Number 44, September-October 2011
Education & knowledge through people & facts
➜ Julio Celis: bridging science and politics ➜ ESO’s Masterclass: building an army of brilliant and caring young oncologists ➜ ESTRO at 30: still focused on its vision for a cure ➜ These big survival gaps are not acceptable: it’s time for governments to act
Editorial Securing quality cancer care: Governments must step up to the plate
Cover Story Julio Celis: bridging science and politics
e-Grand Round State-of-the-art treatment for advanced melanoma
Best Cancer Reporter The future of cancer as told through the story of Renee
Editorial Assistant Corinne Hall
Editorial Advisors Jacques Bernier Fatima Cardoso Franco Cavalli Alberto Costa Vincent T. DeVita
Masterclass The ESO Masterclass: where those most eager to learn meet those most willing to teach
Contributing Writers Marc Beishon, David Cunningham Janet Fricker, Mark Henderson Peter McIntyre, Philip Saylor Tom Waddell, Anna Wagstaff
Impact Factor Denosumab – a new option for solid tumours metastatic to bone Perioperative therapy improves gastro-oesophageal cancer survival
Newsround Selected news reports
Spotlight on... Thirty years on, ESTRO remains focused on its vision for a cure
Systems & Services A minimum acceptable standard of care for every patient
Editor Kathy Redmond firstname.lastname@example.org Assistant Editor Anna Wagstaff
Publishing Advisors Gillian Griffith, Fedele Gubitosi Website Liaison Corinne Hall Art Editor Jason Harris Production HarrisDPI www.harrisdpi.co.uk Printed by Grafiche Porpora Cover photograph Jens Nargaard Larsen Published by European School of Oncology Direttore responsabile Alberto Costa Registrazione Tribunale di Roma Decreto n. 436 del 8.11.2004
All enquiries about Cancer World should be made to: ESO Editorial Office Via del Bollo 4 20123 Milan, Italy e-mail: email@example.com Tel: +39 02 8546 4522 Fax: +39 02 8546 4545 All correspondence should be sent to the Editor at firstname.lastname@example.org
Copyright ©2011 European School of Oncology. All rights reserved
Cancer World is published six times per year by the European School of Oncology. It is distributed at major conferences, mailed to subscribers and to European opinion leaders, and is available online at www.cancerworld.org
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Securing quality cancer care:
governments must step up to the plate ➜ Kathy Redmond ■ EDITOR
our chances of being alive five years after being diagnosed with colorectal cancer are around 38% higher if you live in England than in the Slovak Republic, and around 63% higher if you live in Germany. Similar variations in survival are found for most cancers. In an attempt to explain why this is happening, the Organisation for Economic Cooperation and Development (OECD) recently made a cross-country analysis of how cancer care systems perform. It found that variations in resources, and in access to care, the effectiveness of care, and the way the cancer care system is organised, are all important predictors of survival. The countries that perform best are those that invest in cancer care and health infrastructure in general, have a national cancer plan, set cancer-specific targets, develop networks for service delivery and use quality assurance mechanisms to ensure patients gain access to high-quality cancer care. The message is that underperforming countries need not only to invest more resources into cancer care, but also to improve the process quality and governance of cancer control. Sadly, many European governments are failing to address these issues adequately, while some are doing nothing at all. There is broad agreement that cancer care should be patient-centred, evidence-based, safe, effective and integrated. But defining what this means in practice and how it can be measured can be difficult. A number of European organisations have taken on the challenge of defining standards and quality indicators for specific components of cancer
care and introducing mechanisms for improving quality. The Organisation of European Cancer Institutes recently awarded Comprehensive Cancer Centre accreditation to five European centres that meet quality criteria and are committed to continuous quality improvement. EUSOMA has introduced voluntary certification for specialist breast units, with 22 units across Europe achieving certification to date, while the EBMT has accredited more than 100 European transplantation centres through its long-standing JACIE programme. Other groups are just beginning to set up programmes to improve the quality of cancer care. SIOPE has identified European Standards of Care for Children with Cancer and is working to raise awareness of the need for all children to have access to high-quality paediatric cancer care. ECCO is creating a European colorectal cancer audit structure – EURECCA – to help drive improvements in colorectal cancer surgery. These are all voluntary efforts that are being implemented with little or no funding from governments but lots of enthusiasm from professionals who recognise the potential to do better by embracing the concept of continuous quality improvement. If the OECD is right in asserting that process quality and governance are key predictors of cancer survival, then why are we still so dependent on ad hoc, voluntary efforts to define and measure the quality of cancer care? Governments should now shoulder their responsibilities to implement, in partnership with relevant stakeholders, a systematic approach to quality assurance at all levels of cancer control. What are they waiting for?
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Julio Celis: bridging science and politics ➜ Marc Beishon
Julio Celis is a scientist to his core, and can lay claim to being one of the fathers of proteomics. But it is in helping shape the structures and vision of Europe’s cancer research effort that he has arguably had the greatest impact. Better coordination and networking have shown what’s possible, says Celis, the challenge now is to move from piecemeal short-term initiatives to something more sustainable.
here are two main aspects to complexity in cancer. The first is the hugely challenging biological nature of cancer, as researchers dig ever deeper into the molecular structures and pathways of tumour cells, uncovering layer upon layer of complexity as they go. The second is the world of ‘oncopolitics’ and the way in which healthcare and research organisations are set up to tackle cancer at national and regional levels – and there is arguably no more complex world in oncology than the European Union and its relationship with an expanding number of member states. Understanding how best to bring these two demanding areas together is vital if resources are to be deployed to best effect, and Julio Celis has been bridging both science and politics for some time now to this end. A research biochemist of longstanding, based at the Danish Cancer Society in Copenhagen, and a veteran of many international
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committees, he is now taking his experience to the heart of Europe on behalf of ECCO to help drive a research policy that is formulated by scientists and clinicians in the field – and not only by administrators. “The problem has been that the research community has not looked into the future and prepared the ground to influence decision makers about where we should be going,” says Celis. “We don’t tend to get involved until we are affected in a big way, such as with the clinical trials directive, and we have never really had a Europe-wide vision for cancer research. We have left it to policy makers to decide for us.” Now, if Celis and colleagues on ECCO’s policy committee have their way, Europe’s cancer community will be one of the leaders in the debate on how pan-European research funds can be best be allocated to pursue critical fields such as translational research, where attempts to create collaborative networks among the major comprehensive cancer centres and basic
JENS NARGAARD LARSEN
research centres have so far been piecemeal. But the obstacles are formidable, as he says. Health systems are primarily the provenance of the member states, not the EU, and there is a big disconnect between the existing EU directorate for consumers and public health, DG SANCO, and the research and innovation directorate. Meanwhile, the principal research structure – the framework programmes – have been limited in scope and sustainability. Further, about 95% of all cancer research spend is at individual country level, and the instruments through which member states might channel research funds for long-term translational research platforms do not exist. Large sums are at stake here, says Celis – the UK’s National Cancer Research Institute alone spent more than €550 million on cancer research last year, nearly double the amount it spent around ten years ago. Despite the barriers, Celis insists he knows no
more exciting time in research politics in Europe. This is partly because, after many years of committee work in various pan-European agencies, the research and clinical sides of the cancer community are finally uniting with a much stronger voice. ECCO has established a policy committee to represent the views of the 60,000 strong European cancer multidisciplinary community, and the dream of a European cancer institute or centre is also still very much alive. Celis and colleagues at ECCO called recently for the creation of such a body as a logical next step to unite the continent’s researchers, at least in virtual form. Meanwhile, at the political level there has been progress in recognising the need to establish a research strategy for European science, and for cancer in particular. “Key milestones were the creation of the European ResearchArea [ERA] in 2000, championed by commissioner Phillipe Busquin, the creation of the European Research Council [ERC], and the initiative by Busquin in 2004 to set up a work-
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“It was the first time cancer centres had looked at how they could structure translational research in Europe”
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ing group to look at the fragmentation of cancer research in Europe and to identify barriers,” says Celis. “I was a member of that group, which later made an application to the sixth framework programme [FP6] to set up the Eurocan+Plus project that identified where lack of coordination was particularly detrimental to the progress of scientific knowledge and the quality of care. “One of the outcomes of the project, which was led by Peter Boyle from the InternationalAgency for Research on Cancer, was the recommendation to establish a world-class infrastructure – a platform of European cancer centres for translational research.” There then followed the Stockholm Declara-
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tion, led by Ulrik Ringborg at the Karolinska, which is a manifesto drawn up by 18 cancer centres to achieve such a platform. “It was the first time heads of cancer centres had really sat down to look at how they could structure translational research in Europe,” says Celis. “Following this, and recommendations from the ECCO oncopolicy committee and the Organisation of European Cancer Institutes (OECI), the European Commission funded under FP7 a network of excellence, led by Ringborg, to structure translational cancer research between cancer research centres in Europe, namely the Eurocan platform” (see www.eurocanplatform.eu). The European Partnership for Action Against
Cancer (EPAAC), with its various work packages, is another major programme that has research as part of its remit, and aims to ensure that one-third of all cancer research funding is coordinated across Europe by 2013 – a sum of some €1.5 billion. “This is not achievable of course,” says Celis, but it is an indication of what the research community believes to be necessary. Celis also expects the health component of the next framework programme to have a focus on personalised/stratified medicine. This would tie in with the EU now having an ‘innovation union’strategy that stretches ahead to 2020, which focuses on major societal challenges, and may foster better cooperation among member states. “The biggest words in Europe today are coordination and sustainability,” says Celis. “We have created many networks so far, but little in the way of ensuring things continue. The vision we have at ECCO is to have a sustainable network of comprehensive cancer centres and institutes like my own to build a critical mass of expertise and resources across all the many niches we have in research to solve problems in different combinations – a sort of ‘variable geometry’.” Celis, more than most, is also enmeshed in one of the most complex scientific geometries in cancer – probing the world of proteomics. Until the end of 2011, when he will make Brussels and oncopolitics his main priority, his job is scientific director of the Institute of Cancer Biology at the Danish Cancer Society in Copenhagen. The society is the largest cancer organisation in Denmark, with some 450,000 individual members. Unlike other charities such as Cancer Research UK, it directly employs its own research teams across six departments. For Celis, this position has allowed him to focus exclusively on cancer in the latter stages of his research career, and to get fully involved in oncopolitics. His pedigree as a scientist on this stage could hardly be better. Born in Chile, he was an early convert at school to the then relatively new subject of biochemistry, enthused by a teacher who was carrying out some
experiments on animals. “Chile then developed clinical biochemistry as a career option, and I was able to study subjects such as histology, physiology and pharmacology as well as the core science, which was very valuable to me later,” says Celis. He left for the US to do a PhD, and on his return to Chile was able to get a posting to the Medical Research Council laboratory of molecular biology in Cambridge in the UK, financed by the Wellcome Trust. “I can’t emphasise how valuable networking was to me while I was in Chile under my mentor Jorge Allende – and these are skills I’ve also carried forward. Without networking, it is difficult to progress far in a career.” Certainly, that progression was stratospheric, for Celis found himself working alongside Francis Crick, one of the famous Cambridge DNA duo, and other luminaries such as Max Perutz, Fred Sanger and, in particular, Sydney Brenner, a Nobel winner for work on nematodes (ringworms). Brenner extended his stay in England as a member of the staff when the military coup in Chile made Celis reluctant to return home with his family. There was hardly a better place for Celis to start working in the booming field of molecular biology, and it was Brenner who set him to work on proteins, which has been the core of his research ever since. “But I left Cambridge after five years to take a permanent position in Denmark at the new Department of Biostructural Chemistry, headed by Brian Clark, who was also from Cambridge – it was a critical move that helped secure my career. There is one important aspect of work in England I have taken with me, however, and that is that everyone was working in the lab, not sitting in offices playing with models – except for Crick, that is.” Being a hands-on scientist means better problem solving, especially in research that requires extensive validation such as cancer, and this has been a feature of senior English biologists, he adds. “This is not the case in every country – I see several places where it is not unusual for even younger scientists to leave the lab and direct research from their offices.”
