Health REport Recommendations to reshape policy making
Exclusive interview with European Commissioner for Health & Food Safety
urological guidelines European Association of Urology on developing an evidence-based database
Prof. Dr. Sehnaz Karadeniz, Chair, IDF Europe takes a critical look
coping with prostate cancer
Towards better treatment, prevention and care Five faces of prostate cancer Dr Alastair Lamb outlines research identifying genetic subtypes
european commission 52 Interview: Vytenis Andriukaitas, Commissioner for Health & Food Safety
policy action 54 Piernicola Pedicini MEP 55 Nessa Childers MEP
56 Dr. Alastair Lamb
diagnosis, care & treatment 57 Prof. Jonathan Waxman, Professor of Oncology, Imperial College London 59 Randy AuCoin, President and CEO, Exact Imaging
60 Prof. Dr. Hein Van Poppel, Professor of Urology, University Hospital in Leuven 60 Prof. Dr. Nicolas Mottet, Chair, EAU Prostate Cancer Guidelines Panel
holistic management 61 Gary Steele, Chairman Leighton Hospital 62 Prof. Dr. Bertrand Tombal, Consultant Urologist 63 Dr. Laurent Fossion, Urologist, FeBU 64 Jane Griffiths, Group Chairman, Janssen Europe, Middle East and Africa 65 Dr. Riccardo Valdagni, Director of Radiotherapy, European School of Oncology 66 Prof. Jelle Barentsz, Professor of Radiology 68 Prof. Ronald Van Velthoven, Head of Urology, Institut Jules Bordet 69 Prof. Dr. Louis Denis, Director, Oncology Centre Antwerp 70 Dr. Anjali Zarkar, Consultant Clinical Oncologist, University Hospital Birmingham 71 Leslie Wise, Vice President of Global Healthcare Economics, AngioDynamics 73 Andrew Gilliver, Community Involvement Manger, LGBT Foundation 74 Gissoo Decotiis, Oncology Advocacy Relations, Pharmaceuticals Division, Bayer 75 Angela Culhane, Chief Executive, Prostate Cancer UK 76 Mihaela Militaru, Director, European Cancer Patient Coalition 77 Dr. Ben Pais, Vice President Medical Affairs, Elekta 78 Dr. Chris Booth, Member of Clinical Advisory Board, Tackle Prostate Cancer 80 Dr. Howard Urnovitz, Dr. Nick Plowman, and Prof. Dr. Ekkehard Sch端tz, Chronix Biomedical 81 Dr Riccardo Belli, Medical Director, AstraZeneca 82 Arvind Venkataramana, Research Director, ICPS
diabetes challenge 84 Prof. Dr. Sehnaz Karadeniz, Chair, IDF Europe 85 Dr. Andrew JM Boulton, President, Worldwide Initiative for Diabetes Education
Commission’s action on health priorities within Europe In an exclusive interview with Government Gazette, Vytenis Andriukaitis, European Commissioner for Health and Food Safety, discusses the EU action on cancer, diabetes and healthcare technology
he incidence of prostate cancer and diabetes has significantly increased over the past two decades and continued growth is expected, due to an aging population. While greater awareness of the causes and earlier diagnosis can provide hope for these two major non communicable diseases, they continue to impose a heavy financial burden on our health services. Government Gazette interviews the European Commissioner for Health and Food Safety to find out more about the European Commission’s action on the deadly diseases. Commissioner Andriukaitis, it is often said that the EU action on cancer is one of its earliest policies in the field of health. After thirty years of EU action in the field of cancer can you tell us where we are at the moment? As European Commissioner for health, contributing to cancer prevention, screening and care, is a major concern for me. I personally lost family members to this terrible disease, and I am not alone – most of us have been affected by cancer in some way. This year, we celebrate thirty Against Cancer” which provides user friendly years of EU action in the field of cancer. Since the advice to avoid cancer. It also includes action on European Community leaders first met in 1985 cancer risk factors, in particular laws on tobacco and committed to take action to fight against products and on their marketing, on pesticides, cancer, EU policy has helped save lives through air quality, and protecting its four pillars of action: early workers against exposure to diagnosis, prevention, research carcinogens, as well as action “In the past seven and partnership. on alcohol, nutrition and years, the EU has First, the EU has, since 2003, physical activity. invested nearly € 1.44 recommended population-based Third, during the past seven cancer screening for breast, billion notably in years, the EU has invested cervical and colorectal cancer, international nearly € 1.44 billion notably and has produced European collaborative research in international collaborative Guidelines for all three types of research and coordination and coordination cancer screening. Now a quality of national cancer research of national cancer assurance scheme for breast efforts. This funding aims to cancer units is underway to research efforts.” find new ways to understand recognise the best places where and fight cancer, and to help women in Europe can get high patients. quality care. Early detection of cancer is vital as it gives patients the chance to receive timely and Lastly, a new Joint action was launched in often life-saving treatment. This is true for all 2014 on Comprehensive Cancer Control types of cancer – prostate, lung, skin, etc. – and I (“CANCON”) to deliver a European Guide on urge anyone who suspects symptoms to promptly Quality Improvement in Cancer Control. By consult their physician. presenting evidence-based recommendations for Second, addressing the risk factors is the Commission’s first line of attack to help reduce the burden of cancer. Actions in the past thirty years include supporting the “European Code
all stages of cancer control and care, this guide aims to reduce inequalities in cancer between EU countries. Commissioner, you indicated in several
occasions that your priorities in public health could be summed up by the three words: “promotion, prevention, and protection”. What is the EU action doing on obesity and diabetes, for instance? With an estimated thirty-two million adults aged 20-79 living with diabetes in the EU, we are facing one of the biggest healthcare challenges of our time. If left untreated, diabetes can lead to heart disease, kidney failure, nerve damage and eye complications. Some forms of diabetes are lifestyle-related and obesity is a key risk factor. This is why we must put our efforts into preventing diabetes, starting with our youngest citizens. We must also help people who are living with diabetes. In 2008, one in four children aged six to nine were overweight or obese. By 2010 this figure rose to one in three children. In 2013, this worrying trend forced several European countries to jointly develop a European action plan targeting childhood obesity. The action plan puts forward initiatives to: support a healthy start in life, promote healthier environments - especially in schools and preschools, restrict marketing and advertising for children, encourage physical activity and increase research. In addition, we are also working with Member States through a Joint action (“CHRODIS”)
on chronic diseases launched in 2014 and co-financed by the EU Health Programme. It promotes healthy ageing across the life cycle and aims to help EU countries and regions to exchange good practices in tackling chronic diseases. A special focus will be given to health promotion and disease prevention, multimorbidity (people with more than one long-term condition) and diabetes. Beyond public health, I understand that one of your priorities is healthcare technology assessment. Could you explain how you see the development of EU action in this field? A rapid increase in health technology is a sign of our times. There are more innovative medicines, medical devices and cutting-edge diagnostic tools than ever, and patientsâ€™ expectations are rising in parallel. This is challenging as it increases the pressure on national healthcare budgets, already under intense strain. Decision-makers are seeking answers to essential questions: is this innovative new medicine worth the money, or will an existing, cheaper medicine be as effective? Will buying this new machine save my hospital money in the long-run? Will it be more or less labour intensive? This is where Health technology assessment (HTA) comes into the picture. HTA informs decision makers on comparative effectiveness and efficiency of treatments. Cooperation on HTA at EU level will benefit patients by providing them with better access to innovative technologies. This is a challenging and important task on which the Commission will be concentrating its work in 2016, under my request and guidance. The EU support of HTA cooperation over the past twenty years has delivered tangible results on methodologies and information exchange. It has now paved the way for efficient use of HTA resources in Europe and the creation of a sustainable system of HTA knowledge sharing. In the coming months, I want to harness the commitment of EU countries and stakeholders to accelerate progress in this area, which will pay dividends for all of us.
The concrete building of the links between the technology, I am convinced that the right eHealth countries is now starting, supported by the EU tools that offer safe and efficient care can also help funds from the Connecting Europe Facility alleviate the burden on our healthcare systems. programme. I call upon EU countries to embrace Of course, the EU is made up of twenty-eight the opportunity and join the real work of separate health systems, which themselves are providing citizens and patients easier and better not uniform. This is why interoperability within health services when travelling. and between the countries is vital. The latter is a key aim of the eHealth Action plan 2012Interoperability 2020, which sets out a long is also vital in the term vision for eHealth in establishment of â€œThe EU support of Health Europe. The eHealth Network European Reference plays a central role in solving Technology Assessment Networks (ERNs) interoperability challenges (HTA) cooperation over which should constitute between electronic health a major step forward the past twenty years has systems. for patients and health delivered tangible results professionals. By the Since it was launched in on methodologies and end of next year, ERNs 2011, the Network has for information exchange and will be operational instance adopted ePrescription now enables to envisage an and will bring together guidelines in 2014, laying out highly specialised the type of data needed for efficient use of HTA resources healthcare providers sharing prescriptions across in Europe and the creation of from different EU borders and giving patients a sustainable system of HTA countries in areas where the possibility to get the knowledge sharing.â€? expertise is rare, thereby medication they need anywhere pooling knowledge in the EU, which is particularly on rare diseases. They important for people with will be an additional chronic medical conditions. example of the importance of eHealth as their In addition, the Network also produced patient functioning will involve the use of an integrated summary guidelines in 2013, giving patients the IT platform (e.g. exchanging electronically clinical possibility to have, on request, a summary of their information, tests and diagnostic tools between electronic health record when visiting another professionals). Indeed, it is the application of Member State. The benefit is that for unplanned interoperable eHealth solutions which will allow or emergency care, the doctor in the country of the Networks to interact and fulfil their objectives treatment will have an electronic overview of for the benefit of patients in the EU the patient, and a set of basic administrative and medical information, which will improve patient safety.
We live in a connected world, especially in the area of health. I understand that the Commission is preparing the EU for future developments in the field of electronic health notably. Can you elaborate please? Speaking of chronic diseases and healthcare
Improving patient safety and embracing technology Canvassing for innovative mobile solutions in disease management and improving patient safety, MEP
Member of EP’s Committee on the Environment, Public Health and Food Safety explores measures that could potentially boost the uptake of eHealth and provides an overview of European healthcare
ould you ever want to find that you had a terminal prostate cancer through a smartphone application? Most certainly not. Technology will never replace doctors, but they must embrace it. In fact, telemedicine integrated with healthcare at home would contribute towards the rationalisation of costs and increase the humanisation of care. A patient-centred approach is essential in health treatments, however, unfortunately, sometimes such an approach is not given the right priority. It is essential to promote the humanisation of treatments, for instance, providing home-care medical treatments, which can help patients psychologically and result in better healthcare performance. eHealth and mobile health have a great potential in increasing the efficiency of healthcare treatments and reducing costs. I welcome the identification by the Commission of eHealth as a priority area of activity in the Digital Single Market strategy.
the uptake of eHealth in Europe include establishing online and publicly available patient waiting lists; establishing information points where medical examinations can be booked online; setting audio-visual telecommunications healthcare consultation where the doctor can visit the patient from the institute; guaranteeing free data access to enhance de-hospitalisation, and finally providing home care treatment and telemedicine, which would improve the quality of the treatment and also reduce costs. Pedicini’s initiative report I was rapporteur of the initiative report on “Safer healthcare in Europe: improving patient safety and fighting antimicrobial resistance,” adopted by a large majority of the European Parliament in May 2015. In the report, we identified some key actions which the various member states and the European Commission should take as a matter of urgency in order to increase patient safety and reduce antimicrobial resistance. There is also a need to adopt a patient-centred approach as well as a multidisciplinary strategy when doctors decide on best medical treatments.
eHealth can contribute to the empowerment of patients with key information, making them able to take informed decisions. However, we should make sure that patients and their organisations are actively involved in healthcare treatment decision-making as they have a pivotal role in the uptake of eHealth.
The indiscriminate application of austerity measures, that some member states have applied to the health sector, have a negative impact on patient safety, for example the reduction of medical personnel or of hygiene specialists increases the patient’s risk in getting associated infections. This eventually results in higher expenses for the healthcare sector.
Other measures that could potentially boost
The upstream cause of threat to patient safety
is the political interference in appointment of managers and other health professionals, which implies lower healthcare quality standards. That is the primary reason why the report stresses that member states should “ensure that health managers are appointed on the basis of their merit and not of political affiliation.” Nowadays we are facing a major threat to human healthcare which is antimicrobial resistance. Every year 25,000 European citizens die due to increased resistance to antimicrobial agents and, in 2050, the deaths caused by antibiotic resistance is estimated to be about 10 million: more than the number of deaths caused by cancer. Urgent measures are needed, particularly from the pharmaceutical industry in “real development” of new antimicrobial drugs and, at the same time, to research alternative natural methods to fight drug resistance. Furthermore, we need more appropriate microbiological diagnosis before prescribing any antibiotics; prohibition of sales without prescription; awareness-raising campaigns targeting all population groups to promote an appropriate and responsible use of antibiotics; limit the use of antibiotics in veterinary medicine; eliminating the prophylactic use, as well as strongly restrict the metaphylactic use of antibiotics in animals. Innovative healthcare method to detect prostate cancer The EU health policy should address not only traditional research but also look at innovative healthcare methods which could have an important impact on reducing healthcare costs. For instance, a study published last April on the Journal of Urology showed an alternative method to detect prostate cancer. It showed that a trained canine olfactory system can detect prostate cancer specific volatile organic compounds in urine samples with high estimated sensitivity and specificity. This study can lead to the development of a highly innovative procedure to identify prostate cancer with a highest predictive value compared to traditional methodologies, which have shown scarce specificity and sensitivity. The discovery is particularly relevant considering that prostate cancer represents the fifth most frequent cancer in the world and given the increasing mortality rates within Europe
Reducing mortality rates tops MAC’s latest agenda The MEPs Against Cancer (MAC) group strives to reduce cancer incidence by promoting prevention, reducing mortality through equitable access to high-quality care and ensuring good quality of life for cancer patients. MEP Nessa Childers, Vice President, MEPs Against Cancer Group talks about the European Parliament’s fight against cancer
ancer is an ever growing public health concern. In 2012, cancer was the second most common cause of death in the EU: around 708,000 men and 555,000 women died from it, the main causes being lung, colorectal, prostate, pancreatic, stomach and liver cancer among men, and breast, lung, colorectal, pancreatic, ovarian and stomach cancer among women. Aside from this killer’s human toll, from an economic point of view, cancer is a major burden, costing EU Member States a total of €126 billion in 2009. The main risk factors for cancer are smoking and drinking, an unbalanced diet, excess weight, lack of physical activity as well as environmental and work-related exposure to cancer-causing substances (carcinogens). More than 30% of cancer deaths could be prevented, mainly by avoiding risk factors and adopting a healthy lifestyle. Whilst the provision of health care services ultimately lies within the competencies of each Member State, the EU can still complement the efforts carried out at national level, by sharing best practises and fostering cooperation. Within the European Parliament, in 2005, an informal group was set up by my colleague Alojz Peterle, the standing President. Together with Alojz Peterle, Pavel Poc and myself,
as Vice-Presidents, and other cross-party colleagues, we work on policies against cancer in the belief that European cooperation adds value to Member State actions. The MEPs Against Cancer (MAC) group is a forum where we gather input and exchange views with MEPs, scientific experts, European Commission officials, researchers, Member State representatives and patients. In the current parliamentary term (2014-2019), the group’s strategic goal is to reduce cancer incidence by promoting prevention, reducing mortality through equitable access to highquality care and ensuring good quality of life for cancer patients. The group collaborates with other relevant organisations in order to achieve the goal of reducing cancer by 15% by 2020. Furthermore, in order to establish stronger links with cross-party groups in European national parliaments, MAC has set up an Ambassador scheme.
In order to address the challenges faced by the EU, MAC is working together with other organisations to help further the policy goal of reducing cancer incidence by 15% by the year 2020. Some of the ways in which we are trying to achieve this goal are by addressing the risk factors through legislation on pesticides, tobacco products and through campaigns to raise awareness such as ‘Ex-smokers are unstoppable’. The EU invests a total of €1.5 billion in the fight against cancer– mostly for international collaborative research projects, but also for public-private partnerships and the coordination of national cancer research. Most of the research work is within the field of rare cancers, which are linked to an ever increasing mortality rate in the European Union
Since the economic crisis has hit many EU countries, and that governments have implemented harsh cuts to health budgets as part of their austerity plans, we are also focussing on safeguarding public health in austerity policies to ensure, among other goals cancer patients have access to the medicines they need and that economic policies do not block access to the provision of life saving care.
The five faces of prostate cancer
Prostate cancer can no longer be treated as one disease.
Dr. Alastair Lamb,
Clinical Lecturer in Urology, Cambridge Biomedical Campus, UK, outlines some recent work identifying genetic subtypes of prostate cancer and how this could alter future care
he question that often arises from the patient is “When will this prostate cancer kill me, doctor?”. The question may take a softer form than this but the point is the same: men want to know whether this new diagnosis they have just received is going to shorten their life; whether it means they can no longer go on the long-planned family trip to Australia next year; or whether they’ll see their first grandchild born. Risk stratification And really this is a question about risk stratification. The thing is, as often discussed with men in clinic (or with someone at a dinner party), that it doesn’t necessarily matter if you get prostate cancer; half of all men are going to get it if they live beyond the age of 80. No, the problem isn’t having prostate cancer; it’s what type you have. We already divide men into subgroups in prostate cancer which we believe have different outcomes. Currently we do this on the basis of three things: a blood test (the prostate specific antigen or PSA test), the appearance of tissue under the microscope (the Gleason score), and the size and extent of the tumour based on MRI scanning and digital examination of the prostate (the TNM score). Based on these three things, we divide men into low, intermediate or high risk. (1)But the problem is that we often come across men in the lower risk groups who, contrary to expectations, do very poorly in terms of outcome. Conversely we also have men in the high risk group who actually do unexpectedly well. So, there must be some additional information about the behaviour of such cancers that we are missing with our current approach.
