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Recruiting serology to the long fight ahead against pandemics

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Europe's ability to respond effectively to health threats has already been called into question by the coronavirus pandemic. Heroic collaboration between researchers and policymakers has made the first vaccines available at record speed, but Europe still stands before a major challenge that goes way beyond the current COVID crisis. There is a critical failure to develop and implement the testing technologies that not only can help protect citizens against COVID-19, but that will also be crucial in preserving public health over the longer term, in the face of future and even more deadly cross-border infections, writes European Alliance for Personalised Medicine (EAPM) Executive Director Dr. Denis Horgan.

To address these topics, EAPM hosted two webinars on the matter. The first virtual round table, 'Forward together with innovation: Understanding the need and framing the discussion for Serology testing for SARS-CoV', took place on 17 December 2020, and the on 'Recruiting serology to the long fight ahead against pandemics', on 3 February. Together they comprehensively highlighted the questions still needing answers and gathered input from European and international public health officials and organisations, academia, and industry.

As the experts concluded, action is needed to introduce meaningful testing strategies leveraging the comprehending strengths of the available testing technologies such as serology. This can contribute to more efficiency of vaccination programs.

Not the end of a battle - just the beginning

"We are only at the beginning now," Bettina Borisch, Executive Director World Federation of Public Health Associations, told a recent expert roundtable on serology testing, organised by EAPM to highlight the challenges and opportunities of making the best use of testing. "We are confronted with not just a short-term crisis but a long one, to ensure future capacity for protection." Testing and diagnosis have been Cinderella areas of medicine for too long, she said, urging the use of serology as a vital element in any pandemic strategy. The point was reaffirmed by Kevin Latinis, a scientific advisor for one of the US task forces to tackle Covid, at a follow-up EAPM roundtable in January: "The pandemic has demonstrated dramatically what an asset adequate testing would be, but the opportunity is being missed," he said. Or, as Denis Horgan, EAPM's executive director, who chaired both roundtables, expressed it: "More vaccines are now becoming available, but it is vital to ensure they are used effectively in clinical practice, and for that we need better understanding of which patients will respond to different vaccines and how the vaccines will tackle variants."

The confident but chilling scientific consensus is that the next decades will bring further and more virulent pandemics that threaten disruption and death on an even greater scale than the current outbreak. And while the hope is that vaccines now being created in extremis will overcome the immediate danger, Europe – and the world – can no longer afford to rely on hasty improvisation. The harsh reality is that much of the current vaccine development is shooting in the dark at moving targets.

As the first vaccines reach the general public at the start of 2021, it is still unknown for how long vaccination confers immunity (and, topically, how much flexibility in altering dosage schedules is justified), how it affects different population groups, or to what extent vaccination impedes transmission. As the European Medicines Agency observes in reporting on its first positive opinion on a Covid vaccine, Comirnaty, "It is not currently known how long protection given by Comirnaty lasts. The people vaccinated in the clinical trial will continue to be followed for two years to gather more information on the duration of protection." And "there were not enough data from the trial to conclude on how well Comirnaty works for people who have already had COVID-19." Similarly, "The impact of vaccination with Comirnaty on the spread of the SARS-CoV-2 virus in the community is not yet known. It is not yet known how much vaccinated people may still be able to carry and spread the virus."

Sharper identification of the nature of the virus – and any of its mutated variants – as well as greater precision over the effectiveness of vaccines and measurements of immunity are still urgently needed.

Help is at hand – in principle…

The mechanisms are available to bring that precision and clarification. Notably, serology testing can help confirm the efficacy of vaccination, and could be used to establish a threshold for protection or immunity. It can also confirm an initial antibody response from vaccination, and provide subsequent tracking of antibody levels at regular intervals. Because data from initial vaccine trials will be limited to certain populations and exposure patterns, serology can provide additional data on antibody response and duration to help inform vaccine efficacy in larger, more-diverse populations, and to determine appropriate use in the context of variables such as ethnicity, level of viral load exposure, and individual immune system strength. Testing is vital also to distinguish successful from suboptimal vaccine responses and to detect antibody declines after natural infection.

How serology testing works...

Serology is the study of antibodies in blood serum. Serologic antibody tests help determine whether the individual being tested was previously infected, by measuring the person’s immune response to the virus—even if that person never showed symptoms. Antibodies are immune proteins that mark the evolution of the host immune response to infection, and they provide an archive that reflects recent or previous infection. If maintained at sufficiently high levels, antibodies can rapidly block infection on reexposure, conferring long-lived protection.

Serology tests are not the primary tool for diagnosing an active infection, but they provide information essential to policymakers. They help determine the proportion of a population previously infected with SARS-CoV-2, providing critical information on infection rates at a population level, and providing information about populations that may be immune and potentially protected. Accurate assessment of antibodies during a pandemic can provide important population-based data on pathogen exposure, facilitate an understanding of the role of antibodies in protective immunity, and guide vaccine development. Population-level surveillance is also critical to the safe reopening of cities and schools.

..but not always in practice

Serology testing is not being used systematically, and in many EU countries there is still hesitation over putting in place the organisation and infrastructure to make it possible.