“Everyone was working in the lab, not sitting in offices playing with models – except for Crick, that is” CANCER WORLD ■ SEPTEMBER/OCTOBER 2011 ■
Celis had landed in the University ofAarhus in Denmark, with his late wife Ariana, a medical technologist, where he was to spend many years on cell biology research, continuing with a productive niche in proteins, before moving to the Danish Cancer Society. Here he was able to devote himself full time to translational research from the basic science standpoint, especially on breast cancer. “At first I took forward work I had been doing in Cambridge, with John Smith, on suppressor transfer RNAs, but found there were already many experts on this topic in Denmark. So we turned to cell biology, in particular to the cell cycle and cell transformation, drawing on work I had been doing on separating proteins using gels to study these processes using a biochemical approach. By 1981 we had discovered the PCNA protein [proliferating cell nuclear antigen] simultaneously with a group at the SCRIPPS Research Institute, a molecule that is central to cell life and death, and in 1982 we published the first extensive work on protein expression profiles of normal and transformed cells.” PCNA has been described as the ‘ringmaster of the genome’ and the implications of uncovering this and other proteins involved in normal and transformed cells has great importance for cancer, but as Celis says, this was just the beginning of what has turned out to be one of the most complex branches of molecular biology. There are now known to be as many as two million proteins, thanks to mechanisms such as ‘splice variants’ from the body’s 25,000 or so genes that encode proteins, and the field of proteomics – for which Celis is rightly seen as one of the founding fathers – is even more complex than genomics. “At the start I thought we could look at many proteins at the same time as a way of profiling changes in cells, and indeed we started to build protein databases of what we found, and later as identification techniques became available we were able to tell what the proteins were,” he says. Celis himself has long used a laboratory technique called 2D gel electrophoresis, pioneered by Patrick
O’Farrell, which separates proteins according to their molecular weight and charge and allows researchers to compare proteomic profiles in different samples. It is the kind of hands-on laboratory work he is keen to promote, and he points out that, with the advent of high-throughput technologies such as mass spectrometry and protein arrays, researchers can lose sight of biological questions they should be seeking to answer and instead get wrapped up in a constant discovery mode for work on biomarkers, for example. “In cancer you need a validation mode too,” he says. In 1995, when he turned to look at clinical cancer questions using tissue samples rather than cell lines, he says he had to “convert” himself to a pathologist as well. “I realised I couldn’t do anything without understanding the histology and pathology of tissue samples, which meant doing part of the work myself so I could interpret the data.” Key questions that Celis and the international proteomics community are addressing include the search for biomarkers for early detection, finding new drug targets and predicting how a tumour will respond to a therapy (see also the thematic ‘oncoproteomics’ issue of Molecular Oncology (2010; vol. 4, pp 459–566), where new approaches such as nanotechnology and imaging spectrometry are discussed). At Aarhus, Celis worked on bladder cancer biomarkers, using antibodies to locate the proteins in diseased and normal tissue, as he recognised that an expression level on its own may not be meaningful due to the daunting heterogeneity of the tissues. This was laborious work made possible only through close cooperation with Hans Wolf, a cancer surgeon, and Torben Ørntoft, a clinical biochemist, who were committed to obtaining tumour and control tissue, and points to a much wider problem he sees in translational research. “This type of work not only requires fresh tissue, which is very challenging to organise, but also setting up tumour, blood and urine biobanks so when we come to validate a biomarker, for example, consistent samples are at hand. But samples are often
“They can lose sight of biological questions they should be seeking to answer, and get stuck in discovery mode” 8
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“This gives you some idea of the incredible heterogeneity we are finding in tumours” stored in different systems and at different times – we may have had a focus on translational research in the current European framework programme, but we have failed to create consistent infrastructure to support it – and tumour banks are one of the main resources. It’s this kind of omission that means we are often paying the price of short-term solutions to long-term problems.” When Celis moved to the Danish Cancer Society he switched to translational breast cancer research with the support of pathologist Fritz Rank, taking a year to understand the history of the disease, and his institute is now a key niche player in certain aspects of this major tumour group, such as looking at biomarkers for endocrine resistance and early detection. Naturally he also runs a proteomics subgroup alongside those on breast cancer, cell cycle, apoptosis, metastasis and tumour microenvironment and genomics. On two sides of his large office in Copenhagen he has pinned up many pictures of protein profiles in breast cancer tissues, which show where the protein is being made, in some cases from only certain cells in a tumour. “This gives you some idea of the incredible heterogeneity we are finding in tumours – there are no two sites on a tumour that look exactly alike,” he says. There are images too of premalignant tissue, from which his proteomics lab is working on identifying progenitor cell types, and which could eventually result in biomarkers for early detection of cells that are more likely to progress to tumours. The validation problem with biomarkers is well illustrated by the fact that, of the thousands of articles published on biomarkers, so far fewer than 100 of them are being used.Although he is philosophical about the enormous complexity that nature is putting in the way of the cancer community, Celis says the only way to find more answers is to build the infrastructure that will allow researchers to take the time they need to work on the most clinically relevant questions involving human tissue and fluids, as well as the much easier, but much more homogenous, cell
line and animal samples that are used so extensively. During the 1990s, Celis began to represent Denmark on European organisations in the molecular biology arena (in particular the European Molecular Biology Laboratory and European Molecular Biology Conference) and stepped up his activity in the European Molecular Biology Organization (EMBO). In 1999 he became secretary general of the Federation of European Biochemical Societies (FEBS). It was a this point that the idea of proactively working for a coherent European strategy and structure for scientific research began to take shape. Working with others in the biology sector, Celis and colleagues such as Fotis Kafatos and Frank Gannon created the European Life Science Forum (ELSF) to put pressure on the EU over the need for basic research and in particular to work towards the creation of the European Research Council (ERC). “We soon realised that to achieve this goal we had to also involve all the other branches of science, and we created the Initiative for Science in Europe (ISE), which I chaired after José Mariano Gago, who was science minister in Portugal, and which led to the formation of the ERC.” This was a big achievement, as member groups of ISE included existing science organisations such as Euroscience and the European Science Foundation, among others. “It took us four years, but what I have learnt is how we need to turn a diffuse idea into an object of desire – so that politicians then see the value of it. The European Commission was somewhat sceptical at the beginning, but it got to such a level that they couldn’t stop it and so took it over.” Then in 2008, Lex Eggermont, then president of ECCO, invited Celis to chair ECCO’s new policy committee, which aimed to pull levers at the highest levels to try to progress the pan-European cancer research vision, with initiatives such as the Oncopolicy Forum and the EuropeanAcademy of Cancer Sciences, an independent entity that can provide science-based advice to policy makers. So there are many projects, meetings and com-
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“I have learnt how we need to turn a diffuse idea into an object of desire, so that politicians see the value of it”
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mittees now in European cancer – and to cap it all, Celis is also the current president of the European Association of Cancer Research (EACR), which gives him full ECCO board membership. What outputs does he now see coming from all this activity? “At the science level we need to firmly establish a structure for translational research – how we standardise technology, share data, exchange patients,
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what type of trials we could do, and what novel projects we can take from beginning to end. If we do that it will be first time it is done on this scale anywhere. We also need to demonstrate success stories to interest policy makers. “Then the next step is sustainability, where we need new instruments for organising member states and the European Commission.At ECCO we have proposed for example that comprehensive cancer centres would get matched funding from the EU on a competitive basis, but overall we need new instruments for members states to cooperate on meeting their societal challenges so that we can approach that goal of increasing the coordination of research funding. One enabler would be to have national health and research ministers meet in the same way as their colleagues do for economics.” Celis says that in addition to setting up a virtual European cancer centre, ECCO would like to see a larger European Institute of Health as well as a new mechanism to support top researchers through ‘dream teams’, allowing industry to contribute cash and new drugs for study. He would also like to see more support for research into cancer prevention and early detection. The ECCO policy committee has set out much of its current thinking in a response to the European Commission’s green paper, ‘Future EU research and innovation funding programmes: common strategic framework’. This paper sets out the aims for research and innovation funding for the next framework programme at both EU and national levels from 2014 to 2020, and by focusing on instruments ‘with proven European added value’ there should also be specific funding proposals by the end of this year. In a bid to connect with the public imagination, the framework 8 programme will do its bit to further European innovation and research under the name Horizon 2020. Celis says it is imperative that basic science organises itself as well as other sectors to advise policy makers and influence funding. “Scientists
are not as visible as doctors and patient groups – we need to set out our priorities for the long term that will fit alongside the more short-term projects that tend to dominate decisions,” he says. From next year, no doubt Celis could spend virtually his entire working time in meetings and conferences as the scenario for 2020 unfolds, and with other commitments such as president of the EACR, which was a founder member of ECCO, and has 10,000 researchers in its ranks through national society membership. The EACR is naturally lending its support to the coordination effort and the expected focus on personalised medicine in the next framework programme. It will hold its biannual Congress at Barcelona next year, which Celis will be chairing. He is concerned that the US is still attracting many of the world’s top researchers, and the cancer community there enjoys a close relationship with industry. “One of the aims of the Eurocan platform is to help make Europe a more attractive place for researchers from say Asia to come and work.” Developing the next generation of European researchers is also important, and Celis is one of the organisers of a FEBS lecture course on translational cancer research, taking place in Portugal this September. “This is not just about work – it’s in a nice summer school setting and is a great chance to build a personal network,” he says. As if this isn’t enough, he is also editor in chief of the journal, Molecular Oncology, which majors on issues such as the next steps in proteomics. As always, Celis will be urging that the technology race in techniques such as protein profiling is tempered with realistic biochemistry. Ringborg, director of Stockholm’s Karolinska Cancer Centre, describes Celis as “a remarkable man”, in both his scientific work and his capacity for networking. “I have never met a basic researcher and cancer biologist with such a dedicated interest in the problems of the patients,” he says, and comments particularly on how well
Celis manages to integrate pathologists into the proteomic research he does on tumour progression and tumour subtypes, “in a way that the clinical questions steer the research strategies.” Having worked alongside Celis in some big European projects, including the Eurocan platform, Ringborg also singles out his “unusual capability to organise and convince people about both infrastructures and research strategies,” and also his grasp of the need to find new types of collaboration and financial support to improve the innovative potential in cancer research. Celis’s first wife and fellow researcher Ariana sadly died 13 years ago and he has since found a companion, again a scientist, biochemist Teresa Cabezòn, who also works at the Danish Cancer Society. He has three children and six grandchildren, so family life tends to take all his free time. After he steps down from his research post in 2012 he will be spending most of his time in Brussels to concentrate on oncopolitical duties. With his scientific achievements now largely behind him, Celis is looking for a success in getting more opportunities for researchers in the next framework programme, and more projects under the Eurocan umbrella. “And if we can get member states and the commission to agree to look for new sustainable opportunities we will be in good shape,” he says. “We need to be sure we will be consulted in time when policy makers work on anything cancer related. I’d like also to see more people from outside Europe coming to do their research here.” Of course, there are some who would now say that the whole European ‘project’is in peril following the economic collapse in countries such as Greece, Spain and Ireland, and there is huge strain now evident in high-level political relations. Meanwhile the European Commission is looking for a five per cent increase in the EU budget to meet 2020 goals. Whichever way this goes, for Celis there will be no let up in pushing for sustainable structures that tap into member state funding to secure a solid future for cancer research in Europe.
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State-of-the-art treatment for advanced melanoma Progress in treating melanoma has lagged behind many other cancers for decades. But a number of novel approaches, based on better understanding of the role of the immune system, better selection of patients and the identification of targetable mutations, is now offering a glimmer of hope.
efore 2010, advanced melanoma was considered a disease with very poor prognosis. Mortality was increasing compared to other cancers, and median survival remained at only six to nine months in most studies. There were few, if any, effective therapies. Interferon (IFN) had limited effect, and dacarbazine (DTIC) and high-dose interleukin-2 (IL-2) had no confirmed effect on overall survival. High-dose IL-2, which was a standard in the US, had significant toxicity. There were no positive phase III trials for overall survival. For cytotoxic chemotherapy, there is currently no evidence that single agents, combination chemotherapy or the addition of tamoxifen or IFN to DTIC is superior to DTIC alone. Although some data suggest that the combination of carboplatin and paclitaxel might be superior to DTIC alone, these treatment approaches have not been formally compared. High-dose IL-2 therapy became the standard in the US in 1998, based on data showing a response rate of about 16%. Some responses
The European School of Oncology presents weekly e-grandrounds which offer participants the opportunity to discuss a range of cutting-edge issues, from controversial areas and the latest scientific developments to challenging clinical cases, with leading European experts in the field. One of these is selected for publication in each issue of Cancer World. In this issue, Michael B. Atkins, from the Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center and Harvard Medical School, Boston, USA, provides an update on the latest developments in treating patients with advanced melanoma, and looks at what the future may bring. Daniel Helbling, Onkozentrum Zurich,
Switzerland, poses questions sent in by participants during the e-grandround live presentation, which is summarised here by Susan Mayor.
The recorded version of this and other e-grandrounds is available at www.e-eso.net
CANCER WORLD â– SEPTEMBER/OCTOBER 2011 â–
were very durable, with the median duration of response being 8.9 months and the median not being reached for complete responders. There was limited impact on overall survival, but among responders, any patient who was still responding at 30 months has remained in response for more than 10 years (JCO 17: 2105– 16, Cancer J Sci Am 6 [suppl 1]:S11– S14). High-dose IL-2 appears to be useful and we still use it in the US, but it is toxic and requires inpatient treatment, making it expensive and impractical. Therefore, its use is limited to selected patients treated at experienced centres. Efforts to better select patients who might benefit from IL-2 therapy are warranted and we are currently actively investigating this.
THE THERAPEUTIC LANDSCAPE IN 2010 Looking at the therapeutic landscape in 2010, results may be improving a little bit for non-specific reasons: earlier treatment, better patient selection, improved treatment of brain metastases and better systemic therapy. But new approaches are clearly necessary. Unless new approaches are unquestionably active, it is likely that they will need to be studied in phase III trials. Question: Is there a predictive tool in metastatic melanoma to select on the basis of genetic profile? Answer: There are mutations that help select therapies, particularly for therapies that target protein products of C-KIT or B-RAF mutations. But these mutations may also help us select for who might respond to immunotherapy. We may also need to come up with therapies for patients whose tumours don’t have those mutations.
PROMISING THERAPEUTIC APPROACHES Immunotherapy The benefit from immunotherapy may be limited by the ability of T cells to infiltrate a tumour. Melanomas may vary in their degree of immune infiltration, with about 24% of tumours having a high degree of immune infiltration and 40% having very little T cell infiltration. The higher the degree of immune infiltration, the better the outcome. This is particularly true if the infiltrating cells are CD8+ T cells. Using an immune signature based on gene expression profiling, we have found that patients whose tumours have this signature are more likely to respond to high-dose IL-2 and have a significantly longer median progression-free survival, of 19.4 months for the class 2 immune versus 2.5 months for class 1 antigenic gene expression signatures, respectively (JCO 27:15S, abstract 9003). Another factor potentially associated with response to high-dose IL-2, which may be worth investigating with novel immunotherapies, is mutational status. A significantly larger proportion of patients with B-RAF and, particularly N-RAS, mutations are likely to respond to high-dose IL-2 compared to those with wildtype tumours (JCO 28:15S, abstract 8597). More data are needed on this. Elevated lactate dehydrogenase (LDH) status is a negative predictor for response to high-dose IL-2. If the patient has a high level of LDH released from the tumour, which is a poor prognostic finding, he/she will be less likely to respond to high-dose IL-2 therapy, with a response rate of 6% and no complete responses. It is becoming clear that LDH regulation is associated with hypoxia. Other hypoxia-related genes such as
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VEGF (JCO 27:2645–52) are also inversely associated with likelihood of benefiting from high-dose IL-2 therapy. In summary, with regard to high-dose IL-2 tissue-based predictive biomarkers, a novel immune-based gene expression profile appears to predict for better progression-free survival and, possibly, response to high-dose IL-2. The association of clinical benefit with immune response signature suggests a possible mechanism for high-dose IL-2 antitumour effect based on immune cells that are already present in the tumour and blocked for a particular reason. This is part of the reason we were so excited about some of the novel immunotherapies. The fact that both B-RAF and N-RAS mutational status may predict for favourable response to high-dose IL-2 suggests opportunities for combination studies.An elevated LDH or VEGF may predict for lack of response to high-dose IL-2, so different treatments may be necessary for those patients. Question: Which patients do you treat with high-dose IL-2? How do you select these patients? Answer: In the US, we treat patients who have good performance status (0–1), good heart and lung function, no CNS metastases and, based on the data I have just described, normal LDH. We are not yet selecting patients based on mutational status of their tumours, but we are carrying out a prospective trial to see whether factors including mutational status and immune signature will predict which patients benefit from IL-2 based therapy.
IMMUNOTHERAPY Ipilimumab is a novel type of immunotherapy. When the immune system recognises an antigen on an antigen-presenting cell (APC), binding occurs between a Tcell receptor (TCR) and a co-stimulatory molecule, CD28.
IPILIMUMAB TAKES THE BRAKES OFF THE IMMUNE SYSTEM
By blocking the binding between CTLA4 and B7, this new type of drug allows the immune system to do its job Source: Adapted from Lebbe et al, oral presentation 769O at ESMO 2008
When this binding takes place, CTLA4 is upregulated on the surface of the T cell. This out-competes CD28 for binding to be severed on the antigenpresenting cell, which leads to a shutting off of T cell function. CTLA4 antibodies such as ipilimumab block binding between CTLA4 and B7 and allow for that brake on the immune system to be removed, and for the immune system to continue to expand (see figure above). The two antibodies blocking CTLA4 that have been studied extensively – ipilimumab and tremilimumab – both produce responses in 8–15% of patients with refractory melanoma. These responses are associated with autoimmunity, because taking the brakes off the immune system happens not just within the tumour but also within organs that are protected from autoimmunity by CTLA4. Responses are durable in many patients, with the majority lasting longer than two years: 20–30% of patients have durable disease control longer than three years. In contrast to IL-2, activity is seen in the central nervous system and is not prevented by steroid co-administration. Responses are delayed at onset
and can show tumour flare before response. The CT scan in the figure below shows extensive disease on the patient’s abdominal wall at baseline, which gets worse three weeks into therapy, but has completely disappeared by four months. This pattern is seen in about 10-20% of patients who respond to ipilimumab. It calls into question the standard RECIST criteria for disease progression, and may have confounded the interpretation of some of the early studies with ipilimumab.