Genetic information in each cancer cell An important answer to this problem could be the genetic information stored within the prostate tissue itself. Tissue architecture, tumour growth and, to an extent, release of PSA are all downstream indicators of something that is happening in the DNA of the cancer cells within the tumour. DNA is the library code which contains the information that tells a cell what to do. The machinery within each cell nucleus turns DNA into RNA (Ribonucleic acid) which in turn determines the sequence of amino acids to form a protein which acts out the function of a cell. It’s these ‘molecules’ – DNA, RNA and protein – which are the key to a cell’s behaviour. Protein is notoriously difficult to measure accurately and so DNA and RNA (a surrogate for protein levels) can together be measured to give a molecular impression of current and future cell activity. The five faces of prostate cancer In our study recently published in EBioMedicine (a new open-access journal from The Lancet and Cell Press) we looked at prostates from 259 men from Cambridge, UK and Stockholm, Sweden and measured the DNA and RNA in the tissue looking for mutations in the DNA library code and whether RNA levels had been turned up or down. Based on this, we grouped men with prostate cancer into five distinct groups, each with a characteristic genetic fingerprint, coining the name the “five faces of prostate cancer” in Aine McCarthy’s CRUK blog. Two of these groups had dramatic changes in the number of ‘copies’ of each gene due to mutations in the DNA and these were linked to
marked increase or decrease in RNA levels. By contrast, the two groups had very little change compared to normal prostate tissue. A fifth group was somewhere in between. (2) We were very interested to see that the two groups with dramatic molecular changes did far worse in terms of prostate cancer relapse compared to the other groups. In fact, membership of one of these two groups was a much stronger predictor of poor outcome than current clinical parameters such as PSA, Gleason score or T stage. The future of prostate cancer care Future decision-making in prostate cancer could look very different to current practice. Although we don’t currently screen for prostate cancer (thus lagging behind breast, ovarian and gut cancer) “next-generation screening” based on a composite algorithm of PSA-related tests will soon be available (Lamb & Bratt, Lancet Oncology 2015 in press – details to follow). Having identified a population of ‘at-risk’ men, we will then proceed to diagnosis with a biopsy. We then have to apply the molecular stratification techniques described above to biopsy tissue – the EBioMedicine study looked at prostate removed at prostatectomy which gives larger samples of tissue than biopsy – or even to small amounts of circulating DNA in the blood. An important step here will be to make sure that the right bit of the prostate is sampled and it is likely that high resolution “multi-parametric” MRI scanning will play an important role in selecting the key target in the prostate. The molecular information received from selectively targeted biopsies, alongside the current clinical parameters will inform a more
comprehensive risk stratification which will permit a far more intelligent approach to treatment decision making and subsequent follow-up regimens. The precise form of molecular score is yet to be decided. Two commercial scores are already available (Prolaris and Oncotype Dx) and it is likely that further approaches will soon follow.
clinical benefit, helping men to avoid the sideeffects of treatment including incontinence, impotence and bowel dysfunction, and ultimately saving lives
For these to be used alongside the trio of PSA, Gleason and TNM staging, much rigorous testing will be needed in larger cohorts of men to prove that they really can provide large-scale
Alastair Lamb, Clinical Lecturer in Urology, Addenbrooke’s Hospital, Cambridge & Cancer Research UK Cambridge Institute, Cambridge Biomedical Campus, UK.
1. D’Amico, A. V., Whittington, R., Malkowicz, S. B., Schultz, D., Blank, K., Broderick, G. A., Tomaszewski, J. E., Renshaw, A. A., Kaplan, I.,
Beard, C. J., and Wein, A. (1998). Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. Jama 280, 969-974. 2. Ross-Adams, H., Lamb, A. D., Dunning, M. J., Halim, S., Lindberg, J., Massie, C. M., Egevad, L. A., Russell, R., Ramos-Montoya, A., Vowler, S. L., et al. (2015). Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study. EBioMedicine 2, 1133-1144.
It’s time to take action, or it could be you...
he Government Gazette is distributed through the United Kingdom Houses of Parliament, and the European Parliament. There are 459 male MP’s, 609 male Lords and Bishops, and 473 male MEP’s. Prostate cancer is now the commonest cancer in men, affecting one in nine men. So, the chances are that 51 MP’s and 67 members of the House of Lords, and 52 MEP’s have or will develop prostate cancer. So it could indeed be you, and you of course do have a vested interest in understanding prostate cancer and encouraging advances in research and treatment into this very common disease at a UK national and European level. What do you know about prostate cancer? It’s surprising that almost less than 20% of
Considering that prostate cancer is affecting one in nine men, there are chances that 51 MPs, 67 members of House of Lords and 52 MEPs already have or will develop the commonest cancer of men if policy makers don’t take immediate action. Prof. Jonathan Waxman, Professor of Oncology, Imperial College London gives a complete lowdown on the deadly disease and discusses what needs to be done from a policy perspective men and women only know where the prostate is and what it does. The prostate is a gland at the base of the bladder, and because of the gland’s location, enlargement of the prostate by any benign or malignant growth of the prostate can cause difficulty with urination. The prostate makes a fluid that mixes with sperm to form the seminal fluid which contains high concentrations of fructose, a sugar that nourishes the sperm in its perilous voyages in foreign parts. The number of people affected by prostate cancer has increased incredibly over the last 50 years. In the UK, in the mid
1960’s, around 6000 men were diagnosed with prostate cancer per annum. The latest available figures show that 41,736 men were diagnosed with prostate cancer in the UK in 2012. This increase is replicated around Western Europe where currently 343,174 men were diagnosed. Mortality rates are around 30% both in the UK and in the rest of the EU. What is the cause of prostate cancer? Prostate cancer is generally a disease of older men, increasing in incidence with age so that it is found in some form in up 80% of 80 year
olds.. As the average age of death in the UK has increased by ten years over the last fifty years it might be thought that the change in prostate cancer incidence reflects the changes in the demographics of our society. But not so, because when age is factored in the massive change in incidence is not explained. There is no obvious genetic cause. No single genes have been found to be altered and cause prostate cancer. However multiple genetic abnormalities are seen and are likely to be a secondary event, reflecting the impact of environmental factors on the genome. The evidence showing this has been available from the 1960’s. Entire galaxies of studies have shown that the increase in incidence of prostate cancer is likely to be due to changes in diet, with the star dust firmly sprinkled on meat and dairy products, and in particular on to processed and smoked foods. How is prostate cancer treated? Prostate cancer can be divided into two main types, a mild form that requires no treatment and a more aggressive form that can be confined to the prostate or have spread to involve other organs. Mild prostate cancer looks only slightly different from normal tissue when examined microscopically and is generally associated with low PSA levels. This is a ‘cancer’ that has an excellent outlook and can usually be managed without treatment merely requiring regular follow up blood testing and clinical monitoring. When the more aggressive form is found, and is confined to the prostate, the patient is offered treatment with radiotherapy or surgery. The results of treatment are exactly the same and radiotherapy has much less side effects. The addition of hormone treatment and chemotherapy provides a survival benefit for some subgroups of patients treated with radiotherapy. For patients whose cancer has spread, treatment is with hormonal therapy that blocks the effect of the male hormone, and with chemotherapy. In the UK, doctors are unable to use all the drugs that they would like to use to treat their patients because of the restrictions applied by the National Institutes of Clinical and Health Care Excellence (NICE). What to do about prostate cancer? So how do we act to decrease mortality? We do so by developing national preventive strategies, by encouraging screening, by stimulating basic science research, improved patient care, and through facilitating and making available treatment advances so that new drugs can be given to patients. In some cancers public health campaigns have been effective in reducing cancer incidence. For lung cancer for example, public health campaigns have reduced smoking levels to under 20% of the population, and this has led to decreases in death rates. In many cancers national screening programmes have led to fabulous falls in death rates for common cancers. Cervical cancer screening has led to a decrease in mortality rates by over 50%. Breast cancer screening is associated with a fall of 30%
in death rates, and there is very strong evidence that colonoscopic screening for large bowel cancer is effective in reducing death rates but faecal occult blood testing which is cheaper, is relatively less effective. How about national prevention strategies? In prostate cancer public health campaigns would need to focus on dietary educational campaigns, battling against vested interests, as a very long term strategy to reduce prostate cancer incidence. We need you as our national representatives to campaign on such important public health matters. But, what about prostate cancer screening? Why is there no national screening programme for the early detection of prostate cancer? Firstly it is still not clear that early detection and treatment does lead to a fall in death rates. Secondly we do not have good diagnostic tests. Current screening is based on the PSA blood test. PSA is an enzyme that is produced in the prostate where it acts like biological washing powder to keep the tiny internal tubes clear of gunk, as we clinical scientists call it! PSA spills over into the blood stream and can be measured. Unfortunately, the PSA test is not specific and where blood levels are raised to double the normal range, the chance of a patient having prostate cancer is around 25 – 40%. As a result, if PSA is used to screen normal populations a lot of unnecessary further tests are done. In a recent analysis of over 350,000 men involved in PSA screening campaigns, no benefit was found for screening. So, should you as our national representatives, be calling for investment in new tests for the development of national screening programmes in prostate cancer? Yes! We need a better test that distinguishes between the two different forms of prostate cancer. And basic science research? In the UK in 1996 around £46,000 of public money was allocated to prostate cancer research, a hundredth of the allocation to breast cancer. As a result of a national campaign led by the Daily Mail, I met with Yvette Cooper who was the Minister of Public Health. The minister then announced that central funding for prostate cancer research would be increased to a par with breast cancer, to around £4million pa. A great step forward, but inconsiderable in the context of the cost of developing a new drug for cancer which is around £1.3billion. Basic science research is left to charity, where the major funder in the UK is Prostate Cancer UK, an organisation that I founded to remedy the lack of funding for information, clinical services and for research. But we cannot leave matters of such importance to charity alone. So please focus on targeting national research in this area of great public concern. Improving patient care Breast cancer was taken as a campaigning issue
by women, and led by the glorious radicals of the 1960’s. As a result of feminist campaigns, the care of breast cancer patients has been taken from paternalistic surgeons and into the realms of the multi-disciplinary teams, led by oncologists. Care in breast cancer has been transformed. This standard has not been applied to prostate cancer, where the cancer specialists unfortunately remain distanced by the surgeons, who fail to refer on to their colleagues. As a direct result, in a recent survey we found out that just 1 in seven men who would be considered for chemotherapy for prostate cancer receive treatment, denying these men additional time with their families. In a further survey that I carried out some time ago less than 50% of men with prostate cancer got referred on for radiotherapy to palliate pain, or to Macmillan services. So, we need help in applying the standard for breast cancer care to men with prostate cancer. Making treatment advances available. The survival time for of men with advanced prostate cancer has almost doubled over the last 20 years. This is due entirely to the introduction of new drugs for prostate cancer. But not all the available new drugs are given to men with prostate cancer, and this is for two reasons. The armies of the drug companies marched late into the battlefield of prostate cancer. Some time was spent in realising that there was a significant ‘market’ for prostate cancer drugs. The battle has been engaged and new drugs have been developed, but once developed not all the drugs that could have been given to men with prostate cancer in the UK have been allowed by NICE, on the basis of wonky cost calculations. This is because NICE uses an appraisal system that applies a universal model for judging cancer drugs that is not relevant to cancer. The subjective scoring system calculates cost as judged by the addition of a year of quality added life and is based on the cost of a drug given to 100% of patients for one year. Now, generally 40 – 50% of cancer patients will benefit from a new drug and take that drug for around 6 or 9 months. 50 – 60% stop the drug after a couple of months as it is not working. So the equation comes out of the back of bovines. The bizarre cost formulae championed by NICE and based on research in the 1950’s needs to be reformed. In summary You -- as our national representatives, have a vested interest in making things better for prostate cancer patients. It could be you, it could be, but there is a chance that it might not be you if you do something for prostate cancer
coping with prostate cancer
Targeted prostate biopsy gets cost-effective Exact Imaging’s breakthrough ExactVu™ micro-ultrasound system enables a 300% improvement in resolution over the current ultrasound systems. Urologists can now accurately visualise suspicious regions in the prostate and better target biopsies for better and more cost-effective prostate cancer detection
Randy AuCoin, President and CEO, Exact Imaging
rostate cancer is the most common cancer in Europe for males. In 2012, around 417,000 new cases of prostate cancer were diagnosed in Europe, and approximately 92,300 deaths were attributed to prostate cancer (1). The cost associated with detection and treatment of this disease is very significant to health care systems throughout Europe. Current standard of care Prostate cancer is diagnosed by a pathologist analysing tissue samples taken from a man’s prostate via ultrasound-guided biopsy. When a man is determined to have elevated risk factors or symptoms commonly associated with prostate cancer, a urologist orders a prostate biopsy procedure. During this routine procedure, between 10 and 14 separate tissue samples are collected and subsequently sent to pathology for analysis. Ultrasound is the standard of care worldwide for guiding prostate biopsies. Using a transrectal ultrasound probe, the prostate is imaged and the operator guides the biopsy needle to the various locations he or she would like to collect the tissue samples from. Unfortunately, the resolution on conventional ultrasound systems used for prostate biopsy procedures is inadequate to distinguish between cancerous tissue and benign tissue. As a result, prostate biopsies are collected systematically, simply following a needle placement and spacing protocol with the hope of hitting the cancer if it is present. This “blind biopsy” approach results in a 30%-40% false negative rate (missed cancer). During a recent section meeting for urological imaging (2) organized by the European Association of Urology (EAU), distinguished speaker Dr. Hashim Ahmed from University College London referred to the current standard for performing prostate biopsies as “rubbish.” Existing alternative In an attempt to overcome the lack of adequate resolution on conventional ultrasound systems, some larger institutions throughout Europe
and North America have been experimenting with adding MRI into the workflow for guiding prostate biopsies. This does not eliminate the need for the ultrasound-guided prostate biopsy procedure; rather it adds on a process called MRI/Ultrasound “fusion” whereby suspicious areas identified on MRI can be targeted with the hopes of missing fewer serious prostate cancers. There is a growing body of evidence that if an institution can successfully modify its workflow to add on an MRI procedure and can develop the expertise necessary to master the fusion approach, improved clinical outcomes can be obtained for the patient. Published clinical studies seem to be demonstrating that there are some improvements in clinical outcomes when the MRI/ US fusion workflow is implemented properly and the required techniques mastered. However, an active debate continues regarding the practicality of implementing this approach given the significant increase in total procedure cost, the steep learning curve to get improved results, the considerable change to the standard clinical workflow, and the increased procedure time, just to name a few of the issues. With significant downward cost pressure on healthcare systems worldwide, experts question the practicality of implementing such techniques that dramatically change clinical workflow and significantly increase overall procedure cost. Solution: Using much better ultrasound The lack of resolution on conventional ultrasound systems is the root-cause of the problem of not being able to visualise and distinguish suspicious tissue so that those areas can be “targeted” for biopsy. Exact Imaging has developed a high resolution micro-ultrasound system for urology that addresses the problem of inadequate ultrasound resolution. This micro-ultrasound system was originally commercialised for small animal imaging in the field of pre-clinical research, in which researchers study human disease models in mice and require much higher resolution due to the small structures they are imaging. This proven technology is the gold-standard for small animal ultrasound imaging with over 2,000 systems installed worldwide. Exact Imaging has adapted this revolutionary technology and taken it from mouse to man. The ExactVu™ micro-ultrasound
system offers a 300% increase in resolution and this allows for targeted prostate biopsies to be performed without requiring the add-on of MRI. A 2,000 patient randomized-controlled clinical trial is currently underway at five sites across North America. The trial should conclude in May 2016 and is expected to demonstrate that improved clinical outcomes are possible in an “ultrasound-only” prostate biopsy setting. Approval to market the ExactVu™ microultrasound system in Europe is expected in June 2016. Recommendation
A solution to a clinical problem is only a solution if the healthcare system can afford to implement it. Cost-effectiveness has several components including appropriate patient care, physician expertise required, availability of necessary imaging equipment, procedure cost, and procedure time. Conventional ultrasound is the standard of care for guiding prostate biopsies. It meets all measures of cost-effectiveness with only one exception: it has inadequate resolution. ExactVu™ solves the problem by providing targeted prostate biopsy capability in a cost effective manner within existing clinical work flow. The adoption of this technology will be an important step for dealing with Europe’s high incidence and prevalence of prostate cancer The article is authored by Randy AuCoin, President and CEO, Exact Imaging. References:: 1. Cancer Research UK, accessed at www. cancerresearchuk.org/health-professional/ cancer-statistics/statistics-by-cancer-type/ prostatecancer 2. ESUI 2015 (November 12, 2015: Barcelona)
Improving European healthcare with evidence-based information Prof. Dr. Nicolas Mottet
For almost 40 years, the European Association of Urology has addressed the most pressing concerns of urological diseases.
Prof. Dr. Nicolas Mottet and Prof. Dr. Hein Van Poppel -- on behalf of the EAU -- elaborate on how it strives to assist medical professionals and researchers in developing reliable patient information on 11 urological diseases in 16 European languages
rological diseases represent a collection of various symptoms and conditions, most of them predominantly related to age. Furthermore, with the rise in the elderly population within Europe, we expect an increase in urological problems. Among urological cancers, prostate cancer is the first malignancy in men, the third cause of death from cancer in men, and leading cause of health expenses.
needed. That’s why the European Association of Urology’s (EAU) Guidelines exist and are continuously developed.
Initially considered a simple disease, prostate cancer is now considered a very heterogeneous disease. This heterogeneity implies that its management can no longer be considered a “one size fits all.” It must be individualized and therefore becomes more complex, requiring a close collaboration of multiple specialists in addition to urologists, such as pathologists, radiologists, biologists, radiotherapists, and medical oncologists. On top of this, the individual patient demands, personal objectives, quality of life, priorities and individual life expectancy are also key decision drivers.
The EAU Guidelines cover all urological problems, including chapters on urological cancers (prostate, bladder, upper urinary tract, kidney, urethra, testis and penile) and chapters on non-oncological situations such as kidney and bladder stones, infections, lower urinary tract symptoms, pelvic pain, infertility, male sexual dysfunction, neuro-urology, paediatric urology, among others. They all share the same multidisciplinary approach, rules and methodologies and are regularly updated.