The European Commission has already pointed out that short-term EU health preparedness depends on robust testing strategies and sufficient testing capacities, to permit early detection of potentially infectious individuals and to provide visibility on infection rates and transmission within communities. Health authorities must also equip themselves to conduct adequate contact tracing and run comprehensive testing to rapidly detect an increase in cases and to identify groups at high risk of disease, it has said in its guidance. But at present, European countries are in many cases falling short and functioning sub-optimally.

Charles Price of the European Commission's health department, DG Santé, admitted that despite the recent intensive collaboration among European Union institutions and the member states, "We are still short of consensus on the best serology tests for particular jobs – to assess the level of infection, to inform vaccination strategies, or to inform clinical decision-making on individuals." These all depend on good serology testing, and the EU is trying to coordinate additional observation at country level of vaccinated populations to feed into evaluation of vaccines by the European Medicines Agency, he told the round table.

Hans-Peter Dauben, secretary general of Euroscan, the international health technology assessment network, also admitted that authorities are often too slow: "We don't have a model to improve our understanding of what is going on," he said. Serological data can be collected within existing systems, he said, but there is no consensus on how it can be used.

He pointed out that while there are multiple settings and scenarios where a diagnostic technology can be used, ranging from clinical usage on treatment decisions in outpatient and inpatient care, and in public health interventions on isolation, tracing and tracking, and epidemiology, "Each scenario requires a unique approach with a set of validation criteria located in the relevant decision-making context."

Exploring the questions

Given the current uneven degree of readiness and capacity among European countries to utilize serology testing technology, and the current absence of plans for systematic serological testing for surveillance, Horgan queried how far public health professionals and institutes understand the barriers and enablers to adoption of serology testing in vaccination surveillance systems. And he questioned whether revised recommendations were needed from the EU on testing strategies and on adaptations to different types of vaccines. "We need to know who to vaccinate and how to vaccinate, and we need to allocate resources accordingly," he said.

Achim Stangl, Medical Director at Siemens Healthineers, was concerned that there is insufficient information about what subpopulations particularly benefit from vaccination, such as immunosuppressed patients, lymphoma patients, or very young children. His colleague Jean-Charles Clouet insisted that there are still open questions on vaccines that only testing will elucidate: "The importance has not been fully grasped of showing the impact of vaccination on the immune system, and of conducting long-term monitoring to define an optimal immunity threshold." Latinis focused on the need to understand not only the immunity conferred by vaccines, but also how far and fast it wanes. Or as Stangl put it, "The big question is how long antibodies are present and able to provide immunity

The questions come in the wake of many similar expressions of concern and counsel. The International Coalition of Medicines Regulatory Authorities warned in 2020 of the need for "stringent regulatory requirements for Covid-19 studies" and agreed to provide guidance on the prioritisation of clinical trials and on serology in order to promote a harmonised approach. The US Centre for Disease Control has issued serology testing guidelines listing important applications in monitoring and responding to the COVID-19 pandemic.

The World Health Organisation states clearly that the use of serology in epidemiology and public health research enables understanding of the occurrence of infection among different populations, and how many people have mild or asymptomatic infection, and who may not have been identified by routine disease surveillance. It also provides information on the proportion of fatal infections among those infected, and the proportion of the population who may be protected against infection in the future. Information that might impact serologic recommendations is rapidly evolving, particularly evidence of whether positive serologic tests indicate protective immunity or decreased transmissibility among those recently ill.

What can be done?

Serology is the scientific study of serum and other body fluids. In practice, the term usually refers to the diagnostic identification of antibodies in the serum.[1] Such antibodies are typically formed in response to an infection (against a given microorganism),[2] against other foreign proteins (in response, for example, to a mismatched blood transfusion), or to one's own proteins (in instances of autoimmune disease). In either case, the procedure is simple.

Serological tests are diagnostic methods that are used to identify antibodies and antigens in a patient's sample. Serological tests may be performed to diagnose infections and autoimmune illnesses, to check if a person has immunity to certain diseases, and in many other situations, such as determining an individual's blood type. Serological tests may also be used in forensic serology to investigate crime scene evidence. Several methods can be used to detect antibodies and antigens, including ELISA,[4] agglutination, precipitation, complement-fixation, and fluorescent antibodies and more recently chemiluminescence.

All this increases the chances of monitoring the spread of Covid-19 infection. Vicki Indenbaum of the World Health Organization told the round table that serology will become more important not only before vaccination, but after vaccination takes place, to let public health decision-makers know exactly what is going on, and what proportion of population has been infected. It is, she said, an essential element to ensure trust between policymakers, professionals and the public. Sarper Diler, a Faculty Member Istanbul University Istanbul Medical Faculty in Turkey, similarly urged a more rigorous schedule of serology tests, "before vaccination, and some months after to see whether a booster shot is needed or not, and to see the impact on wider populations." He also called for development of wider array testing to detect antibodies as vaccines – and virus variants – evolve.

What's needed now

A co-ordinated response across Europe – and beyond – is needed now to ensure that serology can play its part in defending citizens against pandemic infections.

Diler emphasised the importance of communication with citizens to minimize fear and anxiety and non-compliance with preventive behaviour: "We have to find a common language to communicate, and right now it is lacking in Europe," he said. His point was reinforced by Latinis and Daubens, who both warned that a confusion of voices is distracting for strategy formation and implementation. Boccia too urged building trust among public and professionals so as to minimise the likelihood of vaccine hesitancy – and for this, she indicated, clarity over the mechanisms of vaccination is essential.