Pivotal trials with ipilimumab A trial presented at ASCO last year (2010) by Steve Hodi (NEJM 363:711–723) randomised patients who were originally HLA (human leukocyte antigen) A2+ to a low dose of ipilimumab (3 mg/kg), either alone or in combination with gp100 peptide vaccine, or to gp100 vaccine alone. Results showed an overall survival advantage for the ipilimumab-containing arms but no advantage for the vaccine, either alone or when added to ipilimumab. A pivotal phase III trial with DTIC +/- ipilimumab (10 mg/kg) completed accrual a couple of years ago and the required events have just been achieved. Positive results showing an improvement in overall survival for the DTIC + ipilimumab arm relative to DTIC alone were recently reported (NEJM 364:2517–26). The Cytokine Working Group has looked at ipilimumab in patients with CNS metastases and we have seen similar activity to that seen in systemic disease. Adjuvant studies are currently ongoing in patients with stage III disease: one in Europe comparing ipilimumab to observation, which is nearing completion, and a second that
CTLA4 BLOCKERS: IT CAN GET WORSE BEFORE IT GETS BETTER This typical pattern of a flare up followed by response must be borne in mind when evaluating response to treatment Source: Courtesy of Michael B Atkins
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IPILIMUMAB: SURVIVAL ANALYSIS
Kaplan-Meier analysis shows a clear survival advantage for both ipilimumab arms in this trial for use as a second-line therapy Source: FS Hodi et al. NEJM (2010) 19:363:711–723. Printed by permission from Massachusetts Medical Society
has just opened in the US, comparing ipilimumab to interferon. The second-line phase III trial presented at ASCO in 2010 randomised patients with pretreated metastatic melanoma to ipilimumab plus gp100 (60%), ipilimumab plus placebo (20%) or gp100 plus placebo (20%). Both the ipilimumab arms showed superior overall survival to gp100 alone, with 44– 46% of patients alive at one year, compared with 25% with placebo alone (see figure above). Twice as many patients treated with ipilimumab were alive at two years compared to those given placebo alone. There was a fair amount of toxicity related to ipilimumab. This was primarily autoimmune toxicity, including dermatologic side-effects, gastrointestinal side-effects such as colitis, and a small percentage of patients with endocrine or hepatic side-effects. These are the major side-effects related to ipilimumab, which need to be kept in mind and treated aggressively with steroids if they occur.
Summing up, it appears that CTLA4 antibody enables immune responses and antitumour responses in some individuals. Tumour expression of PD-1 ligand may prevent immune response even with CTLA4 blockade by inducing T cell death, serving as ‘barbed wire’ to those immune cells that may be in the tumour. Given that melanoma cells have been shown to express PD-1 ligand, CTLA4 antibody effects might be augmented by antibodies that inhibit the PD-1 pathway. Controlling immune regulation may provide a way forward for immunotherapy of patients with melanoma.
If you delay treating auto-immunity, the effects can be severe. But if you are attuned to the problem and react quickly, you can provide this therapy safely in an outpatient setting and patients can achieve the benefit. Nonetheless, it is not as targeted to the tumour as we would like. Question: Can ipilimumab be used as a neoadjuvant therapy in patients who are potentially resectable? Answer: I think that is a potentially useful research tool and ongoing studies are using ipilimumab as neoadjuvant therapy. However, fewer than one-third of patients show responses. I would not advise this outside a research study, as the toxicity might complicate surgery. Question: Are auto-immunity and sideeffects related to response – can they be surrogate markers? Answer: Yes, it appears that autoimmunity is related to response. The response rate in patients who get autoimmune side-effects is 40–50%, while it is closer to 5% in those who do not. This tells us that the mechanism of the response is probably unleashing latent auto-immunity against the tumour cell. At the same time, those patients who
Question: Auto-immunity is a major concern. My first impression was that ipilimumab is not very targeted, because it releases the immune system to fight against anything it finds. Do you think it is really a targeted approach for melanoma patients? Are you not particularly concerned about autoPD-1 ANTIBODY: CHANGE IN TUMOUR BURDEN immunity? Answer: I think people should have a healthy respect for auto-immunity. Patients can get into very serious trouble if the auto-immune sideeffects are not treated quickly with steroids and, if necessary, infliximab. It is interesting that treating the auto-immune side-effects can control them without preTumour shrinkage occurred in more than 50% of venting the anti-tumour patients treated with various doses of a PD-1 antibody response, so you do not have in this phase I trial to be worried about giving Source: M Sznol et al ASCO 2010 presentation, abstract 2506 immunosuppressants the way you might be with other immunotherapies.
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body are now underway, and other chronic inflammatory situastudies are being considered. Overall, tions. If you could block the it is possible that the PD-1 antibody interaction you might be may offer even more tumour-specific able to restore the activity of targeted immunotherapy. the immune system selectively within tumours. TARGETING MOLECULAR A phase I study of an ALTERATIONS IN MELANOMA antibody to PD-1 presented Around 50–60% of melanomas have at ASCO in 2010 (JCO mutations in a very specific area, 28:15S, abstract 2506) V600E or K mutations in B-RAF. A treated 46 patients with complementary 15% of tumours have melanoma with three difmutations in N-RAS and about 30% of ferent doses. Almost 33% patients with mucosal or acral/lentigi(15/46) exhibited tumour nous melanomas have amplifications or responses. All of these mutations in C-KIT (see figure below). responses were ongoing These mutations are not distrib(with the longest >18 uted randomly across melanomas. months) when the results Tumours in moles or in non-chronic were reported. More than sun-damaged skin are more likely to 50% of patients had tumour have B-RAF mutations, but rarely have shrinkage on a waterfall plot Response to PD-1 antibody (1 mg/kg) of liver (upper) and C-KIT mutations. Tumours in chronic at different dose levels (see lung (lower) metastases in a 66-year-old male patient with sun-damaged skin, acral/lentiginous figure opposite page, below). melanoma, who had progressed on high-dose IL-2. A shows the The figure (this page, top or mucosal areas are more likely to baseline and B shows after one cycle of treatment. The patient left) gives an example of have C-KIT amplification or mutamet the partial response criteria after three cycles of treatment, response in a patient with tions. Tumours that have C-KIT mutaand the response was still continuing at 12+ months very extensive liver metastions are very sensitive to inhibitors of Source: Courtesy of M Sznol, Yale University tases as well as some lung C-KIT such as imatinib. The figure metastases that reduced draoverleaf shows a PET scan before and matically within two cycles after four weeks of treatment, with of treatment with PD-1 antibody, even dramatic reduction in the PET uptake develop immune reactions against their at the 1 mg/kg dose. of multiple tumour metastases (JCO tumours probably also have some sort Early trials show tumour response 26:2046–51). of defect in their immune regulation in more than 30% of heavily that allows them to also develop reacMOLECULAR ALTERATIONS IN MELANOMA pretreated patients with tions against their colon, their skin or advanced melanoma (JCO their liver. 28:15S, abstract 2506), PD-1 antibodies and inhibitors which is very exciting. PD-1 antibodies, or PD-1 inhibitors, Responses have also been may provide more tumour-specific seen in other cancers, immune suppression. When T cells including lung, colon and are exposed to the tumour, they up kidney cancer, which are regulate PD-1 on their surface. PD-1 is durable to date. The toxicity a member of the CD28 family involved seen so far has been relain T cell regulation. When it binds to tively mild, without the tumour or antigen that is expressing degree of auto-immunity PD-L1, this causes apoptosis or seen with ipilimumab. exhaustion of the immune cells. This Combination studies with happens primarily in the tumour or in ipilimumab and PD-1 antiPD-1 ANTIBODY: OBJECTIVE RESPONSE
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Experience with C-KIT inhibitors inhibitor of mutant B-RAF (NEJM some improvement in progression-free C-KIT inhibitors have dramatic effects 363:809–819); and GSK 2118436, also survival (JCO 26:2178–85). But there in patients with melanomas containing a selective inhibitor of B-RAF (JCO was no additional benefit when coma variety of C-KIT mutations. How28:15S abstract 8503). Both of these bined with carboplatin/paclitaxel ever, these mutations occur in less than have shown promising data. (E2603, PRISM), either in a first-line 1% of all melanomas. The role of CStudies show that PLX4720 co-operative group trial or a second-line KIT inhibition in C-KIT amplified inhibits tumour growth in B-RAF industry-sponsored trial. tumours is yet to be fully established mutant tumours but has no activity in We did not know whether the poor and it is possible that those with ampliwildtype tumours. Results from a phase response was because sorafenib was fications in C-KIT may be less responI trial of PLX4032 in patients with a poor B-RAF inhibitor or because sive than those with mutations in mutant B-RAF tumours (NEJM B-RAF was not an important target in C-KIT or not responsive at all. 363:809–819) showed tumour melanoma. We needed better tools to Despite being rare tumours in response in 70% of patients, including answer these questions, and two of Europe and the US, mucosal one complete response, even though these have now come along: PLX 4032/ melanomas make up the majority of many had M1c disease (metastases RG7204, which is a more selective melanomas in Asia, parinvolving visceral sites C-KIT INHIBITOR IN PATIENT WITH KIT-MUTANT MELANOMA ticularly in India and beyond lung and/or an China. C-KIT mutated elevated LDH) (see barPretreatment PET scan PET scan after 4 weeks tumours are, therefore, chart opposite). A dramuch more prevalent. matic response was seen Multiple studies are curon PET scan within 15 rently underway with imadays, showing very signiftinib, sunitinib, dasatinib icant reduction in glucose and nilotinib, including an uptake in disease in the international phase III lungs (see scans opposite). trial comparing nilotinib Although this was not versus DTIC in patients a randomised study, surwith C-KIT mutated vival curves from this mucosal melanomas. This phase I study show sigis all very exciting, and nificant prolongation in provides a proof of principrogression-free survival, ple, but it is not the with a median progresanswer for the majority of sion-free survival of around eight months in patients with melanoma. patients with V600E mutations treated at the B-RAF inhibitors in optimal dose (see graph melanoma opposite, lower). Initial studies to deterThis treatment is mine whether B-RAF associated with some toxinhibitors had activity in icity, including arthralgia, melanoma did not select photosensitivity, rash, by mutational status and fatigue, pruritus and palused sorafenib, which is a mar-plantar dysaesthesia, very poor B-RAF inhibitor. although mostly not seriStudies showed limited or ous (grade I and II) no activity with singleSource: S Hodi (2008) JCO 26:2046–51, reprinted with permission © American (NEJM 10:363:809– agent sorafenib. A phase II Society of Clinical Oncology. All rights reserved 819). The most troubling trial of sorafenib comside-effect is cutaneous bined with DTIC showed
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PHASE 1 TRIAL OF PLX4032 IN B-RAF MUTANT MELANOMA PATIENTS Interim best overall response
Reduced glucose uptake by day 15
Above: Interim results for the maximum tumour shrinkage for patients involved in the study show a 70% response rate Right: These PET scans show a dramatic response to the B-RAF inhibitor Source: Bar chart – K Flaherty et al. (2010) NEJM 363:809-819; Scans courtesy of Jeff Sosman, Vanderbilt University
INTERIM PFS FOR PLX4032 malignancies, which look patients with B-RAF like squamous cell cancers. mutant melanoma (JCO They occur in about one29[15S)]:abstract 8509), quarter of patients and and the phase III trial require follow-up with a showed a significant dermatologist. improvement in overall surConclusions from the vival for treatment-naïve phase I study are that patients receiving vemuPLX4032 is tolerable and rafenib compared to DTIC highly effective, even in (NEJM 364:2507–16). patients with extensive prior Findings with B-RAF treatment. Results provide inhibitors have implications proof of concept that B-RAF for how we select patients for mutations are critical oncovarious therapies. In the genic drivers in B-RAF future, I think that melanoma mutant melanoma. studies will divide patients There is a lot of exciteinto three classifications: ment around this therapy, V600 mutant tumours; V600 This plot of interim phase 1 data show that patients with the V600 mutation which is justified, but its wildtype tumours and V600 on B-RAF show a much better progression-free survival in response to true efficacy will depend on mutant tumours that have PLX4032 than those with wildtype (WT) B-RAF the durability of response progressed after selective Source: Courtesy of Keith Flaherty, Massachusetts General Hospital and the ability to impact on B-RAF inhibitor therapy. It is overall survival. very important to carry out Larger phase II and ranstudies designed to enhance domised phase III studies are necesresults were reported at ASCO 2010. the efficacy of selective B-RAF inhibitors, sary to confirm this benefit. These The phase II trial confirmed the effisuch as studies combining them with trials have been completed and the cacy of PLX4032 (vemurafenib) in MEK inhibitors, with other agents
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that might inhibit the development of resistance, and in combination with immunotherapy.
the US Intergroup by Ryan Sullivan taking patients who have primarily B-RAF wildtype tumours or potentially those with tumours containing B-RAF mutations who are resistant to B-RAF inhibitors, and randomising them to either carboplatin/paclitaxel + bevacizumab or carboplatin/paclitaxel + placebo.
Question: If you have a patient with metastatic melanoma, do you always test for B-RAF and C-KIT now? Is this standard? Answer: We test B-RAF status in patients who develop metastatic disease or in those with very high-risk stage III disease with intransit metastases. We then incorporate the result into decision making on which the treatments to offer them. We do not test patients who only have sentinel node involvement or who only have primary tumours as there is, as yet, no role established for B-RAF inhibitors in the adjuvant setting.
ARE WE IN 2011? We are beginning to see a glimmer of hope on the horizon, with novel immunotherapies, some specific and highly active tumour-targeted therapies, antiangiogenic therapies, and the potential ability to select patients for particular tumour types based on molecular profiling.
