Strategic Planning Group published a report regarding lung cancer research (including mesothelioma) . 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 .
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-a 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?
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.
Who? What?
Management Team Director of NCARD Communications
Operational Manager Funding Strategy
Strategy Board UK based expert-body Co-ordination of activities
Accountable to NCARD funders
Liaison with research agencies
Develop Research Strategy
Scientific Advisory Committee National and international experts Peer review of grant applications
Oversee Research Strategy
Wednesday 20th May 2009..Campaigners calling for a new asbestos research centre were in London on They presented a petition with over 22,000 signatures to the Prime Minister at 10 Downing Street.
Jan Egerton presents the Petition to 10 Downing Street Picture by Mick Holder
The petition calls on the Government to provide £7m funding for a National Centre for Asbestos Disease in the UK to aid research into the disease, including mesothelioma the fatal cancer caused by exposure to asbestos.This would be an organisation of existing and new research groups around the Uk working closely together as a virtual centre rather than a bricks and mortar research unit.
Currently the Government provides no funding for asbestos related disease, instead charities like the Mick Knighton Mesothelioma Research Fund rely on donations from the public, many who themselves have bben affected by the disease, to suuport research projects.
Mesothelioma is the least researched of the top twenty cancers, a disease which has devasated millions of families worldwide.
Campaigners calling on the Government for a National Centre for Asbestos Disease in the Picture by Mick Holder
Mesothelioma sufferer, Jan Egerton presented the petition along with Mick Clapham MP, Dave Anderson MP, John Edwards Thoracic Surgeon and Chair of the Mesothelioma Interest Group, Liz Darlinson Mesothelioma UK, Paula Walker Asbestos Forum and Chris Knighton from Mick Knighton Mesothelioma Research Fund.
Tony Whitson, Chair Asbestos Asbestos Victims Support Group Forum says” Inthe US mesothelioma has been gived research priority to bid for funding from the $50million Department of Defense Medical Research budget in regognition of the thousands of veterans exposed to asbestos in service in Naval shipyaards. In Australia, the government has given $6million dollars to fund a National Research Centre. Society has a moral obligation to stand by those who have lost their health and lives in creating this country’s wealth.
For more information contact Mr John Edwards, Consultant Thoracic Surgeon:0114 226 9279 or 07970 833 973 or Paula Walker, secretary Asbestos victims Forum: 01709 360 672 or 07913 392 049