Some consensus emerged from the roundtables on the need for testing itself to be refined and stepped up. Serology assays should have the appropriate characteristics for assessment of need to vaccinate and vaccine response: an automated, scalable serology assay used in the context of vaccination should include key technical features for effective use: measurement of spike receptor-binding domain neutralizing IgG antibodies, very high (≥99.5%) specificity, and quantitative results.

The requirements also extend to infrastructure. This applies to capacity as well as to physical facilities. Availability at a large and accessible scale is key to ensuring that the needs of the population can be met. This would allow for measuring antibodies in relation to vaccine use for establishing a threshold for protection or immunity, for confirming an initial neutralizing antibody response shortly (approximately 1 week to 1 month) after vaccination, and for tracking of antibody levels (at approximately 3, 6, and 9 months and annually) following vaccination. In the event of limited vaccine availability, antibody assessment can also support decision making for administration to the most vulnerable populations.

Strangl pointed out that the unprecedented speed at which COVID 19 vaccines have been developed leaves the scientific community with very limited data on duration of effective immunity and safety, and on the variability of responses among minority and underserved populations, children and the elderly, "many of whom may not develop antibodies to one or another of the vaccines," he added.

In these circumstances, serology testing can prioritize the use of vaccine resources and inform long-term vaccination strategy. Prior to vaccination, it can help prioritize individuals for vaccination , establish serological baselines and help ensure scarce supply reaches the most vulnerable. Testing one week to one month after vaccination can confirm an initial neutralizing antibody response, and help ensure that the antibody response clears the threshold for immunity. Further testing 3 six and nine months after vaccination can confirm persistence and duration of immunity , and can provide the means 2 agree on abridged trial requirements for additional populations. And testing annually after vaccination can assess persistence and duration of immunity and inform requirements for future vaccinations.

As Stangl summarized it: "Successful implementation of broad serological testing will require the right tools." This means quantitive considerations to establish a protective threshold, assess response and monitor antibody levels overtime. It means testing of specificity high enough for investigating responses in low-prevalence populations, and capable of minimizing false positive results. And it means capacity, reach and speed for sufficient production to address large populations, a large fleets of immunoassay analyzers installed worldwide, and high analyzer productivity and ease of use.

The European Commission's Communication ‘Preparedness for COVID-19 vaccination strategies and vaccine deployment’ notes that “to monitor the performance of the vaccination strategies, it is essential for member states to have suitable registries in place. This will ensure that vaccination data is appropriately collected and enables the subsequent post-marketing surveillance and ‘real time’ monitoring activities. Member states should ensure that …vaccination registries are up-to-date". Dauben suggested that all vaccinated patients should be included on a mandatory registry to allow proper study of the effects.

Stefania Boccia of Milan's Università Cattolica del Sacro Cuore quoted the recommendations of the EU expert panel on effective ways of investing in health, including integrating information and communication technologies across care levels and public health, and investment in comprehensive resilience testing of health systems and sharing of lessons. She also highlighted findings from EU surveys of member states over recent months that show the still incomplete status of monitoring systems for vaccine coverage, safety, effectiveness and acceptance. Survey conclusions also note that recommendations will be updated "as more evidence becomes available about COVID-19 disease epidemiology and characteristics of vaccines, including information on vaccine safety and efficacy by age and target group."

A serology-defined threshold (from either natural infection or vaccination) remains a key need, and this periodic testing would offer additional data on antibody response patterns to determine optimal serology testing utilization. Longer-timeframe quantitative testing for waning levels of protective antibody, such as through annual testing, would inform the need to revaccinate/boost.

To bring these changes into play, policymakers will need evidence, along with data points needed to substantiate that evidence. A framework of panels of experts will have to be created in which guidance can be offered to support decisions on the use of serological testing. And as Latinis remarked, "It is ultimately up to us who uses serology testing to convince politicians to implement it."

And where should this go?

The round table concluded that this was a key moment for the development of a new approach to pandemic preparedness. The current spread of infection – lamentable though it is in its human consequences – provides an unprecedented scientific opportunity for improving understanding of immunity, vaccination and related mechanisms. With adequate, and adequately rigorous, testing in place, it will be possible to evaluate without risk of bias different populations being treated with different vaccines across the world.

To allow the benefits to accrue from this situation, data will have to be collected and compared from a wide range of studies, and at a truly global scale. This in turn will depend on all stakeholders being ready to operate outside and across the customary siloes that characterise the health community, and to adopt a common language based on a new literacy. But by extension of the EU's new ambition to build a European health union, and taking as a model such international concords as the Paris climate agreement or the UN framework convention on tobacco control, what could and should emerge is a co-ordinated international response to future health crises of this scale, in an international pandemic treaty.

Cancer

Lung cancer screening is ready to rescue thousands from death: Can the EU take action?

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While Europe mulls multiple praiseworthy schemes to limit the damage inflicted by cancer, one of the most promising avenues is being neglected – and many Europeans are dying unnecessarily as a consequence. Lung cancer, the biggest cancer killer, is still on the loose, largely unchecked, and the most effective method for combating it – screening – is unaccountably being ignored, writes European Alliancce for Personalised Medicine (EAPM) Executive Director Dr. Denis Horgan.