WHAT CAN BE DONE FOR PATIENTS WHO HAVE ELEVATED LDH? We are reluctant to give immunotherapy to patients with elevated LDH or with B-RAF wildtype tumours. One thing that is becoming clear is that patients who have elevated LDH may be the same as those with elevated VEGF, and elevated VEGF levels within tumours correlates with poor outcome. The phase II BEAM study randomised 200 patients treated with carboplatin/paclitaxel in a 2:1 ratio to bevacizumab-containing therapy versus placebo (Advanced Melanoma: Eur J Cancer Suppls 7:13). Survival curves at one year showed a significant, or nearly significant, improvement in overall survival (52% for the bevacizumab-containing arm, compared to 39% for the placebo arm). This was particularly true for patients with M1c disease or those with M1c disease and elevated LDH, with significant benefit for those patients receiving bevacizumab. This has led to a trial proposed in
Question: There has been very little change in adjuvant therapy over the past years. Which patients do you treat with adjuvant therapy? Do you think those new promises will also translate into benefits in the adjuvant setting? Answer: We still use the standard highdose interferon regimen for patients with stage IIB and stage III melanoma who are not eligible for research protocols, but who are physiologically 70 years or less, and able to tolerate interferon. We do not yet know whether the new agents that are showing activity in the metastatic setting will be active and tolerable in the adjuvant setting. The study carried out in Europe comparing ipilimumab to control in patients with stage III disease has had some difficulty with toxicity. So it remains to be seen whether any benefit seen, or the number cured, is sufficient to justify the toxicity that patients may have to undergo. A trial in the US comparing ipilimumab to interferon will be a truer test as patients in the US may be reluctant to take a placebo. Whether the B-RAF inhibitors will have a role in the adjuvant setting is
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unclear because, at the moment, in contrast to immunotherapy, they are primarily palliative. They cause dramatic tumour shrinkage, but do not appear to be causing durable complete responses. Whether this type of activity in the metastatic setting will translate into eliminating tumour cells, which is what we would like to see in the adjuvant setting, requires investigation. Question: For practical purposes, how do you use interferon? Do you think it can be replaced by Pegintron [peginterferon alpha-2b], because that is better tolerated, or do you give one month of high-dose interferon followed by low-dose for the rest of the 11 months? Answer: In the US, we believe that the high-dose, four-week induction period is the most important component of interferon treatment, so we are reluctant to adjust that in any way. We have a lower threshold for reducing or stopping therapy, because we think that most of the benefit of interferon happens within the first 4â€“12 weeks. If we are going to modify the treatment, it is more likely in the last nine months of therapy, either using a lower dose or even omitting it, rather than modifying the four-week induction period. Therefore, we have not moved towards Pegintron, at least in our patient population. Question: Are B-RAF inhibitors active in patients who have B-RAF mutations in their melanoma and who also have CNS metastasis? Answer: PLX4032 has not been formally studied in patients with brain metastases as these patients have been excluded from the trials. But the GSK BRAF inhibitor has been studied in some patients with CNS disease. A study reported at ECCO in 2010 (Advanced Melanoma: Eur J Cancer Suppls, 8) showed activity in the central nervous system. We will see more studies including these patients in the future.
The future of cancer, as told through the story of Renee Explaining in everyday language how the science that brought us the Human Genome Project is giving hope to cancer patients of today and tomorrow is no easy task. Mark Henderson, science editor for The Times in London, won a Best Cancer Reporter Award for this piece, which was originally published under the title, ‘Making cancer history: killing tumours’.
errimack, New Hampshire, usually gets a white Christmas.And when Renee Weaver felt a pain in her back over the holiday season, she assumed she must have pulled a muscle while shovelling snow. When her sight became blurred a few weeks later, there also seemed to be a logical cause. “I’m about to be 40,” she thought. “I must need glasses.” But her optician revealed that neither ailment had so benign an explanation. A mass was pressing on Renee’s right eye but, doctors told her, its cells hadn’t started out there. Though just 39, and a non-smoker since her twenties, Renee had advanced lung cancer. It had already spread to her brain, bones and liver. For the mother of Emily, 13, and Jacob, 10, the diagnosis could hardly have been more devastating. Median life expectancy for a patient with so many metastases is just eight months, and the five-year survival rate is lower
than 10%. “The doctor, when she told us, I really think she thought I was headed for death,” she said. “Like any mother, I just thought of my children. My God, I won’t see them grown.” A serendipitous coincidence, however, has thrust Renee to the heart of a gathering medical revolution that is starting to give patients like her genuine hope
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of beating cancers that would once have carried the bleakest prognosis. With the help of a surgeon who was treating her husband, Tom, for a heart complaint, she came under the care of one of the world’s leading cancer centres, at Massachusetts General Hospital (MGH), 50 miles away in Boston. There, she has become one of the first patients to benefit from a new approach to cancer, based on science’s growing understanding of the human genetic code. Under this strategy, cancer is no longer considered as a single disease, or even as the 200 or more forms that afflict different organs in distinct ways. Genomic insights are instead defining tumours according to the DNA mutations that drive them. This new paradigm is providing doctors with the intelligence they need to attack cancer with smart weapons, Mark Henderson
A mission to inform. The story of non-smoker Renee, whose advanced lung cancer responded dramatically to treatment with a targeted therapy, brings readers realistic hope tempered with caution
calibrated for individual patients, in place of the blunt instruments of traditional oncology. It has already started to change the landscape of medicine, to transform its capacity to contain – and even sometimes cure – this dreaded disease. And it is coming to Britain. This year, Cancer Research UK will begin establishing a network of centres that will use similar genetic techniques to guide treatment decisions for British patients. It will be the precursor to treating every NHS [National Health Service] cancer patient this way, perhaps in as little as five years. Renee’s experience, though groundbreaking for now, could soon be expected to become routine. You might call it the future of cancer. There is a tendency to think of can-
cer as an environmental disease, triggered by exposures such as smoking or ultraviolet light. But at root, it is a disease of the genes. It is the result of DNA defects that cause cells to grow unchecked; carcinogens are dangerous because they inflict this damage. The nucleus of a tumour cell is a place of genetic chaos, with many thousands of mutations. It is these that are the life force of cancer cells, feeding their appetite for proliferation and destruction. But they are also weaknesses that can be attacked. As scientists have started to identify these mutations – abetted by the work of the Human Genome Project – they have begun to develop drugs that can knock them out. Agents such as erlotinib (Tarceva), trastuzumab (Her-
ceptin) and imatinib (Glivec) neutralise the rogue proteins made by defective genes, killing tumours or weakening them so the body can finish the job. They have proved to be capable assassins, often prolonging life by years, but they cannot be deployed indiscriminately. For the most part, they work only against cancers with the genetic signatures they are designed to target. Doctors must know their enemy when planning attacks. What this means, according to Daniel Haber, director of the MGH Cancer Centre, is that “you can no longer do cutting-edge oncology without genetic tests”. It is not enough to diagnose cancer in a patient according to how a tumour looks under the microscope, and where it is in the body. You
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have to read the molecular instructions that are driving it, the genes that make it tick. Some tests that do this have been available for a few years. Indeed, the NHS requires that they be conducted before certain drugs are approved. Trastuzumab is given only to breast cancer patients with a defective HER2 gene, while cetuximab (Erbitux) is prescribed only for colon cancers without mutation in a gene called KRAS. Provision of testing, however, is still patchy, and those patients who do get it are investigated only for the defect that most commonly afflicts their particular cancer.A bowel cancer patient might get a KRAS test, but nothing else. The MGH programme is taking such testing to a whole new level. At Renee’s first appointment, her doctor, Lecia Sequist, ordered a battery of genetic investigations. A sample of her tumour was screened for about 120 different mutations in 13 genes that are known to affect drug response or prognosis. The hope was that she might be suitable for a targeted therapy – or that if nothing appropriate was available, she might be able to join a clinical trial. “For someone like Renee, a young, female non-smoker, we had a high index of suspicion that she might have a suitable mutation,” Dr Sequist said. “We pushed the lab to go as fast as possible and got the results back in eight days.” They provided a filament of hope. “Dr Sequist had told us that if the test was negative, we shouldn’t give up,” Renee said. “But when she said, ‘We’ve got your results back,’there was a tone in her voice. We could tell she was happy.” Dr Sequist was happy because the
test had revealed that her patient’s tumour had a mutation in a gene called EGFR. This is present in about 10– 20% of lung cancers, and it is more common still in patients with Renee’s age, sex and smoking history. It meant that she could be treated with erlotinib, a drug that inhibits EGFR. The test greatly improved her prognosis: about 60% of patients with EGFR mutations respond well to erlotinib. It has also spared her the gruelling effects of chemotherapy: instead of intravenous courses of highly toxic drugs in hospital, she can take pills at home. Renee does not look like a typical cancer patient. The only visible clues to her treatment are a headscarf, to hide hair lost during radiotherapy that shrinks her brain lesions, and a little “teenage acne”. She has had some diarrhoea and nausea, and she has lost some weight. But as her husband says: “We’d rather you were alive with a bit of a rash. I just think you’re a trooper.” The beauty of MGH’s wide-ranging test is that, even had Renee’s tumour lacked an EGFR mutation, it could have revealed other genetic guides. A mutation called ALK, for example, present in about 5% of lung cancers, is common in patients with her profile. “What we’re doing is to capture all we can of what’s happening genetically in the tumour, to look at everything that might possibly inform a treatment decision,” said Leif Ellisen, co-director of MGH’s translational research laboratory, which developed the panel of tests, known as Snapshot. “If you really want to have personalised medicine, you have to test a broad spectrum of mutations in every tumour.”
“We’re testing for all the major mutations we feel can affect therapy, either now or in the near term,” Dr Sequist said. “We’re looking at the mutations for which there are licensed targeted drugs, as well as for some treatments that are currently in development. That way, when the drugs are ready, we’ll be ready too.” Since March, this approach has become the standard at MGH for every patient with advanced lung, breast, gastrointestinal or brain tumours, as well as for malignant melanoma, the most aggressive form of skin cancer. About 900 people with these cancers – the types for which molecular diagnosis is currently most useful – will have the Snapshot test this year. Many more can expect to benefit in future. New genes are being added all the time – there are now 16 on the panel, three more than when Renee was tested in February. The cancers for which it is indicated will widen further as the International Cancer Genome Consortium, a £600 million [€665 million] project to find all the mutations that drive 50 common tumours, begins to deliver results. The initiative has already borne fruit: in December, the entire genomes of a lung tumour and a melanoma were published, identifying many new defects that could be drivers. The next challenge is to roll out such programmes, so that they reach patients in small hospitals, and apply them earlier to treat patients whose cancers have yet to spread. Trastuzumab has already made this second step, slashing recurrence rates after surgery for HER2-positive breast tumours.
A sample of her tumour was screened for about 120 mutations in 13 genes... the results came back in eight days 26
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At a cost of about $1000 and falling, the Snapshot test is well within the affordable range of health providers At a cost of about $1000 [€700] and falling, the Snapshot test is well within the affordable range of health providers such as the NHS. And MGH’s oncologists are convinced that their methods will soon become commonplace. “For this to become standard in five years is not unrealistic,” Dr Sequist said. It is a position with which Professor Peter Johnson, the chief clinician of Cancer Research UK, concurs. “There’s no doubt in my mind that this is the way cancer medicine is going,” he said. So convinced is the charity of the potential of broad-spectrum genetic diagnosis that it is establishing a programme to provide similar services in Britain. In the pilot phase, it plans to set up genetic testing centres at up to six hospitals, with the capacity to scan about 6000 patients a year for a range of mutations. It hopes to extend the scheme to every NHS hospital.
“We think it’s clear that this train is already moving,” Professor Johnson said. “It’s time to take the initiative to apply these insights. Molecular typing of cancer will be in routine practice for many people before long. It’s a matter of making sure we’re ready.” For Renee, the roll-out cannot come too quickly. “If you’re just someone who lives in a small town and doesn’t have access to MGH, is your life not as important as someone who lives near Boston?” she said. “I’m lucky to be an hour away. This should be standard everywhere.” The pace of advance has also awakened business to the possibilities of a major new market. For example, Foundation Medicine, a Boston-based company that launched in April, aims to develop a one-stop-shop for genomic cancer diagnosis that is accessible to any hospital. Its advisers include Eric
Lander, a pioneer of the Human Genome Project. This enthusiasm for widespread genomic diagnosis of cancer has emerged because of the astonishing progress made by targeted therapies in the past decade. Their potential first became clear in 2001 with the advent of imatinib (Glivec), a drug designed to shut down a mutant gene that causes chronic myeloid leukaemia (CML). It transformed treatment of the disease. Patients who would once have been expected to die within months are still alive today, often living ordinary lives. The team who developed it, Brian Druker, Nicholas Lydon and Charles Sawyers, were awarded the LaskerDeBakey Clinical Medical Research Award last year for “converting a fatal cancer into a manageable chronic condition”. Similar targeted therapies have followed for some solid tumours,
The DNA (deoxyribonucleic acid) in a cell’s nucleus makes up genes (bits of code). Genes dictate what a cell does, what proteins it produces (and thus how we are made) and when it reproduces. This replication enables the body to grow and repair itself, but it is also when mutations, i.e., mistakes, occur. These can be inherited or result from
environmental factors such as UV light or smoking (called mutagens). Sometimes our cells can fix these mutations, but if they can’t they are passed on to future copies of the cells. These cells normally cannot survive but in some cases they keep on dividing until a lump, or tumour, is formed.