Major progress has been made, such as the recognition that 50% of the situations are almost indolent, while others are at risk of evolving in the following years, and a minority will have a rapid progression. The recent development of new technologies, new drugs and new approaches requires clarification between experimental and evidence-based data. The latter is the cornerstone of any decision. The amount of published information makes it an impossible challenge for any individual to be fully informed. The same applies for every urological disease. Most urologists take care of all urological situations with a mission to offer the highest possible level of care. To achieve this, help is
Urological Guidelines for clinical practice Guidelines must fulfil some criteria: they must be evidence-based, unbiased and independent; they must be up to date, multidisciplinary when different specialties are involved, and they must involve patients. The EAU Guidelines fulfil all these prerequisites.
An illustration: The prostate cancer guideline panel is composed of 6 urologists, 4 radiotherapists, 2 medical oncologists, 1 radiologist, 1 pathologist and 1 patient representative. The prostate cancer guidelines are now fully endorsed by the International Society of Geriatric Oncology (SIOG), the European Society of Uro-Radiology (ESUR) and the European Society of Radiation Oncology (ESTRO). They are implemented and updated annually, based on structured literature searches, and on systematic reviews (SR). Each SR represents almost one year’s work, including 1 senior member leading the work, 1 librarian, 1 methodologist, and 2 to 4 associates for data extraction. These SRs are the only way to perform an extensive impartial and unbiased summary, leading to practical guidance. The prostate cancer panel is running 5 SRs to be finalized between 2016 and 2017.
A new one devoted to long-term side-effects and quality of life of each treatment has just started, with a patient representative in the leading group. Each year new literature searches will be added. The EAU Guidelines represent a major effort of Europe’s urological and medical communities in order to improve the delivery of care. They are available for free from the EAU’s website (www.uroweb.org) and are published as detailed summaries in the EAU’s journal European Urology. The Guidelines are recognized as an important source of guidance for practicing urologists, and clinicians from bordering specialties, all around the world. They are often used as resource for national guidelines. A formalised endorsement by other associations was achieved in December 2015 for almost all 28 European Union member states, and 14 countries outside Europe including China, Russia, Indonesia, Australia and New Zealand among many others. Endorsement implies support or general approval of its content, acknowledging the value and quality of these documents. EAU Guidelines cannot replace the need for national guidelines. These often exist alongside the EAU Guidelines, adapted to some specific national situations. Educational activities The EAU Guidelines also form the basis of the European School of Urology (ESU). The ESU’s aim is to coordinate and organize all postgraduate teaching and education activities of the EAU at the highest possible level. These activities exist in various forms. The annual European Urology Residents Education Program (EUREP) is one of the ESU’s flagship teaching programmes: it lasts 1 week, and is devised for final-year urology residents. A wide variety of ESU Courses are scheduled during the Annual EAU Congress, at EAU Section
coping with prostate cancer
Patient Information Not only medical specialists require unbiased, evidence-based information. More and more patients are looking for information about their condition and possible treatments. As well-informed patients are better-equipped to talk about issues that worry them, the EAU develops patient information for several urological diseases. It provides reliable information on 11 urological diseases in 16 European languages, which takes into account the latest scientific evidence, expert recommendations, and the needs of patients. On prostate cancer, the patient information leaflets that have been produced, explain what needs to be understood concerning screening, early detection, diagnosis, different management modalities including active surveillance, surgery (open and robot), radiotherapy (external and brachytherapy), hormonal treatment, chemotherapy and novel treatments. This information is in line with the EAU Guidelines to guarantee consistency in content and quality throughout all of its translations and relevant to patients living in different countries. This truly European collaboration encourages a meaningful dialogue between the doctor and the patient, leading to better care. The confirmation of the EAU Guidelines’ impact on healthcare delivery is an ongoing process. It should hopefully confirm that all these major efforts from a multidisciplinary medical community are worth undertaking and reach its objectives: improving patients care by improving medical specialists’ knowledge Prof. Dr. Nicolas Mottet is Professor and Chairman of the Department of Urology at the CHU in SaintEtienne, France, and chairman of the EAU Prostate Cancer Guidelines Panel. Prof. Dr. Hein Van Poppel is Professor of Urology at the University Hospital in Leuven, Belgium, and is EAU Executive, responsible for Education.
Calling for a compulsory screening mechanism in UK By Gary Steele, M.B.E, Chairman, Leighton Hospital PCSG
rostate cancer is the most common cancer in men and is the biggest killer in men with cancer, second only to lung cancer. However, prostate cancer continues to have the lowest public awareness of all the major cancers in UK. The statistics surrounding this so called “silent-killer” are quite astounding. In the UK, only 8% of eligible men are tested for prostate cancer compared to over 60% across the rest of Europe and 28% of men seen for the first time by an oncologist are unable to be treated as the cancer is diagnosed at advanced stages where there is no treatment. Moreover, nearly 80% of all men diagnosed with prostate cancer don’t show any symptoms. Furthermore, as the government generally recommends screening only men over 50 years of age, it is no wonder the diagnosis and mortality rates in the UK from this type of cancer is considerably more than others in the so called modern countries with over 42,000 diagnosed and some 12,000 dying every year from this disease. A few years back, the Leighton Hospital Prostate Cancer Support Group joined forces with the Graham Fulford Trust and some other groups to arrange PSA (Prostate-Specific Antigen) blood testing for Early Detection Prostate Cancer in local and convenient locations. Over the years, we have tested some 50,000 men finding many cancers that could not have been found either due to men not visiting their GP’s or at instances where they have been refused to be tested or treated. We use the normal method of the venous draw to extract a small sample of blood using experienced and qualified phlebotomists. Under the careful direction of our urologists, the samples are taken to The Doctors Laboratory, Salford/London where the blood sample results are analysed and sent to our urologists to be posted on to the patients using the
Medical Detection Dogs
and Regional meetings, and during individual National Societies’ meetings. They are UEMS/ EACCME-accredited. In recent years, e-courses and webinars have also been introduced.
traffic light signal system - green for good, amber for borderline, and red for abnormal with information regarding next steps. The Laboratory also provides a further test on those samples at 1.4 or over by using “free-tototal” which provides further accuracy to the outcome. All men who are tested and treated have been recorded, thereby providing us with the largest database in Europe regarding age, family history and PSA related results for prostate cancer providing statistics in assisting in diagnosing prostate cancer. Currently, we work in association with the charity Medical Detection Dogs where we train dogs to “sniff-out” prostate cancer from urine samples taken from those men attending our testing events. Soon after, the blood and urine samples are laboratory compared using the Medical Detection Dogs based in Milton Keynes, which are able to provide second line screening for cancers that are currently very difficult to diagnose reliably, such as prostate cancer. We are quite excited with this innovative training, which is currently showing a 92% success rate in finding the comparison between abnormal samples and detecting prostate cancer in urine samples. These results are truly spectacular. All cancers are required to be diagnosed sufficiently early if treatment should to be successful and prostate cancer appears to be the most difficult as patients often show no early symptoms. Therefore, we believe a compulsory “screening” programme should be considered which we are sure would reduce mortality rates in the UK and Europe. We know screening for men for prostate cancer is a taboo issue in the UK, however, the recent screening trials completed across Europe showed a considerable and significant fall in mortality in some instances as much as 42%, therefore if screening was introduced in the UK some 5000 men’s lives could be saved annually
From therapeutic nihilism to diversity in treatment options - what can be added? Despite extensive use of radical treatments, such as surgery and radiotherapy, and constant technical innovations, mortality rates remain high. Prof Bertand Tombal, Consultant Urologist, Brussels Saint-Luc University Hospital lists out what’s missing in the battle against prostate cancer
ccording to the International Agency for Research on Cancer (IARC), prostate cancer is the second most common cancer in men. An estimated 420,000 men were diagnosed with prostate cancer in Europe in 2012, accounting for 15% of the cancers diagnosed in men. Despite extensive use of radical treatments, i.e. surgery and radiotherapy, and constant technical innovations, mortality rates remain high. IARC reported 101,000 deaths in Europe in 2012. Patients presenting upfront with disseminated metastases still uniformly die from the disease after a few years. Radical treatments fail to cure up to 30% of the patients diagnosed with a high-risk, undifferentiated, localized or locally advance disease. Ultimately most of them develop metastases and die from the disease. Castration-resistant prostate cancer, an embarrassment of riches? Since the seminal work of Charles Huggins, 1966 Nobel Prize’s laureate, suppressing testosterone, the male hormone, is the reference treatment for advanced metastatic prostate cancer. Hormone therapy induces dramatic responses but of short duration. In most cases, the tumour progresses in a stage of resistance. Complications, especially skeletal, occur rapidly and the issue is usually fatal within two to four years. In 2004, two drugs brought the first hope of cure. Docetaxel, a widely used chemotherapy, extends overall survival by three months and zoledronic acid, a bone targeting agent, delays the onset of
bone complications by several months. Many patients, however, will never receive chemotherapy, being already in their late seventies or eighties when they develop CRPC. Hopefully, four new drugs have entered the market since 2010. Enzalutamide and abiraterone are new hormones that increase overall survival and preserve quality of life in metastatic CRPC patients. Radium 223 is an injectable radionuclide that directly targets bone metastases, delays bone complications, and increase overall survival. Cabazitaxel is a taxane chemotherapy that is active in docetaxelresistant patients. Finally, denosumab is a monoclonal antibody with slightly improved efficacy over zoledronic acid in preventing skeletal complications. What seems an embarrassment of choices on paper is in fact a conundrum for the physicians. Each of these drugs reduces the risk of death by 20 to 30%. This looks appreciable at first sight, but, because the trials have been conducted at an advanced stage of progression, it translates into a survival benefit of merely 3 to 4 months. The late-stage disease niche was chosen because the purpose of the trials was to quickly register, and ultimately market, the new drugs. In addition, the benefit of these drugs is not synergic. For example, abiraterone and enzalutamide modes of action are similar resulting in “cross-resistance”. The patient progressing on a drug is very unlikely to benefit from the other. Finally, these drugs have not been tested against each other’s and physicians are left with no clue about the optimal timing for starting and stopping them and about the best sequence or combination of drugs. What’s missing in the battle against prostate
cancer? Three factors, at least, are keys. First of all, we need massive investment in large international academic platforms that independently study early use of drugs, sequence and combinations. Stampede and Chaarted are academic trials that have evaluated the benefit of docetaxel chemotherapy immediately at diagnosis in metastatic patients and not when the cancer was already resistant to castration. At that earlier stage, docetaxel confers an unprecedented increase in overall survival of 21 months; seven times longer than the benefit seen at the time of resistance to castration. The benefit is impressive for the patient, practice changing, for a cost and a toxicity that is similar to a later use of the drug. Because these studies span over a decade, they challenge the conventional framework of industry’s patent protection. Docetaxel is generic now and the return for Sanofi, the original patent owner of docetaxel, is now negligible. This creates an obvious imbalance between industry sponsored studies proving that a drugs work and academic studies proving when a drug is the most efficient from an individual and a societal perspective. That is why new private-public-academic partnerships must be developed and conditional patent prolonging scenarios must be designed. This is crucial to support trial in cancer with long survival. We need to fill the “translation gap” to understand who dies from cancer and what treatment is most likely to prevent this from happening. In the last decade, we have learned that prostate cancer is an extremely heterogeneous disease. Scientists understand much better the genetic and physiological determinants of this heterogeneity but very
coping with prostate cancer
little of that knowledge is used by clinicians. Patients received broadly validated treatments merely taking into account their individual genetic characteristics. Achieving this will prove crucial in two situations. Firstly, to better identify the 30% of patients with high-risk localized cancer that die from the disease. It is a prerequisite to an early testing of the new drugs in that population. Secondly, to better select patients receiving expansive or toxic drugs to optimize the benefit and cost-efficiency and reduce inappropriate prescriptions. International precision medicine platforms are key initiatives to achieve that goal.
We need to normalize the quality of the delivery of care and include patients reported outcome in the treatment equations. Outside the strict framework of clinical trial, there is no pressure or incentive on clinicians to collect, analyse and report their results. Patients coping with the disease have no reference frame to decide where and how to be treated and what exactly they can expect from treatment. Healthcare providers, including governments, are mostly paying for prescriptions with no or little clue of performance. Considering the gigantic investment that will have to be made to treat cancer, is it still acceptable? The first
and more important step is to secure robust acquisition of quality of indicators by every physician. Initiative conducted by ICHOM needs to be applauded since it provides the first set of consensually accepted indicators ready to be deployed. Proven that we fulfil these three challenges the future of prostate cancer is bright Prof Tombal is Chairman, Division of Urology, Cliniques universitaires Saint Luc, Brussels, Belgium and Chairman Clinical Trial Division, European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium.
Symptoms, treatment, follow-up and everything you need to know about PCa By Dr. Laurent Fossion, M.D., Urologist, FeBU
xact causes for prostate cancer are still unknown, but dietary habits (Western feeding pattern) and genetic mutations seem to be related to the development of prostate cancer (PCa). In patients with two first line relatives ( <55 year) in their family with PCa, screening is advised. Screening for PCa can reduce PCa mortality (cfr. infra ERSPC-study) Diagnosis and care Serum markers, mainly PSA, still play the most important role in diagnosing PCa disease. Physical digital rectal examination (DRE), ultrasound guided prostate biopsies and multiparametric MRI (mpMRI) are the main tools for local evaluation of prostate cancer. The ERSPC-study showed 27% reduction in prostate cancer mortality among those men who participated in screening (PSAmeasurement and DRE). Screening consists of a single PSA-test at the age of 40 years. If PSA < 1 ug/L, lifetime chance of development of PCa is minimal. For older patients, PSAmeasurement every 2-5 years till the age of 70 years is advised. In men with normal findings on mpMRI, the risk of clinically significant PCa is very low. mpMRI has a detection rate of 44-87% of clinically significant disease (that has influence on life expectancy). It can thus avoid over treatment. Probably only 30% of the patients will need an MRI to improve sensitivity and specificity in PCa screening. The quality of mpMRI interpretation remains very important and should be centralised or supervised by experienced cancer centers (quality control). In this stage the interdisciplinary interface between the oncologic trained urologist, the uro-radiologist and uro-pathologist plays an important role.