Screening is particularly important for lung cancer because most cases are discovered too late for any effective intervention: 70% are diagnosed at an advanced incurable stage, resulting in the deaths of a third of patients within three months. In England, 35% of lung cancers are diagnosed following emergency presentation, and 90% of these 90% are stage III or IV. But detecting disease long before symptoms appear permits treatment that forestalls metastasis, drastically improving outcomes, with cure rates above 80%.

Over the last two decades the evidence has become overwhelming that screening can transform the fate of lung cancer victims. Disturbingly, however, EU member states still hesitate over its adoption, and it remains low on policy priorities nationally and at EU level.

A valuable opportunity to remedy this deficiency is in the offing. Before the end of 2020, the European Commission has unveiled Europe's Beating Cancer Plan, a major opportunity to guide national actions. It will be, in the words of Commission President Ursula von der Leyen, "an ambitious cancer plan to reduce the suffering caused by this disease.” Preparatory drafts suggest it will offer a powerful, coherent and almost comprehensive response to the havoc that cancer wreaks on lives, livelihoods and quality of life across Europe.

Almost comprehensive. Because on the potential for lung cancer screening to save lives, it has little to say. The document is commendably strong on prevention, where there is, as it points out, important scope for improvement, with up to 40% of cancer cases being attributed to preventable causes. It also highlights screening as a vital tool in colorectal, cervical and breast cancer. But screening for lung cancer – which alone kills more than those three cancers combined - receives only a few passing references in the draft text, and no endorsement commensurate with the impact of its implementation at scale. This threatens to leave LC screening in its current under-exploited status in the European Union, where although the disease is the third leading cause of death, there is still no EU recommendation for systematic screening, and no large-scale national plan.

The case for action

The most recent studies add to an accumulation of evidence of the merits of LC screening over the last two decades. A just-published IQWiG study concludes that there is a benefit of low-dose CT screening, and "the assumption that screening also has a positive effect on overall mortality seems justified." Some studies show it saves an estimated 5 in 1000 people from dying of lung cancer within 10 years, while others warn that 5-year survival among all patients with lung cancer is barely 20%. Every year, at least twice as many people die from lung cancer as from other common malignancies, including colorectal, stomach, liver and breast cancer. In Europe it causes more than 266,000 deaths yearly - 21% of all cancer-related deaths.

Late presentation precludes for many patients the option of surgery, which – despite continuing improvements in other forms of therapy – is currently the only demonstrated method to improve long term survival. The concentration of patients among smokers adds a further urgency to the introduction of systematic screening. Efforts to discourage and reduce tobacco use will have effects only over the longer term. Meanwhile, the best hope for the millions of smokers and former smokers – predominantly among the most disadvantaged populations of Europe – is in screening. But this is precisely the population that is hardest to reach – reflected in the fact that fewer than 5% of individuals worldwide at high risk for lung cancer have undergone screening.

The prospects for change

Europe’s Beating Cancer Plan (BCP) holds out the prospect of many improvements in tackling cancer, and its vision embraces admirable principles – including the merits of screening, technology and enlightened guidance. It foresees "putting the most modern technologies at the service of cancer care to ensure early cancer detection." But as long as it hesitates over endorsing screening for lung cancer, a major opportunity will remain neglected.

The BCP acknowledge that live are saved by early detection of cancer through screening. They speak approvingly of population-based screening programmes for breast, cervical and colorectal cancer in national cancer control plans, and of ensuring that 90% of the qualifying citizens will have access by 2025. For screening of these three cancers, they even envisage reviewing the Council Recommendation, and issuing new or updated Guidelines and Quality Assurance schemes. But lung cancer screening enjoys no such priority in the BCP, which are limited to allusions, to a "possible extension" of screening to new cancers, and to a consideration of "whether the evidence justifies an extension of targeted cancer screening."

As Europe enters the third decade of the century, significant evidence has already justified action to implement LC screening. It is not the time to be debating whether the evidence is sufficient. The evidence is in. "There is evidence of a benefit of low-dose CT screening compared to no screening," says one of the recent studies. The NLST study demonstrated a relative reduction in lung cancer mortality of 20% and a 6.7% reduction in all-cause mortality in the LDCT arm. 5-year survival in patients diagnosed early (stage I-II) can be as high as 75%, especially in patients who have a surgical resection. Earlier diagnosis moves the focus from palliative treatment of incurable disease to radical potentially curative treatment with a resultant transformation of long-term survival. LuCE claims that five-year survival rates for NSCLC could be 50% higher with earlier diagnosis.

Historic objections to LC screening – in terms of risks of radiation, overdiagnosis, and unnecessary interventions, or uncertainties over risk models and cost effectiveness – have been largely answered by recent research. And given the commitment of the BCP to put research, innovation and new technologies at the service of cancer care ("the use of technology in healthcare can be a lifesaver", says the latest draft), it might well provide for further studies to refine and clarify the areas where LC screening can be even further improved, and the necessary infrastructure and training be consolidated.