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They have even begun to crack one of the deadliest and least tractable cancers of all: melanoma especially those of the lung, bowel and breast. They have even begun to crack one of the deadliest and least tractable cancers of all: melanoma. This skin cancer is readily treatable if caught early, but once it has started to spread it is a reliable killer. Chemotherapy rarely works, and fewer than one in ten patients live for a year. A diagnosis of metastatic melanoma is the proverbial death sentence. On the wall of Professor Mike Stratton’s office, though, hangs a remarkable picture. On the left is a positron emission tomography (PET) scan of a melanoma patient, whose body is riddled with cancer. It is so pockmarked that it resembles a Dalmatian. Next to it is a PET scan of the same body, taken 15 days later. It is almost completely clear: the cancer has melted away. It is an image of which Professor Stratton, who heads the Cancer Genome Project at the Wellcome Trust Sanger Institute in Cambridge, is justifiably proud. For the drug that caused this extraordinary transformation was developed as a result of a genetic discovery made by his team just eight years ago. “It is an incredible kick for me and my colleagues to look at,” he said. “On bad days, I look at that picture and I think things are all right. It gives us huge satisfaction to know that our work can make that sort of difference.” That difference began with the discovery in 2002 that a mutated gene called BRAF is present in about 70% of melanoma tumours. This insight allowed Plexxicon, a biotechnology company, to develop a BRAF inhibitor
Prior to treatment
After 14 days of treatment
A copy of the PET scan images of a melanoma patient that hang on Mike Stratton’s office wall. On the left, it shows the patient before treatment with PLX4032, and on the right, 15 days after starting the therapy
called PLX4032. In initial trials, 80% of patients responded so well that tumours often vanished from their scans; the PET images are from one of the trial’s participants. Almost two years after starting treatment, about one in five patients who responded remains clear. “The response was far more spectacular than we expected,” said Keith Flaherty, of MGH, a leader of the trials. The drug is expected to be licensed next year. The BRAF experience also highlights another fascinating aspect of cancer genomics that is changing the
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way the disease is diagnosed and treated. This is because melanoma, caused by exposure to ultraviolet radiation from tanning salons or the Sun, is not the only cancer in which this gene malfunctions. BRAF can also be mutated in colon, lung and thyroid cancer – all organs on which the Sun doesn’t shine. The same is true elsewhere: EGFR mutations are found in gastrointestinal and brain cancers, and the ALK mutation that drives some lung tumours was originally identified in lymphoma. What this suggests is that cancers
that oncologists would never before have grouped together might well benefit from a similar therapeutic approach. The tissue in which a tumour is found may even be less of a guide to the best treatment than its molecular subtype. While this is still a hypothesis, research is now putting it to the test. Trials are already under way to examine if BRAF and EGFR inhibitors work on cancers no matter where they began. Dr Sequist said: “We used to think there was one cookbook for colon cancer and another for lung cancer. But there may be general treatment algorithms for colon cancer with BRAF that are the same for lung cancer with BRAF. The paradigm that certain drugs only work for cancers in a certain tissue is just old-fashioned.” For all the improvements that targeted therapy has delivered, however, none tell of unqualified success. In the first place, treatments still exist only for a subset of cancers: there is no agent, for instance, suitable for bowel tumours with mutant KRAS. In the second, though most patients whose tumours match a tailored drug respond for a time, their cancers often return. PLX4032, the BRAF inhibitor, is a prime example. In trials, its effects generally delivered about ten months of remission, after which tumours started to progress: some patients who initially had results as spectacular as Professor Stratton’s scans have since died. “That’s still real progress,” Dr Flaherty said. “For a metastatic melanoma patient, even ten months is a reprieve you rarely get with chemotherapy. Then you factor in the quality of life. But of course
it’s not as much as we’d like. We’re not calling it quits.” The problem is that cancers, like viruses and bacteria, can evolve resistance to drugs. This can happen in two ways. A tumour can acquire a new mutation that drives it forward even when BRAF or EGFR is knocked out. Or a few cells in a primary tumour may be resistant from the outset. When the larger number of susceptible cells have been killed, the resistant ones can take their place. But if resistance remains a significant hurdle, there are grounds for optimism that it will not always be an insuperable one. “We’re still losing most of our patients,” Dr Sequist said. “But I do think that will improve.” Several trials are under way in which targeted therapies are being given alongside other drugs that, it is hoped, will prevent or delay resistance. Renee is participating in one of them: as well as erlotinib, she is receiving a drug called hydroxychloroquine, originally developed as an antimalarial, which may have an anti-cancer action. The hope is that this cocktail will prolong the effectiveness of her treatment. The MGH doctors all feel that this multidrug approach to cancer will become increasingly important. Several made the analogy with HIV, which can be controlled with combination therapy, in which different antivirals guard against the development of resistance. The toxicity of cancer drugs may sometimes prevent them being given all at once, as with HIV agents, but it may be possible to deliver what Dr Sequist calls “pulses” of treatment – a few weeks of erlotinib, followed
by a few weeks of something else – to hold a cancer in check. Should tumours regrow, it will also be necessary to retest them for mutations, to pick up any new ones that require fresh therapeutic tactics. There is another reason why cancer researchers and clinicians speak often about HIV. This is that while there is no HIV vaccine, and no cure, the virus can be suppressed for long periods of time. HIV-positive people, such as Lord Smith of Finsbury, the former Culture Secretary, have taken combination therapies for two decades, remaining well enough to hold down high-powered jobs. A once-fatal infection has become a chronic one that can be managed so effectively it is questionable whether one should think of its carriers as ill. The advent of genetically targeted therapies, and the molecular diagnostics that underpin them, has brought a similar goal into view for cancer. As Eunice Kwak, another MGH doctor, put it: “If you could cure cancer that would be phenomenal, but if you could make it similar to HIV, so that instead of being a lethal disease it becomes something you can live with and manage, that would be a huge advancement. It is maybe not so far away.” Dr Haber goes farther, noting that for patients whose cancer is caught early, before it has spread, targeted therapy could really change the meaning of the ‘C-word’ to cure. “We do OK with metastatic cancers, but it’s a big challenge to fight a cancer that has got that big,” he said. “The key is to get targeted therapies in there early.” Professor Stratton agrees. “I think
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The Weaver family, including daughter Emily and son Jacob, pose together at home. Renee said her worst fear when she was diagnosed was the thought of not being able to watch her children grow up. Targeted therapy has, at the very least, bought her more time to spend with them
we will increasingly make cancers chronic,” he said. “But we should be aiming for cures – we can aspire to a higher goal.” Genomic treatment, he says, will do for many tumours what advances in chemotherapy did for testicular cancer patients such as Lance Armstrong. “We don’t think much about testicular cancer now: 40 years ago it was a 100% killer, now 90% of young men are cured,” he said. “These therapies will add to that group of patients who can be treated and hopefully cured. Genomic strategies are proving so extraordinary that I would personally voice optimism that ways will be found.” As genomics brings cancer more sharply into focus, these incremental steps forward are starting to become strides. “As I see it, 20, 30, 40 years of genetics are now coming to an application we didn’t have before, to new therapies that are smartly designed,” Dr Haber
said. “I really think it is a revolution.” It is a revolution that reached the Weaver household on May 5, when, just seven weeks after starting erlotinib, Renee returned to MGH for the results of her second scan. She was braced for the worst. Dr Sequist, though, was smiling as she opened the door. “She told me she had some good news, and showed me the scans,” Renee said. “It shocked us all: the primary tumour had shrunk by about 80%, and you couldn’t see any other spots at all. I’d hoped she might say there had been a little shrinkage, but I hadn’t dared to hope for anything like this.” She is not out of the woods just yet: when erlotinib works, the response
typically lasts a year. But, as Dr Sequist said, hardly any patients like Renee who have chemotherapy do so well. There is a chance, too, that she could become one of the growing group of patients in whom erlotinib controls lung cancer for years. “I’m taking it a day at a time,” Renee said. “Whether the results will be this great next time, who knows? But I’m feeling good. I’m trying to go back to a normal life. Thank God for the researchers and doctors who have made this happen. I don’t want to think about where I’d be without them.” This article was first published by The Times in the June 2010 edition of its monthly science magazine Eureka, and is republished here with permission
“I think we will increasingly make cancers chronic ... but we should be aiming for cures” 30
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The ESO Masterclass: where those most eager to learn meet those most willing to teach
➜ Peter McIntyre Once a year, in a quiet location somewhere in Europe, 60 of the continent’s brightest and most motivated young oncologists gather for a learning experience that can define their careers. This week-long Masterclass lies at the very heart of ESO’s mission, building an army of brilliant and caring young oncologists, many of whom will be the leaders of tomorrow.
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would not let them go for a week. So the courses were cut back to one or two days. “Now we have 60 students for a week. This is exactly what people of this age need. They are now at the age when they have to choose what specialty they will follow but options are still open to them. You cannot come here through paying a registration fee. You have to write a motivation about why you want to come and you have to prepare a case study and then you may be accepted.”
LEARNING FROM DIFFICULT CASES What is now the ESO–ESMO Masterclass in Clinical Oncology celebrated its 10th anniversary inApril 2011 at the Wolfsberg Centre, by Lake Constance, in Switzerland. The venue (it belongs to UBS investment bankers) exudes a sense of calm order. The Masterclass is a ferment of bubbling activity. The daily routine is rigorous: breakfast by 8.00am, first presentation at 8.30am, and (with breaks) presentations through till 4.30pm. Then the day begins again, as the participants split into groups and present and discuss case studies from their own hospitals. By the time they close, it has been 11 hours of intense concentration. The presentations read like a Who’s Who of European oncology:Aron Goldhirsch on breast cancer, Jan Vermorken on gynaecological cancers, Jacques Bernier on head and neck cancers, Eric van Cutsem on colorectal cancer, Rolf Stahel on lung cancer. For the case study discussions, nobody brings a straightforward case. The history is revealed step by step, usually with recurrence or complications following treatment and some tough choices at the end. With 15 to 20 young oncologists in each group there are echoes of the hit TV series House, in which bright young doctors outdo each other in diagnoses and suggested treatment. The faculty member for one group is Nicholas Pavlidis, professor at the Department of Medical Oncology in Ioannina, Greece, and joint chair of the Masterclass. He’s far too nice to be ‘Dr House’, but there is something magical about his ability to pop up with a slide containing the most relevant research results during discussion. And (unIike the malignant Dr House) Pavlidis always brings the students back to the human perspective – these are not cases but people. So one case study involves a mother of two children diagnosed with
he European School of Oncology was famously founded on a misdiagnosis and its unique selling point is to prevent tragedies based on ignorance and lack of education. The legacy on which the School was launched in 1982 was bequeathed by an Italian businessman who was treated for a year for arthritis before discovering that his pain came from bone metastases originating from undiagnosed prostate cancer. The whole premise of the School is that mistakes like this would not happen if doctors were better educated about cancer and if specialists were up to date with and applied the latest research and best clinical practice. The Milan group who created ESO was evangelical about improving doctors’ knowledge and understanding about latest treatments and diagnostic tools. ESO education is about incorporating research that updates state-of-the-art best practice, while retaining tried and tested treatments that work. It is the application of knowledge to the treatment of patients that is at the heart of ESO initiatives, exemplified in its motto ‘Learning to care’. It does this by enlisting the best experts from around Europe to present the evidence for first-line therapies and subsequent treatments, asking and answering “what if” questions on the way. The emphasis is on multidisciplinary ways of working and the importance of becoming a true specialist so that all patients are in the hands of doctors who know the evidence and how to apply it. In the variety of ESO courses – Inside Track, Insight conferences, a course for medical students – the Masterclass in Clinical Oncology for young oncologists has come to be seen as a key event bringing together those most eager to learn and those most willing to teach. The annual Masterclass is a week of intensive learning and interaction for 60 of the brightest and best: 30- to 40-year-olds on the cusp of deciding their ultimate oncology specialism. The course is dedicated to medical and clinical oncologists and the focus is on the big killers: lung, breast, prostate, colorectal and gynaecological cancers. Alberto Costa, director of ESO, says that these Masterclasses take the School back to its roots. “When we started ESO, courses were like this – one week residential courses. But then people had no money and people were too busy, and the hospitals
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What if…? Students bring difficult case studies for discussion with international experts such as lung cancer specialist Rolf Stahel, pictured here
colorectal cancer in 2008. She has been treated for aggressive disease and liver metastases with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). By March 2011, after many cycles of treatment, there is no obvious sign of disease. Should they be adopting invasive diagnostic tests? Pavlidis asks what the outcome will be if the cancer has returned and all agree that they will have run out of options. Gently, he suggests that the additional tests will bring distress to the patient without benefit. Another case concerns a young woman who presented with adenocarcinoma, and was initially treated apparently successfully. But, after recurrence and further treatment, hepatic metastases were found. Despite hepatic metastasectomy, it is clear that the cancer has not been cured. Pavlidis points out that she is still alive six years after her initial diagnosis, and for much of that time has been able to live
a normal life. Is this a treatment that has failed, as the young doctor may feel, or one that has given this young woman years of good-quality life, critical years with her young children? Pavlidis has been described as the ‘father’ of the Masterclass. Almost 30 years ago, in 1982, as a young Fellow at the Royal Marsden Hospital in the UK, he attended the first ESO course in Milan. “If you look at who were participants then, more than 50% of them are now professors in universities inside or outside Europe,” he says. He is sure this pattern will be repeated with the current Masterclass series. “We offer real education by distinguished experts from Europe. What makes the difference is that not only do you teach the big killers but you also have these people sitting in these kind of groups presenting their own clinical cases. We analyse and criticise and give directions.”
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“More than 50% of the class of 1982 are now professors in universities inside or outside Europe” UP FOR THE CHALLENGE The participants are clearly up for the challenge. Jochan Bauer qualified as a doctor seven years ago and now works in internal medicine at the Esslingen Hospital in Germany, specialising in cancer and haematology. “My consultant took part in this Masterclass several years ago and recommended it warmly,” he said. “He is certainly right about this. It updates you on the facts and on standard diagnosis and treatment. It is hard work, but it is definitely worth it.” Andreia Costa, a medical oncology fellow at the Hospital de São João, Portugal, takes her final medical oncology exams in 2012. “This is a fantastic revision for me and it is very important for my training. It is very intensive, but we do get some breaks between sessions. I particularly value the discussion of the cases in small groups and over coffee.” Davit Zohrabyan, a medical oncologist at the Yerevan State Medical University Hospital inArmenia, sees the course as a lifeline to knowledge that is not easily available in his home country. He saved up the questions he could not answer at home so he could ask the experts here. “Armenia is a small country and it is not rich and it does not have big research programmes. It is very important for me and for my country that I get acquainted with the new methods and practice. I want to be informed with all the important new scientific knowledge. I want to work together with science.” Inevitably, after 10 years, the pupils start to become teachers. Elżbieta Senkus-Konefka was one of 53 students on the very first Masterclass held in Montecantini, Italy, in 2002. Now a specialist in radiotherapy and medical oncology in Gdansk, Poland, she has returned for the past two years to lecture on treatment for metastatic breast cancer. “My career is an example of someone who graduates from these courses and then becomes an expert. When I applied I was just starting on medical oncology. I wrote that this was at a very important point for me because I had just switched to a second specialty. Ten years ago hardly anyone from eastern
AN EXCELLENT REPORT CARD Students rate the Masterclass highly for useful and relevant education A review of doctors attending the first nine Masterclasses shows that almost 60% were aged 30–34, and 37% were aged 35–45. Participants were evenly divided, males and females. The vast majority of participants (72%) were medical oncologists, with 6% radiation oncologists and 6% clinical oncologists. Some had not yet finally decided on their areas of specialisation. Two thirds (67%) came from European Union countries, 25% from non-EU countries of Europe and 8% from outside Europe – mainly the Middle East and Latin America. Feedback by students is very positive. Over the first nine years the overall median score for the quality of education was of 3.54 out of 4. Information was rated as useful and relevant (median 3.64) and well balanced with good evidence (3.59), with adequate time for discussion and questions (3.51). Masterclasses have been held in Italy, Spain, Cyprus, Malta, Bulgaria and Portugal, but the Wolfsberg Centre, at Ermatingen, Switzerland, received almost perfect scores for facilities, management and organisation, and it is clear that ESO hopes it will be able to return. Source: N Pavlidis et al. (2010) The Masterclass of the European School of Oncology: The ‘key educational event’ of the school. Eur J Cancer 46:2159–65
Europe went to international conferences or was considered an expert. I was one of the few to do so.” Razvan Popescu, medical oncologist at the Hirslanden Clinic in Aarau, Switzerland, is one of two scientific coordinators. “One of the reasons why I became involved is because of the experience of both good and bad quality teaching that I have had myself.” Popescu is active with the European Society for Medical Oncology (ESMO), and in his work on the ESMO awards committee he saw many CVs of young doctors from eastern Europe who needed support. “Certain countries, not exclusively in central and eastern Europe, have teaching that is mandatory for them to attend, but it does not take them forward – they don’t learn. These young people are the future of
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oncology in Europe. What ESO has been doing, and I am delighted it is now doing it in partnership with ESMO, has been to set up a very, very good course. One of the main drivers for me to continue to participate is the live interaction which develops between the faculty and students. They get the crème of European oncology coming and lecturing, but also interacting with them.” Should the course ease up a little? Can anyone concentrate for 11 hours a day? The other coordinator, Wolfgang Gatzemeier, believes that the benefit is worth the pain. “At the beginning, I say you are here for a marathon. I did it for 10 years and I survived and you will survive as well. I know it is not easy to follow presentations for such a long time, but they also have time to reflect and talk to each other.” He points out that the students do not have to remember everything as they get a book of presentations and access to the slides online.