Treatment The goal of PCa treatment is to cure patients from their (significant) prostate cancer or to delay/postpone metastases and their impact on health and survival. Active surveillance should be offered to all low risk PCa patients. This will help us to reduce over treatment and the accompanying costs and consequences for the patient. Focal treatment is still under investigation but can be seen an alternative for surgery or external radiotherapy for localised (intermediate risk) disease, but it still has the chance to miss lymph node involvement. Localised, significant PCa disease can be cured by open or minimal invasive surgery (laparoscopic or robotic assisted radical prostatectomy (RP)) or by radiation therapy (RT); the latter in combination with androgen deprivation hormonal treatment (ADT) for 2-3 years. The advantage of the surgical RP approach lies in the ability to perform both the lymph node staging and the treatment with curative intention in one operation and does not necessitate ADT. The rationality for lymph node dissection remains adequate lymph node / disease staging, but the impact on survival is unknown. Risk prediction tools help us to predict the chance of lymph node involvement and confirm the need for certain intermediate and all high risk PCa patients. The ideal number of lymph nodes removed is yet to be determined, but lies around 18-20 lymph nodes. Overall lymph node involvement varies from 1-17%. Quality control and definition of postoperative success is known as pentafecta (free surgical margins, no peri-and postoperative complications, continence, potency, survival). These quality parameters are measured in most
European cancer centers and aid to optimise the quality of care. So it is clear that the surgeon does matter. Recently even locally advanced prostate cancer seem to benefit from surgical treatment (RP + lymph node dissection), but often necessitate multimodal treatment, using (salvage) radiotherapy to be able to cure these patients. Metastatic disease treatments consist of ADT hormonal treatment to suppress tumour progression and reduce the consequences of metastases. Focal radiotherapy (stereotactic RT) can help to control symptomatic bone metastasis. New insights in early adoption of chemotherapy in aggressive PCa show promising results on prolonged survival. Follow-up Standard follow up after local treatment with curative intention consists of 5 year follow up to evaluate oncologic outcome (immeasurable PSA) and treat functional and psychological consequences of local treatment. In metastatic disease or in case of biochemical recurrence (measurable PSA suiting remaining PCa) the follow-up is at least 10 years to lifetime long. Cost effectiveness Costs in PCa health care are caused by investigational aspects (PSA-test, biopsies, mpMRI, bone scan), treatment costs (operation or radiation therapy + lymph node operation + ADT) and the costs for the purchase of e.g. the operation robot (in contrast to laparoscopic and open surgery) or radiation device and finally the follow up costs and treatment costs for complications and consequences of treatment (early costs after surgery and late costs after radiation therapy)
Innovative therapies must be made accessible to all
Access pathways must foster innovation to address unmet needs, align evidence requirements as treatment options move earlier in the disease course, and remove barriers to access for patients. Jane Griffiths, Group Chairman, Janssen Europe, Middle East and Africa, Janssen Pharmaceutical Companies of Johnson & Johnson writes on enhancing patient access to innovative therapies
he three million European citizens living with prostate cancer stand to benefit from significant improvements in health as a result of new, targeted medicines. As these innovative treatments become available, access pathways must adjust accordingly by fostering innovation to address unmet needs. Evidence requirements must be aligned as treatment options move earlier in the disease course and barriers to access for patients removed when the value of new interventions is clear. Innovation must be fostered to meet unmet medical needs in prostate cancer Innovative, targeted therapies are needed for castration-resistant prostate cancer (CRPC). Research into the genomic alterations present in CRPC has revealed new drug targets as well as novel biomarkers, which present major opportunities for molecular targeting of patient subgroups. New agents have the potential to be effective earlier in the course of disease, slow disease progression and improve health-related quality of life (HRQoL). Maintaining the pace of pharmaceutical research will require parallel innovation in the approach to regulation and appraisal. Recommendations: • Promote early, transparent dialogue among decision-makers and industry throughout the clinical development and life-cycle of medicines, to better identify appropriate regulatory and appraisal requirements. • Encourage the EU Commission to allocate more funds for research through investment in research centres, advanced databases and
patients’ data registries. Patient access is increasingly fragmented in Europe Most countries have a formal Health Technology Appraisal (HTA) process to evaluate the clinical (and sometimes cost-) effectiveness and the broader impact of a health technology on patients and the healthcare system. The evaluation is often used to inform pricing and reimbursement decisions and in some countries, to provide prescribing guidance. There is currently a climate where cost is affecting the up-take of new medications. Countries are adding additional hurdles beyond national HTA at the regional and hospital levels, which focus on cost and price. These processes lack transparency, include limited dialogue with industry, and the patient perspective is not explicitly taken into account. Some processes restrict prescribers to a limited use of new therapies and limit the choice of medicines. These additional processes delay or deny access to treatments that would bring the most value to patients and society. Recommendations: • If a national HTA assessment considers a medicine value for money, it should be made available to appropriate patients without additional hurdles or unnecessary delays. • HTA evaluations should be exclusively based on evidence, including real-world evidence and outcomes of particular relevance to patients. • Collaboration should be encouraged between the pharmaceutical industry, patient groups, physicians, payers, and representatives of the EMA and the EU Health Commission to
develop standardised tools for HTA assessment Surrogate endpoints and patient-reported outcomes are becoming increasingly important Overall survival (OS) remains the gold standard measure of benefit for regulators. This is most useful in very late-stage disease, as the data will not be affected by patients switching to other effective treatments. As we become better at understanding and diagnosing prostate cancer, and are able to intervene earlier in the course of disease, it may not be realistic to have OS as the gold standard. In pre-metastatic or even local disease, where survival could be up to 10 years, other clinically relevant outcomes, such as overall response rate, progression-free survival, metastasis-free survival and HRQoL should be acknowledged as they offer feasible options to measure clinical benefit. Recommendations: • HTA evaluations should include clinically relevant surrogate endpoints that can address a broad definition of value of early disease stages relevant to patients. • Where OS data are required, HTA should accept adjustments for patients switching drug therapies, and acknowledge the uncertainty of limited long-term data at launch in the evaluation. The patient voice is not always being heard Patients live with the consequences of their condition every day, and have their own individual expectations from treatment. Janssen’s recent collaboration with European prostate cancer patient associations on the Prostate Cancer: Living, not Just Surviving survey highlighted the importance of HRQoL issues, with 66% of patients concerned about fatigue and 85% reporting intimacy problems with their partner. HTA and access discussions should therefore put the patient at the centre of their processes. At present, the degree of patient involvement in national HTA evaluation processes varies by country. For example, patients are not involved formally in France and Italy, whereas England and Scotland have formal processes for patient input. Well-informed patients are vital to this process and Janssen is supporting the efforts of EUPATI to empower patients to engage more effectively in the development and approval of new treatments. Recommendations: Prostate cancer patient representatives should be included in all HTA appraisal processes to provide perspectives on the burden of disease and treatment outcomes. Janssen is including patient perspectives in clinical studies and measuring patient outcome in real life. This patient-centric data should be taken into account in HTA evaluation
coping with prostate cancer
Active surveillance a great alternative to curative therapies The â€˜Active surveillanceâ€™ protocol has become an alternative to curative therapy for prostate cancer that is unlikely to be biologically or clinically significant. However, Dr Riccardo Valdagni, Director, Radiation Oncology at European School of Oncology says men who choose to be monitored under Active Surveillance need to be thoroughly informed of their disease and the observational program
rostate cancer is the most common malignancy among men, with estimated 1,446,483 new cases and 715,257 deaths in 2012. The number of diagnoses has increased since the introduction of PSA as a routine exam in the early Nineties. The good thing is that up to 50% of the new prostate cancers detected can be considered clinically insignificant or indolent. This is a relatively new concept in oncology and means that these very well localised, small and non aggressive tumors, which are diagnosed with a biopsy following PSA rises, would not cause symptoms and/or cause death during oneâ€™s life. Despite this non aggressive behaviour, most of these tumors are still treated with curative standard therapies, i.e. prostatectomy, external radiotherapy and brachytherapy, equally effective treatment options, burdened though by potentially severe side effects. At the same time, we should consider the other side of the coin: there is no way to entirely distinguish upfront, before as well as after the biopsy, non aggressive, clinically insignificant, indolent tumors from aggressive, potentially lethal cancers that need to be treated immediately. In this context of overdiagnosis (cases of early prostate cancer diagnosed following a suspicious PSA, in absence of symptoms) and overtreatment (cases of prostate cancer treated despite their non aggressive and potentially non lethal behavior) active surveillance should be routinely proposed in alternative to radical treatment to very selected men with favourable disease characteristics (in general, PSA < 10 ng/mL, limited disease burden, Gleason score 3+3). Active surveillance is an observational program which monitors the disease by PSA (usually every 3 months), digital rectal examination (usually every 3-6 months) and follow up biopsy (the frequency of the procedures differs according to protocols, with the first rebiopsy usually after 12 months since diagnosis). An
extra biopsy could be prescribed if the PSA Doubling Time, which evaluates the PSA trend over time, is less than 10 years and causes worries. Another exam that has recently gained a new emerging role is the multiparametric Magnetic Resonance Imaging, a very sophisticated procedure which is able to identify areas of more aggressive disease and thus be helpful in addressing and targeting biopsy. Considering the slow evolution of low and very low risk prostate tumors and the possibility of maintaining the chances of curability if treatment becomes necessary, active surveillance permits to avoid or delay treatment and therapy induced side effects until the eventual change of the tumor initial characteristics. It is therefore clear that follow up plays a crucial role since it enables us to monitor the tumor behaviour and potentially detect the more aggressive forms, which may benefit from treatment. It is for this reason that active surveillance protocols need to have well defined criteria for inclusion, follow up and discontinuation. This helps in the selection and monitoring of patients, ready to switch to treatment if the tumor behavior changes. Reasons to discontinue the active surveillance program are usually related to the reclassification of the disease at the rebiopsy. Data coming from the pathologic results shows the upsizing, that is the increase in the number of positive cores over the limit stated in the protocol, and the upgrading, that is the change of the Gleason score, i.e higher than 3+3. Reclassification at biopsy more often happens in the first two years of active surveillance. If this is the case, it most likely does not mean the initially diagnosed tumor is evolved in a more aggressive form, rather the second biopsy enabled to better sample the prostate. Until a few years ago another cause to discontinue active surveillance was PSA Doubling Time if less than 3 years. Since active surveillance studies showed that PSA Doubling Time is not reliable enough to predict an
aggressive tumor, it is now considered a warning to be paid attention to, which might induce the prescription of an extra biopsy or a multiparametric Magnetic Resonance Imaging when available, rather than the immediate discontinuation of the active surveillance program. Although active surveillance is included as an option for low and very low risk prostate cancer in the most important international guidelines, further research is urgently needed to better understand the nature of the tumor and trying to take benefit from non-invasive indicators of its progression or reclassification. Research is currently focused on finding genetic signatures of positive biopsy and adjacent normal tissue and on studying biomolecular markers possibly present in urine and blood (the so called liquid biopsy). Until then, even if AS is part of the most important international guidelines, we believe that active surveillance should be proposed within protocols authorized by the institutional Ethical Committee. What is more, men with prostate cancer who choose to be monitored in active surveillance protocols need to be thoroughly informed of their disease and the observational program. It is important that these patients understand that active surveillance is proposed as an alternative to curative therapies and should be considered in the same way as a treatment. Men need to accept and be compliant to the follow up program, which includes periodic biopsies, a procedure with potential side effects they have to be made aware of. After being well informed on active surveillance, men with prostate cancer should sign an informed consent and thus share with their clinicians the responsibility of being on surveillance
The role of MRI in prostate cancer expands
The role of imaging techniques such as multiparametric MRI (mpMRI) in prostate cancer is set to expand in the coming years, particularly in cases where technology is more integrated with treatment. Prof Jelle Barentsz, Professor of Radiology, Radboud Prostate MR-Reference Center discusses the details
he main disadvantages of the current diagnostic pathway in men with an elevated risk of prostate cancer (PCa) are that: (a) systematic transrectal ultrasound (TRUS) prostate biopsy (PB) misses a substantial proportion (20%) of significant PCa because of inherent systematic sampling errors, especially in the anterior prostate [1,2]; (b) misclassifies pathologic status including Gleason score (GS) and tumour stage ; and (c) detects a high proportion of men with disease that is unlikely to be harmful (clinically insignificant), with subsequently overtreatments resulting in unintended harm . The latter was the main reason for the U.S. Preventive Services Task Force recommendation against prostate-specific antigen- based screening for prostate cancer in 2012 . Can multi-parametric MRI solve these problems? There is increasing evidence, such as two Level 1a systematic reviews [6,7], a Level 1a prospective clinical randomised trial , and multiple Level 1b studies [9,10], that multi-parametric magnetic resonance imaging (mpMRI) is the best method of visualising primary significant PCa. It is, therefore, widely accepted that mpMRI has the performance characteristics to help manage men with suspected or proven PCa [11,12]. The clinical utility in terms of the ability to ‘‘rule in’’ and ‘‘rule out’’ the presence of significant disease depends on using the mpMRI approach, image quality, reading system, and reporter expertise [13–16]. The cancer detection ability of mpMRI is dependent on the anatomic location, tumour volume, and aggressiveness (GS) of the underlying cancer . mpMRI detected lesions
are not always significant malignant lesions ; false positive cancer/non-cancer cases do occur, thus adequate biopsy sampling is mandated for each lesion detected . What type of cancers does mpMRI-TB detect? Literature indicates an improved ability of mpMRI-PB is to detect clinically significant cancers. A recent systematic review showed that the detection rate of clinical significant cancer is higher (44–87%) than the rates reported for TRUS-PB , depending on the definition of clinical significance used for targeted biopsy; this ability applies equally to biopsy naıve and men with prior negative biopsies. Histologic grades on mpMRI-TB show high concordance (88%) with final pathology after prostatectomy, which is a sharp contrast to TRUS-PB (55% concordance rate) . Does mpMRI-PB systematic miss clinically significant disease? The key questions are: (1) what proportion of men with negative mpMRI harbour cancers that would require radical therapy if detected; and (2) what proportion of patients with significant disease would be detected by an additional backup TRUS-PB? The reported negative predictive value (NPV) of mpMRIPB for significant disease has been reported to be high: 63-98% . The central issue is the balance between benefits and limitations of mpMRI- targeted biopsy (TB) when used alone compared with the strategy of combined mpMRI-TB with backup TRUS-PB in men with positive mpMRI findings. This was recently addressed in a very large prospective trial . In 1003 men, there were additional
cancers detected when mpMRI-TB was combined with TRUS-PB. However, of the 103 additional cancers detected, the majority were low risk (83% low risk; 5% high risk). Importantly, 200 combined biopsies yielded only one additional high-risk cancer, but overdiagnosed 17 low risk cancers. Also, there was no change in risk stratification in the majority of patients (857 patients; 85%), with only 19 men (2%) converting from no-cancer or low risk disease to intermediate or high risk with the combined approach. Taken together, these and other data strongly argue against the strategy of combining mpMRI-PB with systematic TRUS-TB in order to improve biopsy yields. Is there a performance difference of mpMRITB in biopsy naive patients compared with those with previous negative TRUS-PB? In previous negative biopsy patients, mpMRIPB greatly increased detection rates (+54%) of significant cancers and markedly reduced (-49% and -18% respectively) insignificant cancers detection, rendering the mpMRI-TB approach clinically effective. Thus both the European Association of Urology 2015 and the UK National Institute of Clinical and Care Excellence 2014 guidelines recommend mpMRI before repeat TRUS biopsy. UK National Institute of Clinical and Care Excellence 2014 additionally recommends against a second biopsy if mpMRI is negative, unless high-risk features are present . Challenges To enhance interdisciplinary communications between radiologists and referring clinicians, it is essential that uniform, understandable terminology and content of radiology reports be used. Reports should include assessment categories of suspicion for clinically significant disease to facilitate the use of targeted biopsy. The Prostate Imaging Reporting and Data System (PI-RADS) of the European Society of Urogenital Radiology (ESUR) has been widely accepted and validated . A new PI-RADS version 2 was recently adopted by the American College of Radiology and ESUR, but has yet to be validated [20,21]. To incorporate mpMRI findings using the PI-RADS system with biopsy strategies new pathways should be developed . Training and quality controls Furthermore, to achieve and maintain good mpMRI diagnostic performance, adequate training, supervision, and quality-control of the acquisition of the images, the PI-RADS assessment, and the targeted biopsy procedure are needed. This is particularly true when complex image registration procedures are needed to enable small lesions to be sampled. Importantly, histology feedback is required with continuous audit checks within the multi disciplinary care teams. An important consideration for these teams is, what to do
coping with prostate cancer
when a negative biopsy is obtained from a highly suspicious region on imaging. Extensive training programs by Specialised Prostate MRI Centres must be developed in order to fulfil the rapidly increasing demand of mpMRI. These Specialised Centres will train and certify multiple Diagnostic Centres of Excellence throughout Europe, where diagnosis of prostate cancer is optimized. To ensure continuous high quality, the training and certification should be followed by a quality control program. In this way, a European prostate diagnostic network of Specialised Prostate MRI Centres (for training and QC) and Diagnostic Centres of Excellence (to provide best quality care) will be created. The potential advantages of such a prostate network are: a) better quality through double reading and inter-collegial consultation, b) faster implementation of newly validated techniques, c) will allow sharing knowledge, and d) create large scientific databases to speed up the validation process. For double reading of prostate mpMRI already tools are available and in some places implemented, being internet connected PI-RADS workstations. Costs The upfront cost per cancer diagnosed is greater using mpMRI-PB methods, in part because of the need for capacity building and tooling up. This may be counterbalanced by changes in the risk stratification of diagnosed patients towards those requiring radical treatments. Modelling studies in the Netherlands and the United Kingdom suggested that an mpMRI-PB strategy can be cost-effective while maintaining the benefits of reduced overdiagnosis and overtreatment together, with improvements in quality of life [23,24]. To get health service provider buy-in, the therapeutic consequences of mpMRI-PB also need to be considered . Conclusions mpMRI-PB changes the risk stratification of men diagnosed with prostate cancer towards improved detection of men with cancers requiring radical treatments. To realise the clinical benefits of mpMRI-PB without overwhelming current resources, appropriate patient selection and investments in diagnostic and communication tools are needed. Imaging interpretation should be aligned with clinical management plans. Effective communication of imaging findings and improved urologic understanding of imaging uncertainties will improve the outcomes for men with suspected prostate cancer. To meet the increasing demand of mpMRI a prostate network of Specialised Prostate MR Centers for training and QC, and Diagnostic Centers of Excellence to provide optimal care should be established as soon as possible * This paper is based on Barentsz et al  and Padhani et al .
Prof Jelle Barentsz, Professor of Radiology
 Djavan B, Ravery V, Zlott A, et al. Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol 2001;166:1679–83.  Guichard G, Larre´ S, Gallina A, et al. Extended 21-sample needle biopsy protocol for diagnosis of prostate cancer in 1000 consecutive patients. Eur Urol 2007;52:430–5.  Hambrock T, Hoeks C, Hulsbergen-van de Kaa C, et al. Prospective assessment of prostate cancer aggressiveness using 3-T diffusion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. Eur Urol 2012;61:177–84.  Bul M, van den Bergh RC, Zhu X, et al. Outcomes of initially expectantly manged patients with low or intermediate risk screen- detected localized prostate cancer. BJU Int 2012;110:1672–7.  Moyer V. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157: 120–34.  Schoots IG, Roobol MJ, Nieboer D, et al. Magnetic resonance imaging– targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultra- soundguided biopsy: A systematic review and meta-analysis. Eur Urol 2015. http://dx.doi.org/10.1016/j. eururo.2014.11.037  Futterer JJ, Briganti A, De Visschere P, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic reso-nance imaging?. A systematic review of the literature. Eur Urol 2015. http://dx.doi.org/10.1016/j. eururo.2015.01.013  Panebianco V, Barchetti F, Sciarra A, et al. Multiparametric MRI vs. standard care in men being evaluated for prostate cancer: A ran-domised study. Urol Oncol 2015;33, 17.e1–7.  Siddiqui MM, Rais-Bahrami S, Baris Turkbey B, et al. Comparison of MR/Ultrasound Fusion–Guided Biopsy With Ultrasound-Guided Biopsy for the Diagnosis of Prostate Cancer. JAMA 2015;313: 390–7.  Pokorny MR, de Rooij M, Duncan E, et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by trans-rectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MRguided biopsy in men without pre-vious prostate biopsies. Eur Urol 2014;66:22–9.  National Institute for Health and Care Excellence 2014 recom- mendations. http://www.nice.org.uk/guidance/cg175/ chapter/ 1-recommendations  European Association of Urology 2015 Guidelines for prostate cancer. http://uroweb.org/wp-content/uploads/09Prostate-Cancer_ LR.pdf  Vache T, Bratan F, Mege-Lechevallier F, et al. Characterization of prostate lesions as benign or malignant at multiparametric MR imaging: comparison of three scoring systems in patients treated with radical prostatectomy. Radiology 2014;272:446–55.  Gaziev G, Wadhwa K, Barret T, et al. Defining the learning curve for mutliparametric MRI of the prostate using MRI-TRUS fusion-guided transperineal prostate biopsies as a validation tool. BJU Int 2015. http://dx.doi.org/10.1111/ bju.12892,  Muller BG, Shih JH, Sankineni S, et al. Prostate cancer: interobserver agreement and accuracy with the revised prostate imaging report-ing and data system at mp MRI. Radiology 2015. http://dx.doi.org/ 10.1148/radiol.2015142818, In press.