Maximizing the opportunities for diagnosis too

There are other aspects of BCP linked directly or indirectly to screening which could – and should – enhance early detection and accurate diagnosis of lung cancer. Draft texts already make mention of exploring "early diagnosis measures to new cancers, such as prostate, lung, and gastric cancer." By providing more precise information on tumours, lung cancer screening has opened the way to more personalized treatment for lung cancer and provides fertile ground for further innovations in technology, image analytics and statistical techniques, and future image interpretation will be increasingly assisted by computer-aided diagnostics. The EU's parallel Mission on Cancer is expected to generate new evidence on the optimisation of existing population-based cancer screening programmes, develop novel approaches for screening and early detection, and provide options to extend cancer screening to new cancers. It will also contribute to providing new biomarkers and less invasive technologies for diagnostics. The new ‘European Cancer Imaging Initiative’ will facilitate the development of new, enhanced diagnostic methods to improve quality and speed of screening programmes using Artificial Intelligence, and promote innovative solutions for cancer diagnostics. A new Knowledge Centre on Cancer will function as an ‘evidence-clearing house’ for early detection through screening. An upgraded European Cancer Information System will facilitate the assessment of cancer screening programmes through improved data collection on cancer screening indicators. The analysis of interoperable electronic health records will improve understanding of disease mechanisms leading to the development of new screenings, diagnostic pathways and treatments.

These are encouraging concepts, and could – if implemented – assist the refinement of early detection and diagnosis. But it would be even more promising if the recognition of improved access to biomarker testing on diagnosis and progression extended to treatment, and to advancing the emergence of personalised medicine. The BCP could be the context for a more systematic development of biomarker testing. Perhaps data on variations in testing rates could be included in the envisaged cancer inequalities registry.

Similarly, taking advantage of other technology advances in treatment could give patients still greater chances of survival and of quality of life. In addition to the critical role played by radiology in screening, radiotherapy itself has advanced substantially during the past two decades, with new technologies and techniques allowing ever more accurate, effective, and less toxic treatments, thus allowing shorter and more patient-friendly regimens. It is now established as an essential pillar in multidisciplinary oncology. And as with all the other opportunities in better screening, diagnosis and treatment, appropriate coverage in healthcare budgets and reimbursement systems is essential if good intentions are to be converted into action.

Conclusion

What is essential is that LC screening programs be implemented in a comprehensive and coherent and consistent manner, rather than arising as a by-product of sporadic ordering of scans by providers without a programme infrastructure in place. Given the potential for such a large number of lives to be positively impacted by a timely diagnosis of early-stage treatable disease, the initiation of these programmes should be given the highest priority by healthcare institutions and providers. The new EU Cancer Screening Scheme envisaged in the BCP should have its vision extended beyond breast, cervical and colorectal cancer screening to lung cancer. The Commission proposal to review the Council recommendation on cancer screening is a positive step forward.

The challenge now is to act, and to implement LC screening – and in so doing, to save lives and prevent avoidable suffering and loss across Europe. If the EU does not take advantage of initiatives such as BCP, long-overdue improvements in lung cancer care will be deferred again, with the worst impact felt in Europe's most disadvantaged populations. Policy makers should recognise this unexploited potential, and should respond by driving implementation.

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European Alliance for Personalised Medicine

EAPM update: How to put Europe Beating Cancer Plan into practice

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It is finally with us – the Europe Beating Cancer Plan was formally launched at an EU level last week (4 February), but as the European Alliance for Personalised Medicine (EAPM) has become only too aware in its years of striving for the very best progress in terms of health care and health issues, the question as ever now is how the plan will be implemented in practice, writes EAPM Executive Director Dr. Denis Horgan. 

Factsheets to the rescue

EAPM has, for the past six months, been very hard at work on developing country-oriented factsheets with leading experts in the field and looks to combat lung cancer across key pillars.   Stakeholders' views on national barriers and enablers in tackling lung cancer were obtained via an online survey during seven structured expert panels. Stakeholder groups represented pathologists, lung specialists, the regulatory field, health systems, industry representatives and patient perspectives.

Factsheets covered the following countries and are available here: Slovenia, Greece, Portugal, GermanyDenmark, Italy Belgium, NetherlandsSwitzerland, SwedenPolandBulgariaCroatiaIsrael and Romania. 

As far as the factsheets are concerned, each concentrate on seven core aspects of lung cancer care, which are as follows:

1.     Screening programmes

2.     Access to molecular testing

3.     Personalised treatment decisions

4.     Early and broad access to personalised treatments

5.     Remote monitoring and personalized interventions

6.     Data empowerment and advanced analytics

7.     Prioritization within national health strategy

In addition, each factsheet for each country provides a policy checklist in conclusion. 

Working together

The European Commission will be looking to seek consensus from member states’ health ministers to move the action plan forward, and it will be an interesting challenge to observe the levels of co-operation from member states on health-related matters following on from the coronavirus pandemic. While member states are in control of health policies, there has nevertheless been divergence between them concerning the COVID-19 responses prepared by the Commission. 

Whether member states will align with the ambition as set in cancer plan with the action committee on cancer within the European Commission is unclear but, given that Eurostat's latest data shows that lung cancer is the third leading cause of death in the EU-27, exceeded only by ischaemic heart disease and cerebrovascular disease, one can only hope that the relevant policymakers and institutions will be able to work together.

The toll from lung cancer cannot be underestimated – it kills more than 80 in 100,000 men in Europe and more than 20 per 100,000 women – and for women that figure is rising. It is far more lethal than other cancers, accounting alone for more than a fifth of all cancer deaths, with other leading cancers - colorectal, breast or pancreatic cancer – at half the rate of lung cancer or less.  