It’s for nurses too. Twenty-two cancer nurses attended a nursing Masterclass held in parallel; this group is discussing issues in patient communication
THE LATEST DATA - IN CONTEXT Gatzemeier, a breast surgeon, believes that the Masterclasses have added value over the large scientific conferences. “When you go to the major conferences and congresses you can get lost in all that they have to offer. Here, in this more relaxed ambience, people are taught by top faculty in a very intensive way. The most important information is presented and everybody has an opportunity to gain as much as possible from what is offered. “We ask people at the end if it is too much and yes, some complain that it is too compressed, but they also always ask us to do something more as well! From our follow-up, we see that for many participants this was a crucial point in their career, so that they may have the opportunity to become head of a department.” ESO is not resting on its laurels. In May this year it held a Balkan Masterclass in Clinical Oncology in Dubrovnik, Croatia, co-chaired by Popescu, who is originally from Romania, and by Semir Bešlija from the Institute of Oncology in Sarajevo, Bosnia. Like the full Masterclass, this was a residential course
paid for by sponsors, although slightly shorter, at three days. The Balkans course was also open to surgeons, who are not covered by the main Masterclass. Popescu explained that the aim was to devise a course that was particularly relevant to the clinical environment in the region. “Some people come and hear things that they won’t ever be able to put into practice, like monoclonals and targeted small agents that cost a fortune. “There are a few people from the region who are exceptionally bright and sometimes manage to come to western institutions and do superbly well. It is painful that if they want to return to their own region they find they are not only struggling with financial issues, they are also struggling with systemic issues and the culture.”
A MASTERCLASS IN CANCER NURSING The Masterclass in Switzerland was not only about doctors: 22 nurses also attended from 15 countries. It was the tenth Masterclass for doctors, and the fourth for nurses. Funding is in place for the nursing
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Happy 10th anniversary. Chatrina Melcher, one of the organisers, with ESO director Alberto Costa (right) and co-chair Nicolas Pavlidis (left) celebrate with cake and presents
a report. I hold meetings with the team and give them my experiences. I write notes every night about what I have seen and all the things I am thinking about how we can do something differently.” EONS is planning to get academic accreditation for the next nurse Masterclass using case studies online afterwards to see how it has changed nurses’practice. Alberto Costa feels that the Masterclass concept is much stronger when it includes doctors and nurses and he praises the sponsors for putting money into education, without wanting to put their names all over everything. Cutting the cake to mark the 10th anniversary of the medical Masterclass, he pointed out that there are now more than 500 people who have been through the course, “a little army of brilliant young oncologists all over Europe”. The average age of those attending the course seems to be dropping and the majority are under 35. It will not be many years before the students attending the Masterclass will not even have been born when ESO began. For now, it can be said that they have grown up together and that together they undoubtedly make a difference to the practice of oncology. The Masterclass is funded by an unrestricted grant from a pool of sponsors through ESO’s Sharing Progress in Cancer Care programme
course to take place alongside the medical course for the next two years. Some presentations are shared with medics, but the nurses also break out to look at the advanced practice of nursing cancer patients. Sara Faithfull, President of the European Oncology Nursing Society (EONS), chaired the nursing course with many of the same objectives. “The idea is that we are training future leaders, so this is very much about clinical experience and about looking at key skills and developing practice. We have looked at putting in place the advanced assessment skills that in many countries aren’t systematic or taught. It is not just about the latest breast cancer treatment, it is about how you would, as a nurse, manage targeted therapies and manage the side-effects and look more specifically at the quality of life issues and enhancing care.” The pedagogical methods used by the nurses are very different, based around group work and group discussion. In a communication segment they discuss how to respond when a patient inevitably asks: “How long have I got?” or when a relative says: “Don’t tell them what they have got.” Nurse training and practice differ across Europe, and EONS has been working to improve online training opportunities for nurses, many of whom get less than three days a year away from the ward for training. But as with the doctors, there is little that can beat the face-to-face interaction. Sandrine Decosterd, from the Geneva University Hospitals, feels that this personal sharing of experience and motivation is most valuable. “This course also gives you a lot of knowledge in a short time – both scientific knowledge and nursing knowledge.” Elana Laska teaches palliative care nursing in Albania, where there are few oncology nurses. As an advocate to improve the role and skills of nurses, she was keen to share her knowledge when she got home. “Every time I go for training I prepare
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Denosumab – a new option for solid tumours metastatic to bone ➜ Philip Saylor Zoledronic acid is a potent bisphosphonate used as the standard therapy for the prevention of skeletal-related events in patients with solid tumours metastatic to bone. Three phase III studies have reported head-to-head comparisons of zoledronic acid with denosumab, an inhibitor of the RANK signaling pathway.
keletal morbidity is a substantial burden in many patients with advanced solid tumours. Pathologic fractures, pain, spinal cord compression and hypercalcaemia are among the potential complications of bone metastases. Osteoclastmediated bone resorption has an important role in the pathophysiology of bone metastases as it weakens the bone and liberates growth factors that can stimulate both cancer growth and further bone turnover.1 Therefore, inhibiting osteoclasts is a rational therapeutic strategy and bisphosphonates and denosumab are two available types of osteoclast inhibitors. Bisphosphonates are analogues of pyrophosphate – a normal component of bone matrix. Once deposited within bone, they inhibit osteoclasts locally. Zoledronic acid is the most potent bisphosphonate available. Since its approval in 2002, it has been the standard bone-targeted treatment for the prevention of skeletal-related events (SREs) in patients with solid
tumours that have metastasised to bone. Denosumab now represents a new class of osteoclast-targeted therapy as it inhibits the receptor activator of nuclear factor κB (RANK) signalling pathway. RANK is present on osteoclasts throughout most of their life cycle and its signalling promotes osteoclast differentiation, activation, and survival.2 Osteoprotegerin (OPG) is an endogenous decoy receptor to RANKligand (RANKL) that negatively regulates this pathway. Denosumab is a monoclonal antibody that functions as an exogenous OPG, suppressing markers of osteoclast activity for several months after a single dose in some settings.3 Three randomised phase III studies have recently compared denosumab with zoledronic acid. Fizazi et al.4 reported that denosumab is superior to zoledronic acid for men with castration-resistant prostate cancer (CRPC) that has metastasised to bone. This phase III study enrolled 1904 men with CRPC who were randomly assigned to
treatment with denosumab (120 mg administered subcutaneously every four weeks) or zoledronic acid (4 mg administered intravenously every four weeks). The primary endpoint was time to first on-study SRE (pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression) and the primary objective was to demonstrate noninferiority of denosumab to zoledronic acid. One of the secondary objectives was to demonstrate its superiority. Median time to first on-study SRE was 20.7 months with denosumab and 17.1 months with zoledronic acid (HR=0.82; 95%CI 0.71–0.95; P=0.0002 for noninferiority; P=0.008 for superiority). Time to disease progression and overall survival rates were similar between the two groups. In another phase III study, Henry and his co-authors reported that denosumab is noninferior to zoledronic acid in patients with metastases due to non-prostate and non-breast cancer.5 This study enrolled
This article was first published in Nature Reviews Clinical Oncology 2011 vol.8 no.6, and is published with permission. © 2011 Nature Publishing Group. doi:10.1038/nrclinonc.2011.70, www.nature.com/nrclinonc
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1776 patients with advanced cancer or multiple myeloma that had metastasised to bone. Median time to first SRE was 20.6 months with denosumab and 16.3 months with zoledronic acid. Noninferiority, but not superiority, was demonstrated for denosumab. The disease progression and overall survival rates were similar between the two groups.5 A third similarly designed study of women with breast cancer metastatic to bone had previously reported superiority of denosumab (HR=0.82; 95%CI 0.71–0.95; P=0.01) compared with zoledronic acid in reducing SREs.6 Taken together, these studies establish denosumab as superior to zoledronic acid in breast cancer and prostate cancer and noninferior to zoledronic acid in other solid tumours. On the strength of these three studies, the FDA approved denosumab in November 2010 for the prevention of SREs among patients with solid tumours that have metastasised to the bone. Denosumab represents an effective new option for the management of skeletal morbidity, but how is the clinician to choose between denosumab and zoledronic acid? It is worth noting that none of the three trials demonstrated a difference in overall disease progression or overall survival. The choice, therefore, must be driven by consideration of drug toxicities and efficacy in preventing SREs. In prostate cancer, denosumab is superior to zoledronic acid. Is it superior enough for clinicians to reach for it exclusively? Zoledronic acid became standard of care for bone-metastatic CRPC when it was shown to prolong median time to first SRE from 10.7 months to 16.3 months – a 5.6-month improvement compared with placebo.7 In the trial reported by Fizazi et al.4, time to first SRE improved by 3.6 months with denosumab compared with zoledronic acid. Simply put, the magnitude of the additional benefit of denosumab over zoledronic acid
is about two-thirds of the benefit of zoledronic acid over placebo. This significant additional benefit should lead us to choose denosumab for men with prostate cancer. The hazard ratio for first on-study SRE was identical in the breast cancer trial, indicating that denosumab should be the standard of care in this population as well. In non-prostate, non-breast tumours, the difference between denosumab and zoledronic acid is simply too close to call. In the trial by Henry and collaborators, enrolment featured approximately 40% of patients with non-small-cell lung cancer (NSCLC) and 50% with a variety of other non-breast, non-prostate solid tumours. In the absence of any specific contraindications, either drug is a reasonable choice. Denosumab seemed to be inferior to zoledronic acid in the subset of patients with multiple myeloma and hence should not be used for this indication. In patients with renal dysfunction, denosumab offers a potential advantage. Zoledronic acid is recommended at reduced doses for stable mild renal insufficiency (glomerular filtration rate (GFR) of 30–60 ml/min) and is contraindicated in patients with evolving renal dysfunction or a GFR of <30 ml/min. Denosumab has a long half-life (28 days)8 and its clearance is not dependent on kidney function. Although denosumab is a rational choice for patients with renal dysfunction, available data are limited because such patients were excluded from the phase III trials that included zoledronic acid arms. Do the toxicity profiles of the two drugs help in deciding which of the two is preferential? Zoledronic acid often causes a flu-like acute-phase reaction, but this is generally mild and resolves without medical intervention. Inhibiting RANK signalling in cells from the immune system raises the possibility of risk of infection after treatment with denosumab,9 but the incidence of
infectious adverse events did not significantly differ during the 2–3 years of follow up in any of the phase III trials.4–6 Hypocalcaemia and osteonecrosis of the jaw (ONJ) are important potential adverse effects of both drugs. Hypocalcaemia can occur with any potent osteoclast inhibitor, although it seems to be more common with denosumab than with zoledronic acid (13% vs 6% in the study by Fizazi et al. and 10.% vs 5.8% in the study by Henry et al.). Because vitamin D deficiency raises the risk for hypocalcaemia, it is important to verify a normal serum vitamin D level before therapy and to encourage calcium and vitamin D supplementation during therapy. ONJ is a rare but important potential toxic effect of both drugs, occurring in 1–2% of the participants in these trials. Appropriate dental care before initiation of therapy is likely the most important preventative measure.10 These three phase III trials are practicechanging for patients with solid tumours that are metastatic to bone. Denosumab should be our first choice in men with CRPC and women with breast cancer. For other solid tumours, zoledronic acid and denosumab are equally supported by highlevel evidence. Details of the references cited in this article can be accessed at www.cancerworld.org
Practice point Three phase III trials establish denosumab as an effective new option to reduce skeletal morbidity in patients with solid tumours that have metastasised to bone. Denosumab is superior to zoledronic acid for patients with prostate or breast cancers and is noninferior for patients with other solid tumours.
Acknowledgement: Philip Saylor is supported by Young Investigator Awards from the Prostate Cancer Foundation and the ASCO Cancer Foundation. Author affiliation: Division of Hematology–Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
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Perioperative therapy improves gastro-oesophageal cancer survival ➜ Tom Waddell and David Cunningham
A randomised phase III study has reported significant improvements in R0 resection rate and overall survival associated with perioperative cisplatin and 5-fluorouracil treatment compared with surgery alone in patients with gastro-oesophageal adenocarcinoma. These data support the results of the randomised phase III MAGIC study that reported a 13% five-year survival benefit from perioperative chemotherapy.