 De Rooij M, Hamoen EHJ, Futterer JJ, et al. AJR. Accuracy of multi-parametric MRI for prostate cancer detection: a Meta-Analysis. AJR 2014;202:343–51.  Bour L, Schull A, Delongchamps NB, et al. Multiparametric MRI. features of granulomatous prostatitis and tubercular prostate ab-scess. Diagn Interv Imaging 2013;94:84–90.  Willis SR, Ahmed HU, Moore CM, et al. Multiparametric MRI followed by targeted prostate biopsy for men with suspected prostate cancer: a clinical decision analysis. BMJ Open 2015. http://dx.doi.org/10.1136/ bmjopen-2014-004895, In press.  Barentsz JO, Richenberg J, Clements R, et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012;22:746–57.  Barentsz JO, Weinreb, Verma S, et al. Synopsis of the PI-RADS v2 Guidelines for Multiparametric Prostate Magnetic Resonance Imaging and Recommendations for Use. European Urology 2016;69:41-9.  Weinreb J, Barentsz JO, Choyke PL. PI-RADS Prostate Imaging- Reporting and Data System: 2015 version 2. European Urology 2016;69:16-40.  Padhani AW, Petralia G, Sanguedolce F. Magnetic Resonance Imaging Before Prostate Biopsy: Time to Talk. European Urology 2016;69:1-3.  De Rooij M, Crienen SJ, Witjes JA, et al. Costeffectiveness of magnetic resonance (MR) imaging and MR-guided targeted biopsy versus systematic transrectal ultrasound–guided biopsy in diag-nosing prostate cancer: A modelling study from a health care perspective. Eur Urol 2014;66:430–6.  Mowatt G, Scotland G, Boachie C, et al. The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation. Health Technol Assess 2013; 17:vii–xix, 1–281.  Willis SR, Ahmed HU, Moore CM, et al. Multiparametric MRI followed by targeted prostate biopsy for men with suspected prostate cancer: a clinical decision analysis. BMJ Open 2014;4: e004895.
Towards a paradigm shift in diagnosis and management Over the past years, there has been a fundamental change in the way prostate cancer has been diagnosed and treated, with patients having a greater variety of options to choose from. Prof
Van Velthoven, Head of Urology,
he last few decades were marked by a widespread use of PSA-based prostate cancer screening and hence by an exponential rise in the number of prostate biopsies, in terms of patients and of biopsies per patient. Some of these biopsies were unnecessarily performed while others missed significant prostate cancers. In addition, more men with low-risk prostate cancer were diagnosed and some were thus unnecessarily treated. The limited specificity of PSA and the low detection rate of prostate cancer on TRUS-guided biopsy generated much of the controversy existing about prostate cancer screening. Furthermore, the poor sampling of cancers under 2D TRUS and the underestimation of Gleason score widely opened the door for the development of more accurate strategies for the diagnosis of prostate cancer. In this context, we had already reported, in a previous study of biopsy-na誰ve men, higher detection rate using the 3D system of Koelis Urostation速 without MRI fusion compared to standard protocol (50% vs. 33%, p < 0.05) ) (1). Our results reflected a wider distribution of prostate cores inside the prostate and thus better sampling. Afterwards, we integrated MRI-targeted biopsy using the same system into our practice. This yielded an overall cancer detection rate of 62.7%, which is higher than most of the studies reporting on standard biopsy (2). In addition, in our study, TAR protocol improved prostate cancer detection rate compared to STD protocol and
Institut Jules Bordet, says the trend is set to continue and the future appears even brighter, particularly in molecular and genetic understandings of tumors
demonstrated higher detection rate of clinically significant disease with fewer tissue samples removed from lesions. In addition, we have used a combined localisation strategy based on a complete match between multiparametric MRI and transrectal ultrasound (TRUS) guided systematic biopsy to assess feasibility, safety, and short-to-mediumterm oncological and functional outcomes of hemiablation HIFU. Results were promising as hemi-ablation HIFU of an entire lobe, delivered with the intention to treat, was a feasible and safe procedure.(3) Functional and oncological outcomes were also encouraging at 3-years of follow up as demonstrated in our recently published updated series.(4) This is a timely issue given the recent concerns about the quality of life of prostate cancer survivors. The principal rationale of such an approach is harm reduction without compromising cancer control: early self-resolving LUTS were the most common complications but no rectal toxicities were reported and the strategy was well tolerated in the genitourinary functional domains. The procedure can also be delivered in an ambulatory care setting. This treatment strategy was associated with a good mediumterm cancer control in well-selected patients (unilateral low- to Intermediate-risk prostate cancer). Furthermore, patients with bilateral significant prostate cancer can also be safely treated by whole gland ablation with good outcomes (5). In our match cohort analysis, functional and oncologic outcomes were similar
between patients treated by brachytherapy and those offered whole gland HIFU (6). However, the earlier decrease of PSA in the HIFU group compared to the brachytherapy group allowed better stratification of responders. In parallel, recent developments of molecular and clinical imaging with better specificity and sensitivity than anatomic imaging provided clinicians with the opportunity to detect lymphatic and/or haematogenous prostatic metastases at an earlier point in the disease progression, resulting in a treatment window for what was called oligo-metastatic disease(7). Since then, a paradigm shift toward more aggressive local control of primary tumor and/ or small number of metastatic lesions has gained interest in the oncologic centres of excellence. In our institution, we have implemented such an approach based on the most accurate metabolic imaging for prostate cancer that is PSMA- PET. In our experience, inherited from our routine practice of large cohorts of robot assisted laparoscopic prostatectomy for organ confined prostate cancer, radical prostatectomy remains safe, feasible and offers good local control in well-selected oligometastatic patients. Apart from the debatable oncologic effect of local control - at present the primary endpoint was to delay ADT - the main advantage is the symptomatic locoregional improvement. Several complications encountered in the late stages of metastatic prostate cancer could be avoided. This could
coping with prostate cancer
translate into an improvement in the quality of life of many patients. Actually, one should bear in mind that treating the primary tumor in such patients remains outside of all urologic guidelines and should be preferably offered under the umbrella of clinical trials. Of note, some of the patients already treated with primary radiation therapy are accurately diagnosed with PSMA-PET showing an isolated organ confined recurrence. In the same way, these patients are offered a curative treatment instead of palliative ADT, a common mistake in the current practice of urology. These patients were treated by salvage whole gland HIFU or hemiablation according to the results of MRI and MRI targeted biopsies. Our
results with both strategies are encouraging, keeping in mind the morbidity of salvage radical prostatectomy in this setting.
3. van Velthoven et al., Prostate Cancer 2014
Finally, we are witnessing at the moment, a paradigm shift in the diagnosis and management of prostate cancer. The future appears even brighter when we see the enormous efforts and advances in molecular and genetic understanding of prostate cancer tumors. The development of new accurate biomarkers will lead cancer revolution and personalized care in men with prostate cancer
5. Limani et al., Prostate Cancer 2014
4. van Velthoven et al., Prostate Cancer Prostate Disease 2015
6. Aoun et al., Advances in Urology 2015 7. Aoun et al, BioMed Research International 2015
References: 1. Peltier et al., Prostate Cancer 2014 2. Peltier et al., BioMed Research International 2015
Rethinking doctorpatient relationships in a digital era By Prof. Louis Denis, M.D. FACS
hough we live in a digital era, most patients reportedly leave their oncologists’ clinics with several questions unanswered.
A great deal of patient dissatisfaction and several complaints are due to breakdown in the doctor-patient relationship. The age old bond between the treating physician and his patient, aptly called ‘le colloque singulier’ is simply lost in the explosion of our oncological knowledge and the proven subsequent need to multidisciplinary medical treatment and multiprofessionality in providing holistic solutions. Should the oncologist be blamed? With the evolving complexity of cancer at different levels, communication and collaboration between doctors and patients become extremely essential in treating any cancer according to evidence based criteria. Guidelines and monograms ease the direction of the treatment but apply to cohorts of cancer patients and not necessarily to individual
patients with unique genetic make-ups and specific psychological, social, financial and spiritual needs. Should the patient take the blame instead? The question of who is to be blamed is often unrequited. It might be extremely difficult – both for the patient and the doctor – to handle the initial phases of diagnosis of cancer. To the patient, it might often read like a death sentence or at the least a drastic change in lifestyle. In the current healthcare climate, both doctors and patients have very little time to communicate and recover from the initial shock. The patient never gets sufficient time to fully come to terms with the medical situation and is often forced to quickly learn the nitty-gritty’s, initiate a dialogue with the treating crew and express their autonomy in a shared decision to initiate the cancer treatment and survivorship. Holistic cancer management unquestionably requires a well-established balance between tumor-centered treatment and patient-
centered care. The tumor-centered treatment is multidisciplinary in nature, essentially based on evidence and forms the scientific base of cancer treatment. Patient-centered care, on the other hand is the multiprofessional aspect involving psycho-social, financial and spiritual expertise and is focused on the patient. Often, the patient comes first before his cancer. The doctor-patient relationship itself is a strong drug! Furthermore, personalised medicine and individualised treatment routines are particularly crucial in successfully diagnosing and treating cancer, as treatments often differ based on the characteristics of the tumour and its genetics. We are entering a new era of cancer treatment with unlimited expectations. Without any doubts, it will take many years to see this tailored treatment become mainstream. We should be aware of this evolution, move into clinical trials and support further research
Latest advances in prostate cancer research and clinical practice
Prostate cancer treatment and care is enjoying great times in terms of expanding available treatment options, such as DC vaccine as well as improving technology in managing early prostate cancer such as robotic surgery. However, more research has to translated into clinical practice fairly quickly, in order to provide patients with better quality of life, says Dr Anjali Zarkar, Consultant Clinical Oncologist, University Hospital Birmingham
n management of prostate cancer, it remains challenging as on one hand there is evidence that the disease is over diagnosed and the men are put through interventions which affect their quality of life (incontinence and impotence) in spite of indolent disease, while on the other extreme it is the third commonest cause of death amongst men in Europe and fourth commonest cause of death in the UK (1, 2). Fortunately, recent data suggests that more and more men with early prostate cancer have been offered active surveillance as an option with the hope that unnecessary morbidity of the treatment is either delayed or avoided.
Dr Charles Huggins in 1941 first published in scientific journal, the relationship of the endocrine gland and prostate gland for which he received Nobel prize. His scientific discovery leads to androgen suppression treatment through removal of the testicles for men with advanced prostate cancer. Over the decades, this has been the most important advancement. Late 20th century, medical/ non surgical castration was the only treatment option for men with advanced disease. Androgen suppression treatment (ADT) alone has offered elderly men with advanced prostate cancer, providing enormous relief and alleviation of pain occurring due to shrinkage of cancer in bones within days. But we had to wait
until 21st century for further advances in management of advanced prostate cancer. Fortunately, in the 5 years we have seen many therapeutic developments such as newer agents (Abiraterone, Enzalutamide, ARN 509, Cabazitaxel, radium 223) as well as benefit of using chemotherapy in early/ hormone sensitive stage of advanced prostate cancer. Last year we saw publication of 2 large clinical trials showing addition of 6 cycles of Docetaxel chemotherapy in men who are commencing on long term androgen deprivation treatment for metastatic disease have extension in life over 10 to 17 months (3,4). This is great news for our patients. The change in the clinical practice is
coping with prostate cancer
likely to provide better quality of life for these men as they are likely to spend less time in castration resistant phase of the disease. Licensing of the newer androgen directed treatments through either inhibition of androgen synthesis or direct inhibition of androgen receptor, has shown improved survival for patients in large phase III trials (7, 8, 9, 10). These patients were previously thought to be refractory to hormonal manipulation (metastatic castration resistant prostate cancer). These results have been practice changing and have provided expansion of systemic therapy in the disease. We need more research and trials looking into AR signaling, mechanism of its resistance to manipulate and expand the treatment options. The next development in treatment of metastatic castration resistant prostate cancer with bony metastatic disease was the new radioisotope, Radium 223. The large phase III trial published in 2013, showed very well tolerated treatment which offers not only improvement in pain but extension of survival (6). While we have more information on using older agents such as ‘Docetaxel’ early in the management of advanced prostate cancer (3, 4), we need more research into sequencing of the newer agents in the management of the high risk and advanced prostate cancer. There is exciting research looking into resistance to newer treatments such as Enzalutamide or Abiraterone due to a splice variant of the androgen receptor. As we speak, patients have been recruited into clinical trials to try newer agents who are likely to be effective in patients who are likely to be resistant to the newer androgen directed treatments due to variant androgen receptor. Attitudes of the clinicians have changed in management of advanced prostate cancer due to expanding treatment options. Patients are offered active treatments with minimal side effects rather than being managed as end of life/ palliative treatment. In spite of improvements in the available treatment options, supportive care and improving attitudes towards treating men with advanced metastatic prostate cancer, survival in these men remains poor without additional treatments (5). Prostate cancer treatment and care is enjoying great times in terms of expanding available newer treatment options such as DC vaccine, gene therapy as well as improving technology in managing early prostate cancer such as robotic surgery or stereotactic radiotherapy. However, we need more research being translated into clinical practice fairly quickly so our patients can enjoy long and better quality of life
References: 1. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Available from:http://globocan.iarc.fr (link is external), accessed December 2013. 2. Data were provided by the Office for National Statistics on request, July 2014. Similar data can be found here: http://www. ons.gov.uk/ons/rel/vsob1/cancer-statisticsregistrations--england--series-mb1-/index.html (link is external). 3. Chemohormonal therapy in metastatic hormone sensitive prostate cancer; NEJM 373(8):737-746, August 2015. 4. Addition of docetaxel, zoledronic acid, or both to ﬁ rst-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial; ND James et al, The Lancet, published on line on 21st December 2015.
5. Survival in newly diagnosed metastatic prostate cancer in the ‘Docetaxel era’: Data from 917 patients in the control arm of STAMPEDE trial (MRC PRO8, CRUK/06/019) ND James, Matthew sydes et al; European urology 67(2015)1028-1038. 6. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer: C Parker et al, NEJM, 2013; 369:213-223. 7. Abiraterone in metastatic prostate cancer without previous chemotherapy: Charles Ryan et al: NEJM 2013 8. Abiraterone and increased survival in metastatic prostate cancer,: Johann S De Bono et al: NEJM 2011. 9. Increased survival with enzalutamide in prostate cancer after chemotherapy: Howard Scher et al; NEJM, 367(13); 1187-1197, Sep, 2012. 10. Enzalutamide in metastatic prostate cancer before chemotherapy; Tomaz Beer et al; NEJM, 371; 424-433;July 2014.
Improved health-related quality of life A valid clinical benefit
Health policy and regulatory bodies should align themselves to improve patient access to clinically safer treatments that decrease the burden on health related quality of life. Leslie Wise, JD, Vice President of Global Healthcare Economics, AngioDynamics explains how such an improved health-related quality of life can provide clinical benefits
rostate cancer (PCa) is the most common primary site of cancer diagnosis in European men (22.8% of the total). (1) Due to aggressive screening policies globally, PCa is often diagnosed at an early stage. Improved screening with the prostate specific antigen (PSA) test and advanced imaging techniques allow most patients to be diagnosed with low- and intermediate risk local disease. (2) The early stages of PCa commonly stay symptomless for years and may never impact mortality. (3)
Using conservative treatment in low-risk Pca patients instead of radical prostatectomy or radiation therapy is a mitigation strategy for avoiding the untenable side effects of urinary incontinence (0-20%), bowel problems (2236%) and erectile dysfunction (19-74%). Nevertheless, for all patients with PCa, regardless to risk level, the psychological impact a cancer diagnosis has a serious impact on patient health related quality of life. This stress is often a compelling motive to choose active treatment over watchful waiting.
As a result, there is much debate regarding the value of PSA screening, with over diagnosis and over treatment as central themes. NIH 2011 conference statement suggested active surveillance or watchful waiting (WW) as a viable option for patients with low-risk PCa. (4)
Health policy, regulatory, and funding bodies must align to build evidence for viable alternatives from these “all or nothing” options and provide patients access to safe, innovative active treatment options which improve patient’s health related quality of life and extending overall survival.
Stakeholders including policy makers, funders, health technology assessment bodies, clinicians and patients are faced with a growing body of contrasting evidence which complicates treatment strategy decisions. Recent evidence from a randomized trial of RP versus WW in men with localized PCa diagnosed before the emergence of PSA screening, showed a survival benefit of RP as compared with WW of 15 years.  On the other hand, the PIVOT trial, initiated in the early era of PSA screening, showed that RP did not significantly reduce PCa–specific or overall mortality after 12 years.  And most recently, a systematic review and meta-analysis confirms that surgery improves overall survival (OS) as compared to radiotherapy. (7) The current state of the evidence seems to strongly suggest that Radical Prostatectomy (RP) provides a clinically significant survival benefit over radiotherapy across all levels of PCa risk. (7) The data on watchful waiting is less clear. In patients with medium and high risk PCa, active treatment is accepted as the appropriate course of action based upon the established evidence. In low-risk, localised PCa, the evidence on overall survival remains contestable. When the quality of life evidence is incorporated, however, clarity emerges. (5-8) Using the data generated by the cross-sectional study within the SPCG-4, with 4 years of follow up, obstructive voiding symptoms were less frequent among men treated with RP, but sexual side effects and incontinence were more common.  When follow-up was extended to a mean of 12 years, men in the RP group reported more distress from their symptoms, suggesting a negative psychological utility for surgical interventions. Overall quality of life (QoL) decreased in both groups through 12 years of follow-up; anxiety was more prevalent among both the RP and WW groups than the disease-free controls . The clinical data
conclusively establishes improved OS with RP when compared to radiotherapy, but an OS benefit for RP vs WW is not as clear. Sadly, all three clinical strategies demonstrate a negative impact on PCa health related quality of life. Where do we go from here? NanoKnife is a CE marked medical device which may be used for the treatment of prostate cancer. It is differentiated therapy designed and proven to spare vascular and critical structures (such as the urinary sphincter, rectum and neurovascular bundles) and preserve options for re-intervention. NanoKnife is a focal therapy, offering patients a minimally invasive treatment providing the curative benefits of surgery, such as clinically proven negative margin clearance, while minimizing adverse effects which reduce HRQOL. (9,10) The body of evidence in cancer demonstrates active therapy provides better OS than WW, prostate cancer appears no different. The concept of RP is to provide a curative option to the patient in hopes of preventing death. Therefore, the increased examination of the role of innovative minimally invasive focal therapies, such as NanoKnife, is critical to providing improved care to patients References: 1. Ferlay, J., Steliarova-Foucher, E., Lortet-Tieulent, J., Rosso, S., Coebergh, J.W., Comber, H., Forman, D., Bray, F., 2013. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur. J. Cancer 49, 1374–1403 2. Bartsch G, Horninger W, Klocker H, Pelzer A, Bektic J, et al. (2008) Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality. BJU Int 101: 809-816. 3. Cooperberg MR, Lubeck DP, Mehta SS, Carroll PR; CaPSURE (2003) Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 170: S2125.