This is a major problem for all member states but is particularly acute in some: Hungary recorded the highest standardized death rate from lung cancer in 2017 (89.2 deaths per 100,000 inhabitants), followed by Croatia (68.4 deaths per 100,000 inhabitants), Poland and Denmark (67.0 and 66.8 per 100,000 inhabitants respectively).

The predominant cause of the lethality of lung cancer is late presentation: 70% of lung cancer cases are diagnosed at an advanced and incurable stage, resulting in the deaths of a third of patients within three months. A leading study shows that from 2009 to 2015, 57% of patients had distant metastases at diagnosis, only 16% of patients had localized disease, and the five-year survival rate among all patients with lung cancer was 20.6%. In England, 35% of lung cancers are diagnosed following emergency presentation and of these 90% are at later stages. 

According to EAPM, mechanisms are available to reduce the morbidity and mortality of lung cancer, but health systems are slow to take advantage of them. Europe’s citizens and patients would benefit from wider adoption of risk-based screening, early use of advanced diagnostics, early access to the growing number of personalized treatment options, better patient follow-up and remote monitoring, and systematic exploitation of data. 

With the correct application of new technologies and methods, the principal beneficiaries will be today’s – and still more, tomorrow’s – patients and their carers and entourage. And correctly implemented, these technologies could even allow health-care spending and even national economics to gain from a reduction in the consequences and even in the incidence and mortality of lung cancer.

Hence, member states should engage fully in the action plan and engage in discussions at an early stage. They should represent their views before officials take over the action plan and begin drafting implementation actions with the other institutions.

Conclusion and recommendations

The fight against lung cancer, for many years one of the most intractable healthcare challenges, and still a major killer, is on the threshold of new victories. A combination of  scientific advances, new technology and new practices brings within reach early diagnosis, effective treatment, and more sustainable allocation of healthcare resources.

It remains for EAPM and lung-cancer stakeholders to continue pushing for political commitments and for structures that provide for evidence based decision-making exploiting the most advanced technologies. The EU Beating Cancer Plan offers scope for tailored interventions to advance the lung cancer agenda.

The overarching key to progress now will be implementation of the action plan, and thankfully, the EAPM factsheets provide a very useful and accessible starting point as to how this can take place. The fact sheets are available here: Slovenia, Greece, Portugal, GermanyDenmarkItaly BelgiumNetherlandsSwitzerland, SwedenPolandBulgariaCroatiaIsrael and Romania. 

Have the best weekend possible, and keep safe.

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European Alliance for Personalised Medicine

Unnecessary loss of life, and how to avoid it - The potential of lung cancer screening

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Unnecessary loss of life – but not from COVID-19. At a time when the coronavirus infection is already inflicting a frightening death toll on the world from a previously unknown health threat, Europe cannot afford to tolerate another unnecessary and large-scale loss of life from a disease that has long been well recognized: lung cancer. But institutional neglect is causing unnecessary loss of life, according to oncologists, pulmonologists, radiotherapists, technology developers and patient representatives from across Europe. In a European Alliance for Personalised Medicine (EAPM) round table they focused on persistent delays in promoting the lung cancer screening programmes that could save thousands of life-years, writes EAPM Executive Director Dr. Denis Horgan.

In Europe, lung cancer, the leading cause of cancer-related morbidity and mortality, causes more than 266,000 deaths each year - 21% of all cancer-related deaths. That's not quite as high as coronavirus's death rate in 2020, but these lung cancer deaths are not a one-off crisis that has provoked an unprecedented mobilisation to bring it under control. Lung cancer deaths are happening relentlessly year after year, and are likely to continue to do so for decades to come - unless incisive high-level decisions are taken to challenge the trend, said Dr. Horgan, introducing the round table. And as Anne-Marie Baird, president of cancer patient group LuCE, pointed out: "These are not just statistics. Each patient lost is a loss to families and friends."

How screening can change the picture

Screening is the most obvious route to arresting this destruction of life. Screening permits the early diagnosis that is crucial in a disease that is frequently discovered too late for any effective intervention. At present, many patients are identified only when their disease is incurable: fewer than 15% will survive for five years. Screening can turn that picture round. For every 1,000 people screened, five of them who would have died from lung cancer will have their survival extended beyond ten years.

A just-published IQWiG study concludes "the assumption that screening also has a positive effect on overall mortality seems justified." Detecting disease long before symptoms makes intervention possible with treatment that drastically improves outcomes, and leads to cure rates above 80%. "A lot of lives can be saved," said Giulia Veronesi of the Ospedale San Raffaele in Milan. And according to Baird, early diagnosis could save up to 4 million people across the world.

The evidence is overwhelming: randomised trials estimate a significant 20% reduction in lung cancer mortality when screening is used to identify those at high risk. But the potential of screening is being largely ignored by European health authorities, and opportunities for saving life are neglected. Irish MEP Sean Kelly warned the round table that "further delay to implementation of the best form of lung cancer screening will mean more unnecessary lives lost".

For Baird, the right form of cancer screening in a high-risk population is the best way of working towards improved European outcomes. Jens Vogel-Claussen, Vice Chair of the Institute of Diagnostic and Interventional Radiology at Hanover Medical School, insisted that it was more than high time to take action: "People are suffering, and we have the ability to stop it."