n 2008, the estimated worldwide incidence of gastro-oesophageal cancer was 1.47 million, accounting for 11.6% of all cancer diagnoses. Perhaps more importantly, the estimated number of deaths in that year attributable to gastro-oesophageal cancer was more than 1.1 million, making this the second most common cause of cancer death after lung cancer.1 Due to the aggressive nature of these cancers, most of the patients have inoperable disease at presentation. However, even in the context of locally-confined disease, the
five-year survival rates with surgery alone are less than 25%.2,3 A study recently published by Ychou et al.2 supports the use of perioperative chemotherapy as a combined modality therapy in this disease setting with a 14% improvement in five-year overall survival compared with surgery alone. This approach has been widely practiced throughout Europe since the publication of the results of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial in 2006.3 The MAGIC study
reported a clinically and statistically significant improvement in progressionfree survival (PFS) and overall survival with the addition of perioperative ECF (epirubicin, cisplatin and 5-fluorouracil (5-FU)) to surgery. As a result of these data, perioperative chemotherapy became the standard of care in most European and Australasian countries. By contrast, patients in North America are routinely treated with primary resection followed by post-operative 5-FUbased chemoradiotherapy.As reported by MacDonald et al.,4 this approach also
This article was first published in Nature Reviews Clinical Oncology as an advance online publication on 7 June 2011 and is published with permission. © 2011 Nature Publishing Group. doi:10.1038/nrclinonc.2011.87, www.nature.com/nrclinonc
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CROSS-TRIAL COMPARISON BETWEEN MAGIC AND FFCD/FNCLCC TRIALS2,3 Trial (n)
Site of tumour (% patients)
Tumour stage to be eligible
LO 14.5 GEJ 11.5 Stomach 74.0
> Stage II Resectable
Epirubicin=50 mg/m2 Cisplatin=60 mg/m2 5-FU=200 mg/m2/day for 21 days
LO 11.2 GEJ 64.3 Stomach 24.5
Not staged Suitable for curative resection
Tolerance to chemotherapy (% patients completing)
Curative resection (% patients)
OS benefit (HR)
Preoperative: 86% (3 cycles) Perioperative: 42% completed 6 cycles
Cisplatin=100 mg/m2 Preoperative: 5-FU=800 mg/m2/day 87% (2 cycles) for 5 days Perioperative: 23% completed 6 cycles
GEJ – gastro-oesophageal junction, LO – lower oesophagus, OS – overall survival
improves overall survival compared with surgery alone, and a recent update with long-term follow-up confirmed ongoing benefit for survival (HR=1.32, P=0.04).4 Nevertheless, the two approaches have never been compared in a randomised trial, and cross-trial comparison cannot establish superiority of either strategy due to important differences in the populations. In particular, whereas the MAGIC trial3 required patients to have potentially resectable tumours, the Intergroup 0116 trial4 required a completed curative resection for eligibility. Another geographical variation in the treatment of gastro-oesophageal adenocarcinoma exists in Japan, where the prevalence and natural history of these tumours differ greatly from those in Western populations. S-1, an oral fluoropyrimidine, has become the standard of care in the adjuvant setting in Japan following the results of a Japanese study that demonstrated a significant improvement in three-year overall survival.5 However, this approach has not been adopted as a standard approach outside of Japan as S-1 is not licensed in many
countries and globally capecitabine is the most established oral fluoropyrimidine. A recent meta-analysis of studies on gastric cancer, with individual data from 3838 patients treated within European, American and Asian trials, supports the use of adjuvant chemotherapy with a 5.7% overall improvement in five-year survival.6 Notably, this overall survival benefit with adjuvant chemotherapy seems to be less than the 13–14% benefit reported with the use of a perioperative approach.2,3 Both the MAGIC trial3 and the study by Ychou et al.2 included patients with adenocarcinoma of the lower oesophagus, gastro-oesophageal junction and stomach, although the recruited patient populations in the two studies differ greatly in terms of the distribution of tumour sites. Selected demographics and the results of these two studies are shown in the table. Of particular note, in the MAGIC trial, 42% of the patients completed six cycles of perioperative chemotherapy whereas only 23% of the patients completed chemotherapy in the trial by Ychou et al. Although preop-
erative chemotherapy was completed successfully in most of the patients, postoperative treatment delivery was limited by factors that included disease progression, postoperative complications, and treatment toxicity. As oncological and surgical expertise continue to improve with the perioperative approach, successful completion of therapy should become possible in most of the cases. The 36% five-year survival rate reported with ECF in the MAGIC study is similar to the 38% rate reported in the study by Ychou et al. that used CF (cisplatin and 5-FU). This inevitably raises the question as to whether epirubicin is necessary in this setting. To address this question, differences between the populations in the two studies must be examined. The study by Ychou and collaborators did not formally stage patients at trial entry and included a predominance of tumours of the gastrooesophageal junction,2 which may have improved outcomes, as a subgroup analysis of the MAGIC trial data demonstrated that junctional tumours seemed to benefit most from perioperative
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chemotherapy.3 Furthermore, a metaanalysis from the Cochrane Collaboration carried out in 2010 explored the benefits associated with various chemotherapy regimens in metastatic gastric cancer, based upon data from more than 5000 patients in 35 trials. In subgroup analyses, the researchers demonstrated significant overall survival benefits associated with regimens that included 5-FU, an anthracycline and cisplatin compared with regimens that lacked either the anthracycline or cisplatin.7 These data support the use of regimens such as ECF in the advanced disease setting, which can be reasonably expected to confer benefit to patients with localised disease. To improve tolerability and patient convenience, capecitabine is increasingly substituting infused 5-FU in regimens such as ECX (epirubicin, cisplatin and capecitabine), which was confirmed to be non-inferior to ECF in the metastatic setting.8 The ECX regimen is currently under evaluation as preoperative therapy in the OEO5 study compared with the standard CF regimen for the neoadjuvant therapy of oesophageal cancer (UKCRN trial no. 854). As therapeutic options for the treatment of gastro-oesophageal cancers expand, clinical trials of multimodality therapy for early-stage disease must incorporate targeted therapies to evaluate the outcome of their addition to perioperative, adjuvant chemotherapy or chemoradiation. In the advanceddisease setting the international randomised phase III ToGA study (n=594) recently demonstrated a significant improvement in response rate, PFS and overall survival when the anti-HER2 monoclonal antibody, trastuzumab, was added to a cisplatin–5-FU doublet in patients with HER2 positive adenocar-
cinomas of the stomach or gastrooesophageal junction.9 Trastuzumab is currently being evaluated in combination with capecitabine and oxaliplatin chemotherapy in a Spanish phase II perioperative gastric cancer study (ClinicalTrials.gov identifier: NCT01130337), and following neoadjuvant chemoradiation and surgery for oesophageal and oesophagogastric junction cancers in the RTOG-1010 trial (ClinicalTrials.gov identifier NCT01196390). The smallmolecule inhibitor of HER2 and EGFR, lapatinib, and two monoclonal antibodies targeting EGFR, cetuximab and panitumumab, are currently undergoing evaluation in the first-line advanceddisease setting and, if successful, will likely be evaluated in patients with earlystage disease. Even though the results of these further studies are awaited, the study by Ychou and collaborators strengthens the current evidence for perioperative chemotherapy with improvements in R0 resection rate, disease-free survival and overall survival in gastro-oesophageal cancer. This study confirms the benefits of this approach and further validates perioperative chemotherapy as a standard treatment option in this disease setting. We expect that the addition of molecularly targeted therapies may further improve patient outcomes in the future. References 1. J Ferlay et al. (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917 2. M Ychou et al. (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: a FNCLCC and FFCD multicenter phase III trial. JCO 29:1715–21 3. D Cunningham et al. (2006) Perioperative
chemotherapy versus surgery alone for resectable gastroesophageal cancer. NEJM 355:11–20 4. J MacDonald et al. (2009) Chemoradiation of resected gastric cancer: a 10-year follow-up of the phase III trial INT0116 (SWOG 9008). ASCO Annual Meeting; 2009 [abstract]. JCO 27:4515 5. S Sakuramoto et al. (2007) Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. NEJM 357:1810–20 6. X Paoletti et al. (2010) Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 303:1729–37 7. AD Wagner et al. (2010) Chemotherapy for advanced gastric cancer. Cochrane database syst. rev. issue 3. art. no.: CD004064. doi: 10.1002/14651858.CD004064.pub3 8. D Cunningham et al. (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. NEJM 358:36–46 9. YJ Bang et al. (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697
Practice points ■
Two large randomised phase III trials have now confirmed a 13– 14% absolute improvement in overall survival associated with perioperative chemotherapy compared with surgery alone in gastrooesophageal adenocarcinoma Significant geographical variation in practice will continue in the absence of a head-to-head trial to confirm superiority of one approach over another Addition of novel targeted agents to perioperative chemotherapy is likely to further improve patient outcomes in the future
Author affiliations: Department of Medicine, Royal Marsden Hospital, Sutton UK (Tom Waddelland David Cunningham). Competing interests statement: David Cunningham declares associations with the following companies: Amgen, Merck Serono, Roche. Tom Waddell declares no competing interests.
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NEWSROUND Selected reports edited by Janet Fricker
Cancer family histories found to be inaccurate ➜ JNCI eneral population reports on their family history for lung, colorectal, breast and prostate cancer were not found to be highly accurate, the 2001 Connecticut Family Health study has reported. Accuracy was greater for reports on first-degree relatives (FDR) than second-degree relatives (SDR). It is well recognised that knowledge of a patient’s family cancer history is essential for estimating their individual cancer risk and making clinical recommendations regarding screening and referral to cancer genetics clinics. It has not been clear, however, whether reported family cancer history is sufficiently accurate for this purpose. In the current study, Phuong Mai and colleagues, from the National Cancer Institute (Bethesda, Maryland), undertook a randomdigit dial survey involving 1019 participants. In the telephone interviews respondents were asked to list all biological FDRs (parents, siblings and children) and SDRs (grandparents, uncles, aunts, nieces, and nephews) who had suffered from cancer. Altogether the participants
reported 20,578 FDRs and SDRs, of which 2605 were sampled for confirmation of cancer reports on breast, colorectal, prostate and lung cancer using state cancer registries, Medicare databases, the National Death Index, death certificates and heathcare facility records. The state of Connecticut was chosen for the study because it has the oldest population-based cancer registry in the US, with records dating back to 1935, thereby facilitating the process of confirming cancer reports. Results showed that, for lung cancer, the sensitivity value was 60.2% and positive predictive value was 40%; that for colorectal cancer the sensitivity value was 27.3% and the positive predictive value was 53.5%; for breast cancer the sensitivity value was 61.1% and the positive predictive value was 61.3% and for prostate cancer the sensitivity value was 32.0% and the positive predictive value was 53.4%. Overall, cancer history reports on FDR were more accurate than reports on SDR. For prostate cancer, FDR had 58.9% sensitivity versus 21.5% for SDR (P=0.002); for lung cancer FDR had 78.1% sensitivity versus 31.7% for SDR (P<0.001); for colorectal cancer FDR had 85.8% sensitivity versus 43.5% for SDR (P=0.004); and for breast cancer FDR had 79.9% sensitivity versus 53.6% for SDR (P=0.02). “In summary, the sensitivity and PPV (positive predictive value) of a reported family his-
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tory of lung, colorectal, breast, and prostate cancers in this population-based survey were low to moderate, especially among SDR, but the specificity and NPV (negative predictive value) were high,” write the authors, adding that there is a need to promote family history awareness and to find better tools to capture it accurately to ensure that appropriate risk assessment and clinical care recommendations can be made. “Improved knowledge about cancer might encourage people to be more willing to communicate about it with others, either when sharing information about their own diagnoses or when asking for information about their relatives’ diagnoses,” they write. In an accompanying commentary, Rachel Freedman and Judy Garber, from the Dana Farber Cancer Institute (Boston, Massachusetts), said that although for the foreseeable future detailed family cancer histories will continue to provide the basis for identification of susceptibility genes, ultimately genomic analyses will become a routine part of cancer with predispositions to cancer identified at a young age. ■ PL Mai, AO Garceau, BI Graubard, et al. Confirmation of family cancer history reported in a population based survey. JNCI 18 May 2011, 103:788–797 ■ R Feedman, J Garber. Family cancer history: healthy scepticism required. ibid pp 776–777
FOLFIRINOX improves survival in metastatic pancreatic cancer ➜ NEJM n comparison with single-agent gemcitabine, FOLFIRINOX was associated with a survival advantage as a first-line treatment in patients with metastatic pancreatic cancer, a phase II-III trial has found. However, the FOLFIRINOX regimen (oxaliplatin, irinotecan, fluorouracil and leucovorin) showed increased toxicity. In 2010 pancreatic adenocarcinoma was the fourth leading cause of death from cancer in the US, with five-year survival rates of 6% in Europe and the US. Since a randomised trial showed significant improvements in median overall survival for gemcitabine compared with fluorouracil, gemcitabine has been the reference treatment regimen. However the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone. Data are lacking on the efficacy and safety of the combination chemotherapy regimen FOLFIRINOX compared with gemcitabine as a first-line therapy in metastatic pancreatic cancer. Between December 2005 and October 2009, Thierry Conroy from Nancy University (France) and colleagues from 48 French centres randomised 342 patients in a ratio of 1:1 to receive FOLFIRINOX (n=171) or gemcitabine (n=171). Inclusion criteria included an Eastern Cooperative Oncology Group performance status score of 0–1 (on a scale of 0–5, with higher scores indicating greater severity of illness). Six months of chemotherapy was recommended in both groups for patients who had a response. Results show that the overall survival at a median duration of follow-up of 26.6 months was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group (HR=0.57, 95%CI 0.45–0.73; P<0.001). The median progression-free survival was 6.4 months in the FOLFIRINOX group compared with 3.3 months in the gemcitabine group
(HR=0.47, 95%CI 0.37–0.59; P<0.001). The safety profile of FOLFIRINOX was less favourable than that for gemcitabine, with FOLFIRINOX associated with a higher incidence of grade 3 or 4 neutropenia, febrile neutropenia, thrombocytopenia, diarrhoea, and sensory neuropathy, as well as grade 2 alopecia. Despite this higher incidence of adverse events, however, a significant increase in the time to definitive deterioration in the quality of life was observed in the FOLFIRINOX group. At six months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (HR=0.47, 95%CI, 0.30–0.70; P<0.001). “Our findings suggest that FOLFIRINOX is a first-line option for patients with metastatic pancreatic cancer who are younger than 76 years and who have a good performance status (ECOG 0 or 1), no cardiac ischemia, and normal or nearly normal bilirubin levels,” write the authors. The success of the trial over previous studies, they suggest, may be due to the fact that the selection criteria were more rigorous. ■ T Conroy, F Desseigne, M Ychou, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. NEJM 12 May 2011, 364:1817–25
15 years follow-up: radical prostatectomy beats watchful waiting ➜ NEJM fter 15 years of follow-up, radical prostatectomy continues to be associated with a reduction in the rate of death from prostate cancer as compared to watchful waiting, the latest results of the Scandinavian Prostate Cancer Group 4 (SPCG-4) study have shown. Subgroup analyses also showed that the risk of death from prostate cancer after radical prostatectomy was increased by a factor of seven for men who had tumours with extracapsular growth, and that the benefits of
prostatectomy were confined to men under 65 years old. In 2008 the SPCG-4 study group reported that radical prostatectomy, as compared with watchful waiting, reduced the rate of death from prostate cancer. The current study, which presents an additional three years of followup, represents the only randomised investigation thus far to demonstrate that surgery reduces the risk of mortality from prostate cancer. Between October 1989 and December 1999, Anna Bill Axelson and colleagues, from Uppsala University Hospital (Uppsala, Sweden), randomly assigned 695 men with newly diagnosed localised prostate cancer to radical prostatectomy (n=347) or watchful waiting (n=348). Results at a median follow-up of 12.8 years show that 166 of the 347 men in the radical prostatectomy group and 201 of the 348 in the watchful waiting group died (P=0.007). Death was due to prostate cancer in the case of 55 of the men assigned to surgery and 81 assigned to watchful waiting. At 15 years the cumulative incidence of death from prostate cancer was 14.6% for the surgical groups versus 20.7% for the watchful waiting group (P=0.01). Subgroup analysis showed that the survival benefit was limited to men under 65 years of age, and that the risk of death from prostate cancer for men with extra-capsular tumour growth who underwent radical prostatectomy was seven times that for men without extra-capsular tumour growth undergoing the same procedure. Gleason scores were also highly predictive of the risk of death from prostate cancer: among 129 men who had tumours with Gleason scores of 2 to 6, only 5 died from prostate cancer. The current analysis showed that the number needed to treat with surgery to avert one death was 15 overall and seven for men younger than 65 years of age. This compared with 19 in the earlier analysis. “Although extra capsular growth is not a perfect predictor of lethal disease, our findings indicate that these men could be a group for which adjuvant local or systemic therapy