4. NIH State-of-the-Science Conference Statement on Role of Active Surveillance in the Management of Men With Localized Prostate Cancer, 2011 5. Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, Nordling S, Häggman M, Andersson SO, Bratell S, Spångberg A, Palmgren J, Steineck G, Adami HO, Johansson JE; SPCG-4 Investigators. 2011. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 364(18):1708-17. 6. Chang, Y., 2013. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) in Perspective. J Clin Med Res. 2013 Aug; 5(4): 266–268 7. Wallis CJ, Saskin R, Choo R, Herschorn S, Kodama RT, Satkunasivam R, Shah PS, Danjoux C, Nam RK. 2015. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2015 Nov 30. pii: S0302-2838(15)01160-4 8. Bill-Axelson A, Garmo H, Holmberg L, Johansson JE, Adami HO, Steineck G, Johansson E, Rider JR. 2013. Long-term distress after radical prostatectomy versus watchful waiting in prostate cancer: a longitudinal study from the Scandinavian Prostate Cancer Group-4 randomized clinical trial. Eur Urol. 2013 Dec; 64(6):920-8. 9. Van den Bos W, De Bruin DM, Veelo DP, Postema AW, Muller BG, Varkarakis IM, Skolarikos A, Zondervan PJ, Laguna Pes MP, SavciHeijink CD, Wijkstra H, De Reijke TM and De La Rosette JJMCH. 2015. Quality of Life and Safety Outcomes Following Irreversible Electroporation Treatment for Prostate Cancer: Results from a Phase I-Ii Stud. , J Cancer Sci Ther 2015, 7:10. 10. Valerio M1, Dickinson L2, Ali A3, Ramachandran N4, Donaldson I2, Freeman A5, Ahmed HU2, Emberton M2. 2014. A prospective development study investigating focal irreversible electroporation in men with localised prostate cancer: Nanoknife Electroporation Ablation Trial (NEAT). Contemp Clin Trials. 2014 Sep;39(1):57-65.
coping with prostate cancer
No “one size fits all” in prostate cancer
The incidence of prostate cancer in gay and bisexual men is the same as in hetrosexual men. Andrew Gilliver, Community Involvement Manger, LGBT Foundation discusses why very little is known about services for this group of men
rostate cancer is undoubtedly the most common cancer in Europe for males, and the third most common cancer overall. With over 400,000 new cases diagnosed every year it is clear that this form of cancer is affecting a wide and diverse group of people. There are more than two million people in the UK alone living with all forms of cancer and it is estimated that 40,000 of these are from LGBT communities. Although the incidence of prostate cancer in gay and bisexual men is the same as in heterosexual men, the psycho-social effects may differ and there is little or no research or resources in the UK about cancer among trans people. According to the ‘Stonewall Gay and bisexual Men’s Health Survey’ across Britain in 2012, 90% of gay and bisexual men in the UK have never talked with a healthcare professional about prostate cancer, more than two thirds – about 68% -- of gay and bisexual men aged over 50 have not had a discussion. However, in the last few years, greater awareness has been created in communities affected by prostate cancer who may be gay, bisexual or other men who have sex with men whose support needs are not being met, not to mention the invisibility of trans women who may not identify as male and may not have had a prostatectomy as part of any gender reassignment surgery. There is evidence that healthcare professionals need support in understanding and empathising with the
needs of this community. Without an improved working relationship between healthcare professional and gay, bisexual and trans (GBT) patients there is a risk that GBT people with prostate cancer may make less than ideal decisions about their treatment and care. Although there is a need to improve education and training of healthcare professionals, there are organisations that are looking specifically at the needs of LGBT people affected by all cancers. In the UK, Macmillan Cancer has recruited their first ever full time LGBT project worker to look at the needs of this community. The US has also been discussing LGBT patient’s experiences of cancer. In Europe individual organisations such as Prostate Cancer UK are including LGBT service users in their wider work by producing targeted information for gay and bisexual men. Individual LGBT organisations such as LGBT Foundation, based in Manchester have been highlighting these issues and support for groups such as Out with Prostate Cancer (OWPC) the UK support group who inform health professionals and community members alike. Community surveys suggest that gay men in general drink and smoke more than straight men, putting them at greater health risk. There is currently an absence of reliable data on the health needs of gay and bisexual men and many gay and bisexual men don’t discuss cancer with a healthcare professional. There is a need for gay and bisexual men to become more aware of the risks of health issues such as cancer, and be more open about discussing their sexual orientation with health professionals to help them understand wider health issues.
The wider issue of gay and bisexual men being treated with hormone therapy for prostate cancer is of concern, especially for men who have sex with men. In some countries, chemical castration has been historically used to treat homosexuality as well as prostate cancer and this clearly needs to be taken into account by health professionals when counselling this group. Currently, little is known about the cancer risks of transgender women and hormone use and further research is needed. Transgender people experience high rates of smoking, drinking and HIV, and are at greater risk for developing cancers. Some doctors speculate that it might be better to check the prostate through the neo-vagina instead of exploring the rectum. The hormones of transgender women can lower PSA levels but this is not a reliable sign of good prostate health. Cancer organisations (and others) are beginning to realise that everyone is not the same and one size does not fit all when promoting care services. Acknowledging that there will be a sizeable group of patients and service users who are not heterosexual is important to enable the service provider to be sure that they are providing appropriate services and asking the right questions
coping with advanced prostate cancer
It’s time to speak up... against advanced prostate cancer The International Prostate Cancer Coalition (IPCC) survey found that many men with advanced prostate cancer don’t discuss symptoms like fatigue, pain or difficulty sleeping. Bayer’s newly launched ‘Men Who Speak Up’ program encourages them to do so. Gissoo Decotiis, Oncology Advocacy Relations, Pharmaceuticals Division, Bayer HealthCare Pharmaceuticals, Inc speaks about the findings of the survey change over time. Specific symptoms like fatigue, weakness, troubled sleep, pain and discomfort, difficulty walking or climbing stairs, and daily use of pain relievers may serve as a warning that prostate cancer is progressing. (2,3,4) If prostate cancer spreads, or metastasises, beyond the prostate gland, it often first grows into nearby tissues or lymph nodes before spreading to the bones.
rostate cancer represents a serious disease impacting a staggering number of people. Globally, it is the second most common cancer and the fifth leading cause of cancer-related death in men. More than 1.1 million men worldwide were diagnosed with the disease in 2012. (1) These figures do not capture the number of caregivers, spouses and family members who were also impacted by the diagnosis. When the two are combined, the impact could grow exponentially. Often, in early-stage prostate cancer, there is a significant amount of conversation at home and at doctors’ clinics about the diagnosis and individual treatment options. Unfortunately, for men who have been living with prostate cancer for several years, those important conversations sometimes stop or do not expand to help them understand how their cancer may
Approximately nine in 10 patients (90 percent) with advanced prostate cancer develop bone metastases, impacting survival and quality of life. (5,6,7,8) Therefore, diagnosing and treating bone-related symptoms at the earliest onset is critical for patients. Unfortunately, recent real-world research and insights from physicians and patients have validated the belief that men with advanced prostate cancer don’t always speak up when it comes to symptoms. Eight leading patient advocacy groups that comprise the International Prostate Cancer Coalition (IPCC) commissioned the global survey with support from Bayer. Conducted through “Harris Poll online” tool, the survey examined the perspectives of more than 1,300 men with advancing prostate cancer and caregivers across 11 countries. Findings from the 2015 IPCC Symptoms Survey, the largest conducted in advanced prostate cancer to date, revealed that nearly half of men (45%) sometimes ignore their
symptoms. (4) Of those men whose cancer had already spread to their bones, 40% had experienced some sort of pain for seven months or more before they were diagnosed with metastatic disease. (4) A number of factors contributed to men failing to speak up about their symptoms. Three out of five men (56%) admit that they don’t recognise that the pain they are experiencing could be related to their cancer. (4) It’s surprising that men living with advanced prostate cancer – who should be well informed about it’s symptoms – could overlook them. But these symptoms can mimic common signs of aging or hard work, contributing to the confusion. Further results found that more than half of men (55%) often think that their pain is just something they have to live with, and one out of three (35%) report that talking about symptoms like pain makes them feel weak, supporting the notion that men are conditioned to grit their teeth through any discomfort they may experience. (4) Difficulty discussing symptoms may be culturally-driven as well. Of those surveyed, 40% in the EU region say they are not comfortable discussing how they are feeling physically with their doctor, compared to only 11% in the U.S. (4) The survey results brought to life some of the critical issues facing men with advanced disease and highlight the need to encourage more conversation, which led to the development of a global initiative from Bayer called Men Who Speak Up (www.MenWhoSpeakUp.com). Men Who Speak Up builds upon the recognition that much more should be done to help men with prostate cancer become vocal about their disease. In the survey, men reported, that they would be motivated to speak up about symptoms if it improved quality of life (65%) or activity levels (57%), or if it prevented their cancer from getting worse (54%).4 In practical ways, the program helps men and their caregivers pinpoint the symptoms of advanced prostate cancer and empowers them to have important conversations with their healthcare providers to get the help they need. Bayer is proud to support the prostate cancer community, with these efforts to make a
meaningful difference in the lives of patients by giving them the tools they need to better navigate important discussions about their symptoms with their loved ones and physicians. Opening the lines of communication for discussions about symptoms is not always easy, but it is critically important. Men Who Speak Up provides useful resources including a symptoms tracker, a doctor discussion guide, informational fact sheets and helpful statistics to facilitate those conversations Led by U.S. advocacy organization CancerCare, the IPCC is comprised of Europa Uomo, the Spanish Group of Cancer Patients (GEPAC), Patient Advocates for Advanced Cancer Treatments (PAACT), Prostate Health Education Network (PHEN), Prostate Cancer Research Institute (PCRI), Us TOO International and ZERO – The End of Prostate Cancer. References: 1. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http:// globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed on January 23, 2016; 2. Autio KA, Bennett AV, Jia X, et al. Prevalence of pain and analgesic use in men with metavstatic prostate cancer using a patient-reported outcome measure. J Oncol Pract. 2013;9(5):223-229 3. Farrell C. Bone metastases: assessment, management and treatment options. Br J Nurs. 2013;22(10):S4, S6, S8-S11 4. Prostate Cancer Symptoms Survey: IPCC data in file. Global Results, 2015 5. Petrylak DP, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520 6. Goh et al. New Multidisciplinary Prostate Bone Metastases Clinic: First of Its Kind in Canada. Current Oncology. Volume 14, Number 1
New hope for prostate cancer sufferers in UK Today, we know more about prostate cancer than we could have imagined a few years ago. However, better outcomes will only be achieved through a radical “shift in the science” around diagnosis, treatment, support and prevention, says
Angela Culhane, Chief Executive, Prostate Cancer UK
t is unacceptable that men living in the UK have a lower likelihood of surviving prostate cancer than men in most of Europe.
There are various factors which may be behind this. The extent of PSA testing could be one. Unlike the UK, some European countries have implemented a population-wide screening programme using the PSA test. In the UK, the National UK Screening Committee believes there is insufficient evidence to use the PSA test in this way, citing false positives and false negatives associated with the test as resulting in more harm than benefit. At Prostate Cancer UK, we know the PSA test is weak but until we and our research partners develop a better test, it is the best means of achieving early detection of prostate cancer in men without symptoms, especially those at higher than average risk of the disease.
longer alone in struggling with the high cost of new medicines and it may be that in time we will see a shift in European survival rates as a result. What’s needed is an EU-wide solution that can incentivise the pharmaceutical industry to make their new treatments more affordable. Without this, survival outcomes across the continent will very likely suffer. These initiatives will certainly help more men survive this disease, but, at Prostate Cancer UK, we are convinced that better outcomes for men with prostate cancer will only be achieved through a radical shift in the science around prostate cancer diagnosis, treatment, support and prevention.
Today, we know more about prostate cancer than we could have imagined a few years ago. We’re getting to grips with how it evolves, what it looks like at a molecular level, and how it can vary between one man and another. There are new life-prolonging treatments for advanced Variation in access to new treatments could also disease and in the last year alone, we’ve seen be a factor, as high prices lead to treatments research reveal unprecedented survival benefits being rejected by health technology assessment by introducing an existing treatment earlier or systems and therefore denied to patients. But using it in a more targeted, concentrated way. there is evidence to suggest that the UK is no
7. Tannock IF, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512 8. Jin, Dayyani, and Gallick. Steps in Prostate Cancer Progression that Lead to Bone Metastasis. International Journal of Cancer.
Prostate Cancer UK will play our part by investing as much as we can in research, focusing on three concrete areas; better diagnosis, better treatments and better prevention. We’ll target a better diagnostic test. We’ll harness our better understanding of prostate cancer to enable precision medicine and identify what men can do to prevent ever getting the disease. But we’re just a charity and we need other more powerful players to step up too. The UK government and the EU Commission
must sustain investment in medical research, while establishing cost-effective means for trial results to be easily translated into practice. They must also make sure there are effective ways to accelerate the adoption of these innovations into the health systems and ultimately, getting them to men. At the same time, we need more research pioneers to come forward, whether they’re in Europe or elsewhere in the world. Investment in prostate cancer research can only happen if there are researchers to invest in and it’s critical
that more of these scientific innovators make shifting the science for prostate cancer their goal. And in the meantime, we’ll map those areas where there is variation in the treatment and care men receive – from gold standard to worst case. We’ll highlight and target what needs to change, sharing the good-practice models and solutions that we’ve already identified - or developed ourselves - and we’ll empower men to get what’s best for them
Bladder cancer: So expensive to treat, but almost forgotten The alarming truth is that bladder cancer is the most expensive to treat, however very little policy action has been taken to prevent this urological disease. Furthermore, there are large gaps in our knowledge and understanding about treatment options.
Mihaela Militaru, Director, European Cancer Patient
Coalition discusses the current state of awareness
e know and it seems redundant, that the best way to control cancer is by lowering the chances of contracting cancer. As with many other genitourinary cancers (prostate, kidney or bladder cancer), it is not always possible to prevent bladder cancer, but we can combat some of its risk factors such as smoking or professional exposure to carcinogenic substances. As an organisation representing patients, our first concern rests with informing patients. Over the years we have conducted a number of surveys and studies. Yet, it is still surprising to see that people are not adequately informed about the major risk factors for developing cancer and in particular bladder cancer and the symptoms that could reveal bladder cancer. The European Cancer Patient Coalition (ECPC), the largest cancer patients’ umbrella organisation in Europe, works to ensure that all European cancer patients have timely and affordable access to the best treatment and care available, throughout their life. While we work across all cancer groups, this year we aim to focus on some cancers that receive less attention such as bladder cancer, which is also often known as “the forgotten cancer.” Bladder cancer is actually the fifth most common cancer in the western world and the second most frequent urological cancer after prostate cancer. However, bladder cancer is highly overlooked by policy-makers and investment in research from public and private sources are barely sufficient.
In March this year, the ECPC will launch a White Paper on bladder cancer in the European Parliament, a work coordinated by our organisation with the support of international specialists in the field. The document lists various treatments, novel opportunities, prevention and diagnosis solutions and guidelines, in the hope to raise public awareness, better educate policymakers and fine-tune bladder cancer policies in the interest of current and future patients and the society in general. We see a positive development in prevention policies. For example, both the European Commission and EU member states have developed policies tackling major health determinants and the main risk factors that increase the burden of cancer. Also, governments, based on scientific evidence, have developed legislations to ban the use of dangerous residues or to limit the exposure to carcinogens at work. More such efforts have to be pursued in the future. In addition to this, educating primary care physicians and the public about the key risks and symptoms of bladder cancer should be a priority. Since some of the risk factors for
bladder cancer are the same or similar to kidney or prostate cancer, doctors should inform patients and tailor the information to the profile of the patient, about the risk factors of cancer also looking at patient’s family history or genetic factors. Due to high recurrence rates, intensive surveillance strategies, and expensive treatment costs, the management of bladder cancer contributes significantly to medical costs. As such, bladder cancer is the most expensive cancer to treat per patient. Despite its economic and human cost, unfortunately there is no new major development within the realm of bladder cancer research and treatment. Therefore, prevention at this point becomes extremely important. Our organisation and the patients that work with us encourage us to continue promoting the role of patients in this fight. From prevention to diagnosis to treatment and recovery, patients need to be kept well informed about the options of treatment and the impact a treatment can have on the patients’ quality of life
coping with prostate cancer
Delivering state-of-the-art radiotherapy for all
n the year 2011, the UN General Assembly committed to the prevention and control of Non-Communicable Diseases (NCDs) and in 2013 the WHO member states committed to reducing premature mortality from NCDs with 25% by 2025 (baseline 2010). This implies that 1.5 million cancer deaths have to be prevented each year in order to achieve this so-called “25-by25 target.” Prostate cancer has the fifth highest incidence of cancer deaths with 1.1 million deaths worldwide annually, and approximately 50-60% of these patients would require some type of radiotherapy. Radiotherapy has been used for more than a century for the treatment of cancer, but also benign diseases. In the last 2-3 decades new radiotherapy techniques have resulted in improved clinical outcomes in prostate cancer. As a result all international treatment guidelines clearly recommend the use of radiotherapy for the treatment of patients with prostate cancer. Recent evidence demonstrates that the efficacy of radiotherapy in the treatment of patients with low, intermediate and high-risk prostate cancer is comparable with surgery, whilst adverse events tend to be advantageous for radiotherapy, especially with regard to the patients’ sexual function after treatment. There are various types of radiotherapy that can be used and the decision for a certain type usually depends on the type of prostate cancer. For low-risk prostate cancer brachytherapy, either with low dose rate (LDR; also known as treatment with “seeds”) or high dose rate (HDR), is a good treatment option. External beam radiotherapy treatment (EBRT) is also a frequently used technique for low-risk prostate cancer. EBRT has evolved over time and use of modern EBRT like 3-Dimensional Conformal Radiotherapy (3D-CRT) and especially Intensity Modulated Radiotherapy (IMRT) have resulted in very good clinical outcomes. In intermediate and high-risk prostate cancer patients, the combination of EBRT with a brachytherapy boost has proven to be an excellent, cost-effective treatment option.