Marie-Pierre Revel of the University of Paris Descartes Service de Radiologie at the Hôpital Cochin described the paradox that there is strong scientific evidence of the benefit of lung cancer screening, and there are now optimized screening strategies that offer dose reduction and provide few false positives – but implementation is still awaited. There are only a few European countries that operate national screening programmes. And Witold Rzyman, Chief Thoracic Surgeon in the Medical University of Gdansk, demanded: "Why is screening not yet implemented in the EU? Its merits have been apparent for ten years, and there is wide interest in it from across the medical community involved in cancer care, in biology, equipment, therapy, and surgery."

Impediments to action

Why is lung cancer screening being neglected? There is more than one reason. But none of them is good.

The most simple but most sombre reason would seem to be the negative prejudice about lung cancer. Since this is a disease most prevalent among smokers, a vestigial sense of "these people have brought their misfortunes on themselves" still persists, often compounded by the challenges of securing engagement from hard-to-reach populations where fatalism, if not nihilism, can inhibit the search for care.

But this is an unacceptable reflex in an EU committed to equity of healthcare opportunity and to overcoming the unevenness that permits inequalities not only from country to country but also from one section of the population to another. To reverse this tendency it should be enough to reflect that disadvantaged communities – for this is where smoking remains most common – deserve additional rather than less attention, as part of a policy of redressing imbalances. Mechanisms and approaches are available and are being constantly refined in national pilots to make possible effective intervention with high-risk populations on the ground. But it still needs a shift in priorities at policy level.

Another factor is the persistent negative perception of the risk-benefit ratio of lung cancer screening. The belief remains in many quarters that its merits are insufficiently demonstrated, its processes too ponderous or too imprecise, or that it can generate too many false negative results, breeding delusions of complacency, or false positives prompting unnecessary and potentially harmful interventions. The perception is amplified by outdated views of lung cancer screening and treatment as low-tech and offering little hope of improved outcomes.

But that is manifestly inaccurate. Since the beginning of the 21st century, the opportunities for treatment of lung cancer have expanded dramatically, with the earlier dependence on histology and chemotherapy being supplanted by growing insights around tumour biology, and diagnostic technologies that allow targeted treatments. Risk-based lung cancer screening strategies now focus on at-risk patients stratified on scientifically objective criteria, with AI increasingly recruited for reinforcing quality assurance. Where lung cancer screening programmes have been implemented, annually, up to 3% of participants are diagnosed with lung cancer, 50–70% of them with stage I disease, and these patients usually undergo surgery with curative intent.

There are further refinements underway in methodology and in equipment: the ever-more precise identification of the target population that will derive the greatest benefits, improving participant recruitment and compliance, the ideal frequency of screening, integration of screening with other public health interventions – including effective smoking cessation, and demonstrations of cost-effectiveness.

Richard Booton, Clinical Senior Lecturer and Honorary Consultant Respiratory Physician at The University of Manchester and North West Lung Centre, explained how stratification obviates the need to screen unnecessarily: the right criteria relating to factors such as age, smoking history, body mass, or cancer history can bring new degrees of accuracy to screening programmes. "The efficiency of diagnostics and treatment high when there is an adequate structure," he told the round table. Luis Seijo Maceiras, co-director of the Department of Pulmonology at the Clínica Universidad de Navarra, pointed to the improved predictive identification of risk factors and the additional precision that improvements to biomarkers will bring.

Yolande Lievens, chairman of Radiation Oncology at Ghent Faculty of Medicine and Health Sciences, expounded the major improvements in radiotherapy, with less toxic treatments and shorter and more patient-friendly regimens, widening the treatment options available to patients identified early as a result of screening. And the advances in radiology now permit screening with low-dose techniques that provide unprecedentedly high levels of image detail, eliminating the risks perceived in imaging techniques of a decade and more ago.

Cost has also been advanced as a prohibitive aspect of lung cancer screening, but studies now demonstrate that in populations with a history of smoking, the benefits even in economic terms – to say nothing of the personal value – outweigh the investment. And, as Francesco de Lorenzo, Past President of the European Cancer Patient Coalition, remarked, it is necessary to compare any costs of screening with the huge slice of healthcare budgets taken up by treatment of late-stage cancer patients whose disease was not identified early enough to prevent metastasis. Marko Jakopovic, head of the Thoracic Oncology Unit in Zagreb's University Hospital Centre, endorsed the point vigorously, pointing to the cost of spiralling costs of new immunotherapy-based treatments.

The misperception of lung cancer and a wide lack of awareness of the evolution of lung cancer screening have conspired to produce systematic institutional neglect.

While the EU has for nearly twenty years had in place recommended screening guidelines for breast, colorectal and cervical cancers, still no EU guidelines exist for lung cancer screening. Worse, the current EU plans for updating its existing screening guidelines once again omit lung cancer. "It is surprising that the biggest cancer killer doesn't have screening guidelines," said Cristian Busoi, the Romanian physician who chairs the European Parliament's internal market and consumer affairs committee, in his opening remarks to the roundtable.

The absence is all the more striking since, as Horgan pointed out, most EU countries did very little on screening for colorectal or breast cancer until after the EU recommendation emerged in 2002 – at which point, most of them initiated plans. The EU's emerging European Beating Cancer Plan is another case in point: it highlights screening as a vital tool in colorectal, cervical and breast cancer, but on screening for lung cancer – which alone kills more than those three cancers combined – it offers only a few passing references in the draft text, and no endorsement commensurate with the impact of its implementation at scale.