Radiotherapy is indispensable in the treatment of patients with prostate cancer. Over the years, new techniques have resulted in improved clinical outcomes. However, providing access to state-of-the-art radiotherapy to all requires continuous investments in radiotherapy facilities and training of radiotherapy staff, says Ben President Medical Affairs, Elekta of the radioactive beam. It can also play an important role in optimising radiotherapy of individual patients. All radiotherapy treatment parameters are stored in databases. This implies that the treatment results of all patients could be relatively easily analysed and used to define patient cohorts in these databases that could then have a predictive value for the response of comparable patients to a certain type of radiotherapy. Millions of patients have already been treated with radiotherapy, so the connection of all these data could mean a big step forward in supporting the process of “personalised” radiotherapy. This process of connecting data will of course require support from healthcare authorities. Support on a legal and regulatory level, but of course also financially. Delivering state-of-the-art facilities to all
Enabling personalised radiotherapy
There is no solid data describing the global RT treatment resources and there are large variations in the deployment of the treatment units, but estimations are that only about 40-60% of cancer patients have access to RT services. Lack of investment is the main cause of limitations in access driven by a fear of high operational costs in addition to large upfront investments.
The optimal use of radiotherapy is directly associated with good quality imaging and treatment planning software. Software plays an important role in radiotherapy anyway: besides its central role in treatment planning, it is a prerequisite for the alignment of the images showing the tumour and the targeting
As a consequence of insufficient access to radiotherapy, high-risk prostate cancer patients are, sometimes treated with hormone therapy alone. Randomised controlled research has demonstrated that this leads to dramatically worse overall survival within 5 years of diagnosis. Underinvestment is not only
Pais, MD, Vice
happening in low-income countries, but also in middle-and-high-income ones, including several European countries, preventing upgrades of “old fashioned” radiotherapy services. It has been demonstrated that image guided radiotherapy substantially helps improve treatment results. More patients survive. At the same time, toxicity and adverse events as a result of radiotherapy treatment decrease. These favourable clinical characteristics of radiotherapy provide the strong basis for its cost-effectiveness that has been demonstrated in several health economic models, amongst others also in the treatment of prostate cancer. Knowing that the elderly population, over 65 years of age, will continue growing in the next 1-2 decades, the number of cancer patients will grow accordingly. Proper investments in RT, both in facilities and human resources, will enable treatment of large numbers of cancer cases to save lives, and also bring positive economic benefits. Prostate cancer accounts for a large number of deaths, almost 100.000 in Europe annually. Improved access to radiotherapy will support reaching the targets defined by the UN General Assembly and the WHO Member States to prevent death from (prostate) cancer
Navigating through the maze of prostate cancer
The Melbourne Consensus Statement (2013) A group of international experts reviewed the latest information and the above conflicting guidelines. (6) They stated the following: • Randomised trials have confirmed that PSA screening reduces deaths from PCa for men age 50-69. • Healthy men aged 50-69 should be informed of the pros and cons of screening. • PSA screening should be part of an overall risk assessment for PCa and, as in the EAU guidelines, can be commenced in a man’s 40s to help predict future risk. • Men over 70 with more than 10 years life expectancy should not be denied screening, once counselled. • To avoid overtreatment, screening should be uncoupled from treatment.
Medical practices are increasingly based on well established guidelines produced by a group of experts in the field. Trying to navigate one’s way through these guidelines can be akin to walking through a maze and the ongoing advances can make it more difficult. Dr. Chris Booth, Member of Clinical Advisory Board, Tackle Prostate Cancer, tries to make sense of the multiple guidelines on prostate cancer
lthough early diagnosis and treatment of prostate cancer is usually curative, screening of men with no symptoms using the blood test Prostate Specific Antigen (PSA) remains controversial. (1) Though its use has clearly reduced the death rate, (2,3) it has also led to unnecessary and potentially harmful invasive prostatic biopsies and overtreatment of small, non-aggressive cancers leading to serious complications such as impotence and incontinence. Best medical practice is increasingly based on application and adherence to best practice guidelines produced by panels of “experts.” (4) However, the problem with prostate cancer is that there are multiple guidelines and, worse, they conflict. This synopsis provides a summary of the current major guidelines and hopefully permits a clearer understanding for both men and doctors considering screening. United States Preventive Services Task Force (2012) The task force recommends against screening for men of all ages on the basis that 1,000 would need to be screened to save one life, but 30-40 men would suffer complications due to overtreatment. This opinion was strongly criticised by the American Urological Association (AUA), mainly for failing to highlight the particular risk for men with a
family history of PCa and especially black African-American men who carry a 1 in 4 lifetime risk of developing PCa. American Urological Association (2013) The AUA suggests screening for AfricanAmerican men and those with a family history. For men aged 55-69, it recommends shared decision making with a clinician to achieve an informed choice. A baseline PSA could then be used to help quantify future risk. The association also recommends against screening for men over age 70 with less than 10-15 years life expectancy. American College of Physicians (2013) For men aged 50-69, the ACP recommendeds letting men make an informed choice ultimately based on their own preference. In particular, it discourages screening below 50 and above 69. European Association of Urology (EAU) (2013) Based on two current randomised clinical trials, the guideline states that screening clearly reduces mortality from PCa. The EAU recommends a baseline PSA at age 40-45 to predict future risk and in the majority of cases to reduce the frequency of future PSA screening. It also advocates the use of “risk calculators.”(5)
In summary, the majority of international expert panels advise screening for men with a family history of PCa and black African and African Caribbean men from age 40. They recommend that clinicians obtain a baseline PSA in a man’s 40s to predict future risk and further link PSA to a “risk calculator” to assess need for and frequency of future PSA screening. It is anticipated this will reduce the overall number of PSA tests for both individuals and nationally. They also suggest not screening men with less than 10 years life expectancy. UK clinical practice UK mortality for PCa lags behind most of our European neighbours (7) and only a minority of UK men seek screening. For those men who do, NICE guidelines are crude while Public Health England’s “Prostate Cancer Risk Management Programme” is complex for patients and apparently unknown to 50% of GPs. (8) Consequently many men requesting a PSA in Primary Care are put off screening. Regarding the management of early curable PCa, the National Prostate Cancer Audit (9) suggests nearly a third of UK men have received unnecessary aggressive, invasive treatment with radiotherapy or radical prostatectomy for small, non-aggressive cancers. However, this audit relates to clinical practice between 2006-2008. Not surprisingly best practice specialist care has changed since then. Firstly PSA sensitivity and specificity can be improved by measuring free PSA, the free to total PSA ratio and utilising the variant human kallikrein2 (hK2), leading potentially to far fewer negative prostate biopsies. (10) Secondly, men under consideration for prostatic biopsy are now increasingly undergoing an MRI scan first. Only those with an abnormality on MRI then proceed to biopsy and the biopsy itself is no longer random but is
coping with prostate cancer
targeted upon the MRI abnormality.
5. European Urology: 2014: 63: 627-633
Thirdly treatment decisions for biopsy positive men are reviewed by specialist MultiDisciplinary Teams.
6. British Journal of Urology International 2014: 113(3) 186-188
Finally UK men with PCa are now taken through an informed decision making process with at least one consultant and a specialist nurse before a final treatment decision is made. The consequence of this has been a consistent increase in the proportion of UK men with early stage, low grade PCa (stage T1/T2; Gleason Score ≤6) who avoid radical treatment and opt instead for active surveillance.
8. Journal of Clinical Urology: 2014: 7(1): 45-54
7. World Life Expectancy: WHO 2011 9. National Prostate Cancer Audit, Royal College of Surgeons of England, 2014 10. British Journal of Cancer: 2010: 103(5): 708-14 11. British Journal of Medical and Surgical Urology; 2012: 5: 4-10
Conclusion UK medical students and GPs receive little formal urological training (11). Further, men themselves remain largely unaware of prostatic disease and messages from both specialists and public health are, to say the least, mixed. This calls for better education on both sides.
How outdated references can be misleading
cience fails to face the limitations of statistics. As a result, flawed statistics in scientific literature is increasingly worrying clinicians as it might often lead to negative and highly biased outcomes. Very often, newspapers and scientists, in an attempt to create maximum impact for their articles, tend to publish relative statistics, which in turn misguide GPs relying on such literature. An editorial published in the the British Medical Journal (BMJ), entitled “Full disclosure about cancer screening” (1) and a related analysis entitled “Cancer screening has never been shown to save lives” (2) are particularly highly misleading due to outdated references used by the authors to support their case.
If we are to reduce significantly the current UK death rate from PCa, Primary Care PSA screening should be provided for appropriately informed men and linked to risk calculation. This is best achieved through collaboration between Public Health, Commissioners, GPs and Specialists together promoting a consistent message to both men and the medical profession
In the above mentioned articles, emphasis is given to the differences between cancer specific and overall mortality, however it is unacceptable to use a reference that is 13 years old. (3) It is equally misleading to quote references comparing PCa mortality statistics from the pre-PSA era and present these as if the data was current. (4) Regarding death from either metastatic PCa or locally advanced PCa, this is almost always thoroughly unpleasant and to be avoided if at all possible; screening almost always achieves this.
References: 1. European Urology 2014: 65: 1046-1055 2. Lancet Oncology: 2010: 11: 725-732 3. European Urology 2014: 65: 329-336 4. British Journal of Urology International 2014: 114(3): 323-5
So far as PCa and PSA screening is concerned, these BMJ articles from foreign authors, who are not urologists, are outdated, unbalanced, do not reflect current UK practice, do not reflect the international consensus (5) that advocates PCa screening based on an individual assessment of risk and informed decision making and do nothing to help men at risk, particularly those with a family history and black African and African Caribbean men, from this serious and frequently fatal disease References: 1.Gigerenzer G, BMJ, 2016; 352, 8 2.Prasad V et al, BMJ, 2016; 352, 22-23 3.Black C W et al, J.Natnl Cancer Inst, 2002; 94(3), 167-73 4.Fang F et al, J.Natnl Cancer Inst, 2010, 102(5), 307-14 5.Murphy D G et al, BJU International, 2013, 113, 186-188
Genes, mutations and cancer risk While 7% of all cancer is hereditary, changes to genes -- called mutations can play an important role in the development of cancer. Dr. Howard Urnovitz, Dr. Nick
Plowman and Prof. Dr. Ekkehard Schütz from
Chronix Biomedical outline the differences between tests for hereditary and somatic cell mutations
Testing for somatic or acquired cell mutations (real time detection of cancer)
lot of attention is being focused on gene tests and cancer. Cancer gene tests started out in the 1990’s as a single marker that estimated your risk of getting cancer. Today, tests measure actual cancer dynamics in real-time. The human body is composed of 50 to 100 trillion cells starting from one fertilized egg that differentiates into almost 200 different types of cells. These trillion of cells, when working in harmony, create a healthy individual. So, what is cancer? Cancer occurs when a cell no longer listens to the body’s signals and grows uncontrollably. The blueprints for life are stored in a chemical in the nucleus of a cell known as deoxyribonucleic acid (DNA). The DNA is organised into sequences that are known as genes. The DNA blueprint, or genome, can become altered called a mutation. Mutations lead to the cancer’s independence from homeostatic controls that normally stop relentless/cancerous cell divisions. Mutations carried from generation to generation are known as hereditary mutations. Hereditary mutations rarely cause cancer alone, but when acquired or somatic mutations occur, the cells are more easily ‘tipped over’ into the cancer state; therefore, people carrying these hereditary mutations are predisposed to cancer. We will outline here the difference between tests for hereditary and somatic cell mutations. Testing for Predisposition to Hereditary Cancer (Assessment of risk of developing cancer by pedigree) Approximately 7% of all cancers are hereditary (i.e. the person has inherited a faulty (mutated)
gene which facilitates cancer initiation). From your family tree, one can get an idea as to an individual’s risk. For example, an inherited gene mutation linked to breast or ovarian cancer is more likely if several other women in the family have developed breast or ovarian cancer – particularly at a younger age (e.g. < 50 years) or where those relatives developed cancer in both breasts or a near male relative has developed prostate cancer (or cancer of the gastrointestinal tract or the otherwise rare male breast cancer) – again particularly at young age. From this vignette, it can be appreciated that family history gives a clue as to hereditary risk predisposition. Some risk mutations are associated with ethnicity (for example on important faulty/mutated gene predisposing to breast/ovarian cancer runs more strongly in people of Ashkenazi Jewish descent). Nowadays, it is possible to screen for these faulty/mutated genes in a well-person screen – if your family history suggests a risk. It is recommended to screen for the common gene mutations (associated with a particular cancer) in such persons. The list is not exhaustive but includes the most common gene mutations. The advantages of such gene testing for an individual is that more frequent screening (e.g. colonoscopy for colorectal cancers) may be employed or even pre-emptive surgical procedures to forestall or cure early cancer, where there is a proven familial/genetic predisposition. Again, all these hereditary tests measure future risk and not real-time. Hereditary mutation tests can be performed on a blood draw.
Cancer is caused by mutations in DNA that lead to a “triggering” of cell multiplication, outwith the needs of the body signals. This last phrase is important as cells are dividing all the time in the body and increase this rate in response to stimuli (e.g. wound repair), but all this cell multiplication is regulated to the body’s requirements. Cancer occurs when the cell multiplication is relentless and without the body’s requirements. The genomic revolution has created Next Generation Sequencing (NGS) whereby the entire genome can be mapped within hours. Much has been learnt concerning genetic mutations and how best to measure them. This year will see a shift in emphasis from measuring the single point mutations (SNPs) to using NGS to track genome instability through measuring copy number instabilities (CNIs). CNIs are a hallmark of all cancer cells with gains and losses of genetic material. These gains and losses can range from alterations spanning large chromosome regions to smaller duplications or deletions. Importantly, cell-free DNA fragments from cancer cells appear in the blood carrying this hallmark of cancer, which can be detected with a simple blood test. Although on a more “macro” level than individual gene mapping, the correlation with cancer is very strong and there are indeed identifiable certain patterns (“hot spots”) which seem to uniquely correlate with cancers arising in different organs. This year, Chronix Biomedical will be presenting results from prospective, blinded studies on the power of measuring CNIs. CNI blood detection has a variety of applications from a pan-cancer screening blood test for all cancers to predicting treatment outcomes after one cycle of therapy. All these tests are available to physicians today on peripheral blood draws
coping with prostate cancer
Canvassing for a European network of national cancer institutes With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. However, Dr Riccardo Belli, Medical Director, Immunooncology, Global Medicines Development, AstraZeneca says building a European network of cancer institutes and developing dedicated patient databases are crucial in helping identify new predictive biomarkers and accelerate the launch of new therapy
rostate cancer is nowadays considered one of the most common cancers in men, in part as a result of introduction of PSA (Prostate-Specific Antigen) screening that lead to a consistent increased diagnosis of early stage prostate cancers. Since the advent of PSA evaluation, fewer than 3% of men have metastases at the time of diagnosis, and 75% of men have non palpable cancer. (1) However, early detection and treatment that have no effect on life expectancy, often increases side effects without improvement of quality of life and health care expense, while decreasing the value of PSA and rectal examintation. (2) Population-based screening of men aged between 55 and 69 years, using PSA testing, has been evaluated in randomised trials. After a median follow-up of 13 years, the European screening trial demonstrated a relative reduction in the risk of prostate cancer mortality of 21% (29% if adjusted for non-compliance). However, 781 men needed to be invited for screening and 27 patients needed to be treated to prevent one death from prostate cancer. Risk-adapted early detection of prostate cancer using a baseline PSA level has also been evaluated in retrospective cohort studies. The baseline PSA at or before the age of 50 years is associated with the risk of prostate cancer mortality over the subsequent 25 years. (3) Widespread population PSA screening for prostate cancer reduces prostate cancer mortality at the expense of over diagnosis and overtreatment and is not recommended by different group of experts. (1,2,3,4,5) Therefore, there is a need for new methods of using
noninvasive biomarker to inform patients and the physician about detection of prostate cancer at an early stage, to determine cancer aggressiveness, treating aggressive cancers and actively monitoring indolent (slow-growing) cancers. The ultimate goal would be to treat more patients who are at risk, and reduce the number of patients who aren’t. Moreover, most prostate cancer–related deaths are due to advanced levels of the disease. The current standard of care consists of prostatectomy and radiation therapy, which may be supplemented with hormonal therapies. Recurrence is common, and many develop metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such as hormone refractory or castration resistant prostate cancer. With advances in understanding of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treatment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents modulate growth factors and/ or their receptors, which are abundant in cancer cells. Other reagents target the downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated in transformed cells or metastatic tumors. In this setting, the building of a European network of national cancer institutes and the availability of a dedicated European patient database could
be considered to help identify new predictive biomarkers, anticipate the launch of new target therapy and accelerate the time to access new drugs and target experimental therapies References 1. SA Brosman Prostate-Specific Antigen Testing Medscape Jan 13, 2015 2. NCCN clinical practice guideline in oncology Version I 2016 3. C. Parker, S. Gillessen, A. Heidenreich, A. Horwich Cancer pf prostate: ESMO clinical practice guidelines Ann Oncol (2015) 26 (suppl 5): v69-v77. 4. Moyer VA, US Preventive Services Task Force (2012) Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 157:120–134. 5. N. Mottet, J. Bellmunt, E. Briers, R.C.N. van den Bergh, M. Bolla, N.J. van Casteren, P. Cornford, S. Culine, S. Joniau, T. Lam, M.D. Mason, V. Matveev, H. van der Poel, T.H. van der Kwast, O. Rouvière, T. Wiegel. Guidelines on Prostate Cancer, European Association of Urology 2015. Riccardo Belli is Medical doctor, DAAD (Deutscher Akademischer Austauschdienst), Guest Fellow - Tumor Immunology at Charite Campus mitte, Berlin, Germany. ECPM (European center of pharmaceutical medicine) training held by the university of Basel, Switzerland.
6th EU Prostate Cancer Roundtable: An Overview
he 6th edition of the EU Prostate Cancer Roundtable took place in Brussels on the 26th of January 2016. It brought together MEPs, senior representatives from the European Commission, leading urologists, oncologists, radiologists, representatives from interest groups as well as charity organisations to examine the ongoing challenges in managing prostate cancer more effectively, explore practical solutions to reach an EU-wide consensus and implement a forward action plan. The objective of this meeting was to discuss important developments in the diagnosis, treatment and cure for the cancer as well as analyse current EU policy in the sector with a view to put forward recommendations to policy makers and other key stakeholders. Arvind Venkataramana, Research Director at the International Centre for Parliamentary Studies, provides an overview of the discussion as well as key policy and other recommendations that were put forward over the course of the roundtable. Current EU policy Alojz Peterle, MEP, Former Prime Minister of Slovenia and current President of the MEPs Against Cancer (MAC) Group began the discussion on important technological advancements in the treatment of prostate cancer and the role it has played in the development of current policy. The MAC Group has been in existence for the last 10 years and it’s objective has been to consider
every key technological, social, demographic and medical development before putting forward any policy recommendation in the area of cancer. The discussion then moved to healthcare policy in general and the consensus was that healthcare, as a whole, needed a similar approach where policy isn’t largely influenced by clinical inputs. Instead, it should also consider patient feedback. Policy recommendations should move beyond statistics and take into account the qualitative aspect of treating prostate cancer, rather than just prolonging a patient’s life. The importance of early detection There was a general agreement that early detection is key to successfully tackling prostate cancer. The knock on effects of late detection has proven to be catastrophic. Research has shown that PSA tests done at early stages have significantly reduced mortality rates and should be the norm across the EU. Incidentally, three of the participants were diagnosed with prostate cancer and were unanimous in pledging their support for PSA testing and the key role it played in ensuring that cancer didn’t spread and was treated appropriately. Quality and transparency of data Interestingly, data and information sharing in the area of breast cancer has significantly reduced the number of deaths as a result of it. The same needs to be done in the EU for prostate cancer. A clear framework has to
be developed for the smooth, efficient and real-time flow of information across member states. In addition, more robust population based data collection has to be initiated for long term research purposes such as studies on how certain ethnicities are more prone to prostate cancer than others. Big Data is another very interesting development that has transformed other industries. The group felt that it can help combat prostate cancer by ensuring data is used for better, multi-modal, multi-disciplinary and combination approaches in the diagnosis and treatment of prostate cancer. The discussion then moved to important developments in imaging and the role it has played in detection. The good news is that the quality of MRIs has improved significantly in the EU. However, there is no EU standard in place to ensure consistency in the quality of scans. More EU funding for research The current economic climate isn’t ideal but a conscious effort has to be made from all quarters to ensure that there are no cuts to funding in cancer research - more specifically, prostate cancer, according to a majority of the participants. Further, there is a need to conduct in-depth research in preventative measures at the same time as treatment, as cuts in funding at this point could seriously derail current efforts. The last five years have seen an increase in funding and studies have found a direct link between funding and reduction in deaths due to prostate cancer.
coping with prostate cancer
Although PSA testing is the most widely used and successful tool to detect the cancer, research funds should go into alternate testing methods including more evidence based testing. In the meantime, the EU should not encourage the use of other tools unless it has been tested and researched thoroughly. A multi disciplinary approach The EU should set up a Centre for Excellence where a multi-disciplinary approach to the treatment of prostate cancer is carried out. This has to go beyond just radiologists, urologists and other clinicians exchanging information. There should be technological inputs, patient care perspectives as well as any policy changes included within this multi disciplinary system. We should move away from the current “one-size-fits-all” approach. There has to be a systemic change to how long it takes for new technologies, breakthroughs and developments to become available to patients. Key policy makers have to do more to ensure there is a ‘fast-track’ route for genuine breakthroughs to quickly move from trials to being approved as delays can cost lives. Key recommendations - Better quality of MRIs, imaging and screening must become a legal norm rather than just a recommendation. - EU needs to do more to ensure guidelines are followed and should play a bigger role in shaping them. - Research funding should not stagnate and policy makers should ensure it grows year on year. - There needs to be a set budget in place to ensure there is an education programme across the EU. - PSA should be the only recommended test until we find proven alternatives. - Clinical trials and the approach towards it needs to be more efficient. - There has to be a greater consensus on the treatment of the cancer across the EU. A Centre of Excellence is a good starting point. - Labelling laws need to be revisited. - More research on the cause of deaths is important so that future research parameters can be accurately defined. - Apart from EU-wide initiatives, there is scope for exchanging information from other countries that have had better success rates. - The EU should implement a standard on less invasive procedures unless absolutely necessary. - Patient satisfaction measures should be put in place to measure the effectiveness of treatment. - The EU should ensure there is wider access to trademarks. - The EU should ensure newer technologies are implemented before they become obsolete. Fast tracking leading breakthroughs can be very effective. - Screening should go beyond just being population based. - In addition to treatment, future policy should focus more on patient rehabilitation and care.
Participants of the Roundtable included: Director, Association of European Cancer Leagues, President, Austrian Association of Urology, Head of Urology, Algemeen Stedelijk Ziekenhuis, President and Managing Director of Diagnostics, Almac Diagnostics, Vice President, Medical Director of Diagnostics, Almac Diagnostics, Vice President, Global Healthcare Economics, Angiodynamics, Senior MD, Immuno-oncology, Angiodynamics, Senior MD Immuno-oncology, AstraZeneca, Health Policy & Public Affairs Europe, Bayer HealthCare, Chair, Belgian Society for Sexual Medicine, Consultant Urologist, Brussels Saint-Luc University Hospital, Head of Urology, BUPA, Director, CHAPS - The Men’s Health charity, Chief Executive Officer, Chronix Biomedical, Chief Medical Officer, Chronix Biomedical, Vice Chairman, European Cancer Patient Coalition, E-Health Manager, European Coordination Committee of The Radiological, Electromedical And Healthcare IT Industry (COCIR), Director & Member, Steering Committee, European Network of Cancer Registries, Ex-officio Board Member, Europa Uomo - The European Prostate Cancer Coalition, Secretary General, European Association of Urology, Director, European Cancer Patient Coalition, Policy Officer on Cancer and Rare Diseases, European Commission, Scientific and Policy Officer, DG Research & Innovation, European Commission, MAC President and Rapporteur, European Parliament, Vice President Medical Affairs, Elekta, President and Chief Executive Officer, Exact Imaging, Head of Urology, Institut Jules Bordet, Chairman, University Hospital Gasthuisberg, Katholieke Universiteit (KU) Leuven, Urologist, Maxima Medisch Centrum, Veldoven, Assistant Professor of Public Health-Head of the Centre for Health Care, National Institute of Public Health of Slovenia, Director, NHS European Office, Chief Executive (Interim), Prostate Cancer UK, Professor of Radiology and Chair, Prostate MRI Reference Centre of Radboud, Medical Director - Oncology, Sanofi, EU Commerical Lead, Sanofi, Public Health Officer, World Health Organisation Europe, Oncologist, Ziekenhuisnetwerk Antwerpen (ZNA) Middelheim. The next edition of the prostate cancer roundtable will take place on January 24, 2017. If you wish to attend, please contact firstname.lastname@example.org
tackling the diabetes challenge
Taking a critical look at the diabetes challenge To reverse the diabetes epidemic and related challenges, we need a paradigm shift, a coordinated and comprehensive approach at every stage, integrated health care, alignment of sectoral policies for health, a multi-stakeholder involvement, a greater responsibility and contribution from NGOs and civil society. Prof. Dr. Sehnaz Karadeniz, Chair, IDF Europe takes a look at the worrying issues around the European health priority
iabetes is a multi-faceted issue. A person with diabetes can live a life in very good health, or may have to deal with multiple organ damages leading, for example, to visual loss or renal insufficiency. In this case diabetes is not only a health concern for the person, but also an important social and economic issue for the family, the community and the country itself. Today we have a large evidence base on how to prevent type 2 diabetes, which accounts for roughly 90% of all diabetes cases, and on how to maintain the quality of life in people with diabetes through early diagnosis and timely treatment. To what extent, however, is current knowledge translated into real life? Unfortunately, the answer is not that promising. Current estimates show that diabetes increases beyond predictions. According to the recently released Diabetes Atlas, 7th ed (IDF, 2015), the prevalence of diabetes in the European adult population has increased from 4.9% in 2000 to 9.1% in 2015, rising to an estimated 10.7% for 2040 if we cannot halt or reverse trends.
This means nearly 60 million people aged 20 and over living with diabetes in Europe: a population larger than those of many European countries! And over 23 million are not even aware of their condition. Other worrying issues are the 60 million adults at high risk of developing diabetes, as well as increasing rates of type 2 diabetes in childhood. With 1 in 3 11-year olds overweight or obese, there is much cause for concern. National prevalence rates for diabetes show a wide variation from 13.9% in Malta, to around 4.5% in Tajikistan (IDF, 2015). In absolute terms, the Russian Federation holds the European record with 12 million people with diabetes, followed by Germany with 6.5 million. Diabetes is a costly disease. There is a large disparity in health spending on diabetes between and within world regions, which may -to some extent- also reflect expenditure policy priorities of individual countries. Only 19% of the global health expenditure on diabetes was made in low- and middle-income countries, where 75.4% of people with diabetes live.
In 2015, nearly 156 billion USD were spent on diabetes in the European region. The average diabetes-related expenditure per person with diabetes was 2,609 USD in Europe (1,622 USD in the world), with over 10,000 USD in Luxembourg, Norway and Switzerland, but less than 300 USD in Armenia, Kyrgyzstan, Tajikistan, Turkmenistan and Uzbekistan. These are both direct and indirect costs, mainly due to diabetes related long-term complications which entail increased use of health services, loss of productivity and disability. In other words, if we were to invest in prevention, raising awareness, diabetes education, good care and management, we would have the opportunity to prevent or avoid advanced cases needing dialysis, eye surgery, amputations and other costly interventions which also negatively affect the quality of life of people with this condition. Our healthcare systems, however, have traditionally been organized to address acute problems and patientsâ€™ urgent needs, rather than respond to chronic conditions such as diabetes.
To reverse the diabetes epidemic and related challenges, we need a paradigm shift, a coordinated and comprehensive approach at every stage, integrated health care, alignment of sectoral policies for health, a multi-stakeholder involvement, a greater responsibility and contribution from NGOs and civil society. Several declarations, resolutions and recommendations exist at the global and European levels, inviting Member States to take action against diabetes. A European Parliament resolution addressing the EU diabetes epidemic was adopted in March 2012 by the European Parliament. A meaningful result, however, can only be achieved through national diabetes strategies, their successful implementation and close monitoring. According to the last all-Europe audit (Diabetes Policy Puzzle, 2014), 30 out of 47 European countries have a national plan covering diabetes, and 10 plan or are
in the process of developing such a strategy. What is important though is their scope and implementation in order to make a change in real life. According to the audit, these plans vary with regard to their content and scope, some focusing more on diabetes prevention, others more targeted at tackling complications in people with diabetes. Over 95% of European countries report diabetes prevention policies and campaigns targeting obesity and overweight, promoting healthy eating, physical activity, smoking cessation or tackling harmful use of alcohol. Monitoring and evaluation, nevertheless, remain a major weakness in most of these plans. These gaps in scope, inclusiveness, implementation, monitoring and evaluation need to be addressed in order to generate a positive response to the challenges created by diabetes. The International Diabetes Federation European Region (IDF Europe, the
European chapter of the International Diabetes Federation) will continue to actively contribute in this respect. We are an umbrella organisation of 70 diabetes organisations in 47 European countries, representing both people living with diabetes and healthcare professionals. Through our activities, we aim to influence policy, increase public awareness and encourage health improvement; we promote the exchange of best practice and high-quality information about diabetes throughout the European region. Our main advocacy targets at the European level are EU institutions, the Council of Europe and the World Health Organisation European Region. As IDF Europe we welcome any idea, collaboration and partnership which would make a positive difference in the lives of people with diabetes.
Let’s help prevent the diabetes epidemic “Unless drastic steps are taken through national and international programmes to attenuate the increasing prevalence of diabetes, the costs to both the individual and society will be vast.” Prof
JM Boulton, MD, Prof of Medicine,
University of Manchester, UK discusses ways to prevent the 21st century epidemic
uperior doctors prevent the disease; mediocre doctors treat the disease before it is evident; inferior doctors treat the full-blown disease. - Nai Ching, 2600 BC. There is a clear and important message in this quotation from the first Chinese medical text, for all health care professionals and providers working in non-communicable diseases. I had the pleasure of listening to an inspirational speech in Bangalore earlier this
year by Narendra Modi, the Indian Prime Minister. He clearly stated that the major threat to the health of India was no longer from infectious diseases such as tuberculosis and malaria, but from non-communicable diseases including diabetes. Perhaps he had read the recently published International Diabetes Federation’s (IDF) “Diabetes Atlas” (December 2015) (1) which estimated that there are currently >415 million people with diabetes worldwide that is predicted to increase to 642 million by the year 2040. Both the IDF
estimates of >70 million adults with diabetes in India and approximately 3-4 million in the UK are very conservative. Whereas the quoted figures are for adults aged 20-79 years of age, predominantly with type 2 diabetes, the figures for type 1 (insulindependent) diabetes in youngsters also make for depressing reading. Studies from Finland report an increasing incidence of type 1 diabetes (2) which are supported by more recent data from the USA that have reported
tackling the diabetes challenge
a >50% increase in diabetes in young people between 2003 and 2013, with the highest figures seen in those aged 12-18 years. (3) Thus one must ask the question: what can be done to address this global public health tsunami. (4) The answers to this question can be found in the Chinese proverb. At present, most physicians are treating the full-blown disease, diabetes. Unless drastic steps are taken through both national and international programmes to attenuate the increasing prevalence of diabetes, the costs to both the individual and society will be vast. Thus, the NHS should be focusing on prevention. Primary prevention – that is, preventing the development of diabetes, in this context in a high risk population, is practical and cost-effective. (4) Studies from both the USA and Europe have confirmed that “lifestyle intervention” (that is, better diet and more physical activity) can significantly reduce the development of diabetes in those people with “Impaired Glucose Tolerance” or “pre-diabetes” (5,6) The American study suggested that increasing activity to 150 minutes per week was sufficient exercise – that could involve taking a 45 minute walk per day, not necessarily requiring vigorous activity in a gymnasium. (5) Screening should focus on high-risk populations that might include those with a family history of diabetes in a first degree relative, the significantly obese population, those with a history of gestational diabetes and those from certain ethnic groups such as from the Indian sub-continent and African-Caribbeans. Secondary prevention implies the prevention of the late diabetic complications in subjects who are known to have diabetes. Most important of all is the achievement of good blood glucose control, and also maintaining normal blood pressure readings and cholesterol and lipids. It must be remembered that 80% of the vast cost to the NHS of treating diabetes (estimated
by Diabetes UK to be > £10 billion a few years ago), is spent on the management of complications, especially diabetic foot disease and kidney failure, with many such cases being potentially preventable. The national diabetic eye screening programme attests to the effectiveness of such screening, as following its establishment, diabetes is not now the leading cause of blindness in working age adults in the UK. Whereas the costs of treating the late complications are staggering, screening for them is inexpensive. The concept of the “annual review” for diabetes patients is not new: indeed, I wrote an editorial on this topic some 25 years ago when editor of Diabetic Medicine. (7) Thus all those with known diabetes should be screened at least annually for early signs of the long-term complications. As discussed above, an annual retinal photograph at the local optician is now the standard of care in the UK for retinopathy screening. A simple urine test together with a blood pressure check can identify early kidney disease, whereas for the feet, the most important action is to remove the shoes and socks and examine the feet.
reduced morbidity and mortality, but also to reduced health-care expenditure. In contrast to the chronic, noncommunicable diseases such as cancer and heart disease, many regard diabetes as a “mild disease” or “a touch of sugar”. Nothing could be further from the truth: the outlook for those diabetic patients on dialysis with foot problems is worse than for most cancers and heart disease. It behoves us in diabetes care, therefore, to heed the words of our Chinese ancestors – and become superior doctors. References 1 International Diabetes Federation. IDF Diabetes Atlas 7th edn, 2015. 2 Hartutsalo V, et al. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 2008; 371: 1777-1782. 3 Lin L, et al. Prevalence of diabetes in a large US commercially insured pediatric population 2002-2013. Diabetes Care 2016; (In press).
Simple tests of sensation in the feet (can you feel the vibration of a tuning fork, the touch of a finger, tell hot from cold, etc) can easily identify early loss of feeling in the feet (neuropathy), while examination of the foot pulses can identify vascular disease. Those found to have evidence of nephropathy (kidney disease) require appropriate therapies to prevent progression such as optimizing diabetes and blood pressure control. If foot problems are detected, education on foot self-care, regular podiatry and advice on appropriate footwear are indicated.
4 Nanditha A, et al. Diabetes in Asia and the Pacific: indications for the global epidemic. Diabetes Care 2016; (In press).
Although such screening programmes are now widespread in the UK, they should be universal. Such primary and secondary prevention programmes lead not only to
7 Boulton AJM. The annual review: here to stay. Diabetic Med 1992; 9: 887.
5 Knowler WC, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346; 393-403. 6 Tuomilehto J, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with Impaired Glucose Tolerance. N Engl J Med 2001; 344: 343-1350.
6 1 0
E an h c rea betes o t a ers in di d l o re keh nd ca a t s nd ent a a s m r ake anage m m cy oli ctive p e e car y, eff h t c l hea ccura y e a er k ostic h t n e tog diag g d gin ve rin mpro b i g etin us for e el m nsens v e l co gh-
p o r u E es
t e b a i D
pr A h
m u i lg
e B s,
e s s ru B 6,
1 0 2 il
2 e l ab
d n u
o R e
Topics include • EU diabetes policy advancements & research • The cost of treatment: bringing down cost without compromising on quality • Living with diabetes: the psychological aspects • Improving preventative measures • Raising awareness of Type 1 Diabetes • Future technologies • Type 2 Diabetes: bariatric surgery vs medication For more information: www.diabetes.parlicentre.org
Get involved in the discussion and have your say
Published on Mar 30, 2016
Published on Mar 30, 2016
The March 2016 edition of Government Gazette includes a Health Report that addresses some of the most pressing questions relating prostate c...