This semi-official neglect of lung cancer screening is, in some ways, self-reinforcing. The lack of Europe-level involvement perpetuates national divergences of approach – ranging from mildly interested in some member states to frankly indifferent or even hostile in others. The diversity and range of approaches was amply illustrated by presentations from panellist after panellist. The diversity in turn feeds back into an absence of pressure on individual countries or authorities to take initiatives – and crucially, to fund them. With member states going their own way, there are few opportunities to scale up useful demonstrations and to harmonise best practices.

"Every country faces challenges in implementing lung cancer screening, but these would be more easily overcome by a concerted EU approach," believes Luis Seijo Maceiras, Co-director of the Department of Pulmonology at the Clínica Universidad de Navarra. "An EU impulse would pressure Spain and overcome inertia among the health authorities."

Revel noted that the European Society of Radiology and the European Respiratory Society favour organised pathways to adapt Europe's health systems to earlier diagnosis of lung cancer and reduced mortality, rather than relying on unsupervised initiatives. "Now is the time to set up and conduct demonstration programmes focusing on methodology, standardisation, tobacco cessation, education on healthy lifestyle, cost-effectiveness and a central registry," she said. Tit Albreht, associate professor of public health at Ljubljana University's Faculty of Medicine and a key figure in EU cancer policy development for more than a decade, agreed: "We need implementation experience," he said in his closing speech to the round table.

Solutions

The impediments to action can be resolved. There are technical answers to satisfy earlier concerns about methodologies and techniques, and there are political initiatives that can create a more conducive healthcare framework for integrating lung cancer screening.

The opportunities for treatment, particularly in populations evidently at high risk, can be amplified. Those at highest risk are most likely to benefit from lung cancer screening, less likely to participate, more likely to be of lower socioeconomic background and more likely to be current smokers, said Booton, who spelled out some of the approaches he has used to ease access in geographies where hard-to-reach subjects live.

Local engagement and appropriate health education, proximity of screening services and smart integration into an organised healthcare structure for follow-up can transform reluctance and boost recruitment, he claimed. Even modifying the terminology – to the more neutral 'lung check' – can diminish hesitancy, he suggested. The path would be made easier, he urged, with appropriate guidelines in place, to "provide a framework for implementation, promote early detection, reduce mortality, assist prevention, and reduce inequality and utilization of healthcare resources".

Lievens too saw the merit of guidelines as a necessary aid to wide-scale implementation. They could, the panel agreed, mean that valuable local and national pilots would be taken account of at EU level. They would also promote collaboration between specialties and primary care, or reimbursement and financing, standardise reporting, ensure education of healthcare professionals, and even extend to access to and reinforcement of the necessary infrastructure for testing and data exchange. Albreht stressed the need for integration of screening, into systemic health promotion, early detection, diagnosis, and treatment.

There are potential opportunities in the near future to remedy some of the current deficiencies and to take advantage of what lung cancer screening can do.

Jan-Willem van de Loo of the European Commission's Health Research department spelled out the options emerging from the Cancer Mission now in preparation, with its goal of optimising existing screening programs and developing novel approaches for screening and early detection. It has set a target of Increasing the proportion of cancer diagnosed at an early stage by 20% by 2030 – and lung cancer screening could play a central role in that effort.

The Cancer Mission – along with the EBCP and other EU initiatives, such as the EU4Health programme with its €5.1 billion budget - could provide funding for further studies that would win greater acceptance and lead to its widespread adoption at scale. Busoi expressed commitment to the fullest political support for official EU engagement in lung cancer screening, from himself, and from his group in the Parliament. And Kelly fully endorsed all measures that might lead to achieving the Cancer Mission goal.

A straightforward proposition

Over the last two decades the evidence has become overwhelming that screening can transform the fate of lung cancer victims. Disturbingly, however, EU member states still hesitate over its adoption, and it remains low on policy priorities nationally and at EU level. In consequence, funding for it, and reimbursement of screening services, remain patchy and inadequate, and it is not yet integrated satisfactorily into healthcare systems.

The proposition is straightforward. Lung cancer is currently both the most commonly diagnosed cancer (accounting for 11.6% of all cancer diagnoses) and the leading cause of cancer-related mortality (18.4% of overall cancer mortality) in both men and women worldwide. Every year, at least twice as many people die from lung cancer as from other common malignancies, including colorectal, stomach, liver and breast cancer. The majority of patients with advanced lung cancer die within 5 years of diagnosis. But patients identified with stage early disease have at least a 75% chance of survival over 5 years.

Screening is particularly important for lung cancer because most cases are discovered too late for any effective intervention: 70% are diagnosed at an advanced incurable stage, resulting in the deaths of a third of patients within three months.

In England, 35% of lung cancers are diagnosed following emergency presentation, and 90% of these 90% are stage III or IV. To substantially reduce lung cancer mortality over a longer period, early detection using low-dose screening in asymptomatic individuals can offer life and quality of life-years to individuals currently condemned to unidentified progression of disease to an incurable stage.

The tools are there to improve the situation. They are just not being used. As Sebastian Schmidt of Siemens said: "Efficacy is proven. Don't waste more time!" Or, as Revel reflected: "Now we have all the evidence we could be blamed for doing nothing."

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