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would be beneficial,” write the authors, adding that continued follow-up data from the SPCG-4 study might allow them to identify prognostic markers in men assigned to watchful waiting that can serve as trigger points for active treatment. In an accompanying commentary, Matthew Smith from Massachusetts General Hospital Cancer Center (Boston, Massachusetts) writes, “The survival benefit with prostatectomy in men with low-risk disease is the most important new finding of the SPCG-4.” He adds, however, that the findings may not be relevant for men today who have earlystage low-risk prostate cancers identified by prostate-specific antigen screening. ■ A Bill-Axelson, L Holmberg, M Ruutu et al. Radical prostatectomy versus watchful waiting in early prostate cancer. NEJM 5 May 2011, 364:1708–17 ■ MR Smith. Effective treatment for early-stage prostate cancer – possible, necessary or both? ibid pp 1770–72
Sunitinib improves PFS in pancreatic neuroendocrine tumours ➜ NEJM ontinuous daily administration of sunitinib doubled progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (NETs) in comparison to patients receiving placebo, a phase III trial has concluded. The trial also showed objective response rates and overall survival data that consistently favoured the sunitinib arm. The trial was terminated early by the data monitoring committee due to the risk of serious adverse events, disease progression and death among patients receiving placebo. The incidence of pancreatic NETs, which arise from endocrine cells in the pancreas, is increasing, but five-year survival rates are still below 43%. Surgery has been the main-
stay of treatment, with somatostatin analogues used to relieve symptoms resulting from hormone hypersecretion. The only approved chemotherapeutic agents remain streptozocin alone or in combination with doxorubicin. In both preclinical models and phase I and II trials the multitargeted tyrosine kinase inhibitor sunitinib, which was rationally designed to inhibit VEGFR and PDGFR, showed activity against pancreatic NET tumours. In the current study, conducted between June 2007 and April 2009, Eric Raymond from Hôpital Beaujon, (Clichy, France) and colleagues from 42 centres in 11 different countries randomly assigned 171 patients in a 1:1 ratio, to receive best supportive care with either sunitinib at a dose of 37.5 mg per day (n=86) or placebo (n=85). Eligible patients had pathologically confirmed, well-differentiated pancreatic endocrine tumours that were advanced, metastatic, or both, and were not candidates for surgery. In February 2009 the data and safety monitoring committee recommended discontinuation of the trial because of the greater number of deaths and serious adverse events in the placebo group, and differences in PFS. Results show that median PFS was 11.4 months in the sunitinib group versus 5.5 months in the placebo group (HR for progression or death = 0.42, 95%CI 0.26–0.66; P<0.001). The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cut-off point, nine deaths (10%) were reported in the sunitinib group versus 21 deaths (25%) in the placebo group (HR=0.41, 95%CI 0.19–0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhoea, nausea, vomiting, asthenia, and fatigue. Most sunitinib-related adverse events, report the authors, were manageable through dose interruption or modification. “The improvement in progression-free survival observed among patients who received sunitinib provides support for previous preclinical and clinical data suggesting that neuroendocrine tumors may be particularly sensitive to combined inhibition of
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VEGFRs and PDGFR,” write the authors, adding that the improvements were achieved without adversely affecting quality of life. Although early termination of clinical trials may result in overestimation of treatment effects, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death and the favourable survival data provide strong evidence of a clinically meaningful benefit for sunitinib, say the authors. ■ E Raymond, L Dahan and JL Raoul. Sunitinib malate for the treatment of pancreatic neuroendocrine tumours. NEJM 10 February 2011, 364:501–513
Opportunities found for improving colorectal cancer patients’ quality of life ➜ British Journal of Cancer ost factors that adversely affect quality of life in patients with colorectal cancer (CRC) can be modified, a UK study has suggested. Advances in treatment for CRC, which represents the third most common cancer in western countries, is resulting in more people being cured and also surviving longer with the disease. The adverse effects of both the disease and treatment can be longterm and include lack of energy, bowel problems, poor body image and emotional problems, as well as difficulties with sleep, fear of recurrence, anxiety, depression, sensory neuropathy, gastrointestinal problems, urinary incontinence and sexual dysfunction. As many people with CRC are more elderly, they often have additional functional limitations and comorbidities such as geriatric syndromes, heart disease, chronic obstructive pulmonary disease or other cancers. To tackle the challenge of improving quality of life in patients with CRC, Nicola Gray and colleagues from the Centre of Academic
Primary Care at the University of Aberdeen (Scotland), set out to identify the potentially modifiable and fixed factors most associated with better or worse quality of life. In the study 496 people diagnosed with CRC completed the EORTC-QLQ-C30 quality of life questionnaire, which comprises five functional scales (physical, role, cognitive, emotional and social) and three symptom scales (fatigue, pain, nausea and vomiting). Additional symptoms commonly reported by people with cancer (dyspnoea, loss of appetite, insomnia, constipation and diarrhoea) and the perceived financial impact of the disease were also assessed. The mean age of participants in the study was 66 years, with 70% being over the age of 60. Results show that, of the unmodifiable factors, female sex (P<0.001), more self-reported comorbidities (P=0.006) and having metastases at diagnosis (P=0.036) significantly predicted poorer quality of life, but explained little of the variability of the model, giving a correlation coefficient of R2=0.064 (1 = perfect correlation and 0 = no correlation). However, when the modifiable risk factors poorer role (P<0.001) and poorer social functioning (P=0.003), together with fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013), were introduced, the model fit improved considerably (R2=0.574). “We found that physical, psychological and social factors were all significantly and independently associated with overall QoL. Most predictors were modifiable, with symptoms, depression and limitations to usual activities being most important,” write the authors, adding that the influence of unmodifiable factors was small, with the remaining independent predictors offering the potential for intervention. Fatigue, for example, has been shown to respond in a variety of diseases to programmes of graded activity, say the authors, while depression and anxiety have improved with nurse led interventions, exercise and antidepressants, and difficulties with travelling may be helped by interventions to reduce the
need for it, such as providing more locally based follow-up. “If we wish to improve QoL in people with colorectal cancer, then we need first to identify those most at risk, and second to intervene to address factors which are modifiable,” conclude the authors, adding that any future interventions will require rigorous evaluation. ■ NM Gray, SJ Hall and S Browne. Modifiable and fixed factors predicting quality of life in people with colorectal cancer. Br J Cancer 24 May 2011, 104:1697–1703
Short-term radiotherapy added to surgery delivers long-term gains in rectal cancer ➜ Lancet Oncology or patients with resectable rectal cancer, preoperative short-term radiotherapy reduced local recurrence by more than 50% compared to surgery alone, reports the Dutch Colorectal Cancer Group. In the long term follow-up of the total mesorectal excision (TME) trial, investigators found that a reduction in local recurrence was maintained, and that overall survival was improved in a subset of patients. The TME trial, undertaken by Cornelis van de Velde and colleagues at Leiden University Medical Centre (Leiden, Netherlands), was the first study to suggest that, in combination with TME, short-term preoperative radiotherapy delivered added value. Results at two years showed a decreased risk of local recurrence for irradiated patients (2% vs 8%, P<0.001); while results at six years again showed a decreased risk of local recurrence for irradiated patients (6% vs 11 %, P<0.0001). In both cases no difference was found in overall survival. However, the possibility that radiotherapy might not prevent, but merely postpone, local recurrence could not be excluded. The current publication
reports on the long-term results after a median of 11.6 years follow-up. In the TME trial between January 1996 and December 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned, in a 1:1 ratio, to TME preceded by 5x5 Gy radiotherapy (n=897) or TME alone (n=908). The patients were recruited from 118 European centres and one Canadian centre. Results show that the 10-year cumulative incidence of local recurrence was 5% in the group assigned to the short-course preoperative radiotherapy plus TME versus 11% for the TME alone group (P<0.0001). Again overall survival did not differ between the two groups. However, in the subset of patients with TME stage III and negative circumferential margins, survival was 40% in patients receiving just TME versus 50% in patients receiving TME plus radiotherapy (P=0.031). In an accompanying editorial, Rob Glynne-Jones, from Mount Vernon Cancer Centre (Northwood, London, UK), comments that the fact that the results do not show a difference in survival implies that some subgroups may be being disadvantaged by radiotherapy in terms of survival. Indeed, he adds, the results showed that death from a second malignancy was more frequent in the radiotherapy group than in the TME-alone group (14% vs 9%). “Preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III,” conclude the authors, adding that future staging techniques should offer possibilities to select patient groups for which the balance between benefits and sideeffects will result in sufficiently large gains. ■ W van Gijn, C Marignen, I Nagtegaal et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol June 2011, 12:575–582 ■ R Glynne-Jones. …and a two-edged sword in their hands. ibid pp 519–520
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Thirty years on, ESTRO remains focused on its vision for a cure ➜ Marc Beishon ESTRO was set up in 1981 to ensure that radiation oncology could play its full part alongside other disciplines in the developing field of cancer care. This May, thousands of members celebrated its achievements at an anniversary conference, and then turned their focus onto the many challenges ahead.
he European Society for Radiotherapy and Oncology (ESTRO) celebrated its 30th anniversary in London this year at a special conference that brought together its main regular events as well as introducing a new one, the ESTRO International Oncology Forum, which included 'the opportunity to review 30 years of radiation oncology in 30 hours.’ “You don’t usually have an anniversary clinical track at conferences – it was a unique chance to review the evidence-based medicine generated over the last 30 years and how it prepares us for the future,” says Jean Bourhis, ESTRO’s current president, and head of the radiation oncology department at the Institute Gustave Roussy in Paris. Although the history of radiation oncology goes back much further, the
society can certainly be proud of its achievements, which are chronicled in a book prepared for the occasion, ‘Three decades of ESTRO: a vision for cancer cure’. It details the desire of ESTRO’s founders, who had mostly trained in the US, to establish a more united front in Europe after they had witnessed divisions in specialties in America, and indeed there was an idea for a ‘European Society of Oncology’, integrating all disciplines. But the feeling prevailed that radiotherapy needed its own distinct voice, as medical oncologists began their rise, but they would also include allied disciplines such as radiobiology and medical physics. There was the challenge too of distinguishing radiation oncology from the much larger community of radiology at a time when some saw radiotherapy as a dying specialty, as the era of chemother-
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apy started to take hold.After holding its second meeting at the European Association of Radiology’s conference in 1983, ESTRO went its own way in the following years. Special mention is made of Emmanuel van der Schueren, widely recognised as a brilliant clinical scientist and the driving force behind ESTRO, first as executive secretary and then president, and also editor of the society’s journal, Radiotherapy and Oncology. A professor of radiotherapy at Leuven, Belgium, he died far too soon from cancer in 1998, but has left a lasting impact on European oncology. Van der Schueren’s fellow ESTRO founders must be name-checked too, as they are also pivotal figures – Klaas Breur, Jerzy Einhorn, Michael Peckham and Maurice Tubiana – who together set in train an organisation that has built
FEWER'S VIEW PHOTOGRAPHY © ESTRO
up a membership of close to 5000. As befits a field that covers a wide territory, scientifically and clinically, there are now several regular meetings in addition to the main ESTRO conference, which is annual but takes place at ECCO every other year. There are biannual meetings for physics and for the GEC group (Groupe Européen de Curiethérapie – a clinical trials meeting that merged with ESTRO in 1990). More recently, ESTRO has started running PREVENT, on the side-effects of radiotherapy, and an event on novel targeted drugs and radiotherapy. And there is CERRO, an experimental radiation oncology meeting, as well new events on head and neck oncology and molecular imaging. As Bourhis notes, meetings and the journal contribute to communication, one of three pillars that ESTRO is organising its work around. “We are growing our own meetings and also organising more with multidisciplinary partners,” he says, noting that working with other specialties is in his opinion still the most pressing issue at clinical level in Europe.
An inspired leader. Emmanuel van der Schueren was a moving force behind the founding of ESTRO 30 years ago Spreading best practice. Delegates had the opportunity to visit University College Hospital in London to see the latest in precision beam delivery from a high-energy linac. The custommade thermoplastic face mask helps ensure the patient is precisely positioned for every session
PULLING UP STANDARDS The second pillar, education, is particularly important because of the variations in quality in using increasingly complex equipment and regimens. Bourhis says ESTRO has been careful not to expand its courses too quickly so as not to compromise quality, but it now runs more than 30 courses both inside and outside Europe – twice as many as in 2005. Significant numbers of attendees come from eastern Europe, Africa and the Far East, he says, with about 40% from western Europe. It all adds up to some 3000 attendees and 200 teachers a year. ESTRO’s core curriculum has also recently been revised, and it has now been integrated into the national teaching programmes of countries such as the Netherlands and Spain. E-learning is playing an increasing part in ESTRO’s education plans, adds Bourhis. The society has a platform called Eagle (ESTRO's application for global learning), for online tutored courses, which has so far been used for rectal cancer, with courses for breast and head and neck to come. Another offering, called Falcon, is a combined workshop/online platform for anatomic delineation and contouring, which aims to address one of the biggest and most unpredictable sources of error in radiation oncology. “At ESTRO 30 we also launched the ESTRO Fellow, a position that people can attain after gaining a certain number of credits and passing an exam,” says Bourhis. The third pillar of ESTRO’s work is policy, which Bourhis says has probably been the most challenging for all cancer societies in Europe, but which has received a big boost now that ECCO is more effectively presenting a joint front. ESTRO past-president Michael Baumann, whose contribution to the field of radiation oncology was profiled in Cancer CANCER WORLD ■ SEPTEMBER/OCTOBER 2011 ■
ESTRO is acting once again to raise awareness of the economic benefits of its specialty True to its founding vision. The anniversary book chronicles ESTRO’s achievements so far. The anniversary conference focused on carrying that vision forward into the next decade
World Jan–Feb 2006, is the current president of ECCO. He and other ESTRO leaders have been uncompromising in fighting ESTRO’s corner in European oncopolitics, but it has been tough to gain the level of representation they feel the society needs within ECCO, and also politically on the European stage. The level of investment needed by healthcare systems in radiotherapy is much higher than most other medical treatments, and ESTRO is acting once again to raise awareness of the economic benefits of its specialty, recognising that awareness of radiotherapy remains poor among not only the public and politicians, but also healthcare purchasers. A new project called HERO (Health Economics in Radiation Oncology), run by a taskforce from Europe and Canada, has started to look at the need for radiotherapy, its provision and accessibility, waiting lists, staffing, cost accounting and economic evaluation. Taskforce member Yolande Lievens,
from Leuven, explains that the project is an extended update of a 2005 study that was funded by the European Union called QUARTS (Quantification of Radiotherapy Infrastructure and Staffing). The radiation oncology community has still “barely started” evaluating the economic aspects of its treatments, she says, while other disciplines such as medical oncology have been doing better for some time. Aims of the HERO project include the development of economic models to calculate the value for money of treatments, and using data for lobbying and policy making. Preliminary data from a questionnaire were presented at ESTRO 30, with final results expected in 2013.
A VERY WIDE AGENDA ESTRO has one of the widest agendas of any cancer specialty, covering as it does, for example, core European curricula for clinicians, physicists and radiotherapy technicians. This, together with the various meetings and educational activities, makes it quite a challenge just to organise its own affairs, let alone tackle
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the wider multidisciplinary integration that Bourhis says is vital. A long list of actions are in train to address issues such as increasing membership and attracting younger members – the society would like to increase its number to 8000 by 2015, which would still be only about half of its target ‘market’. Like other European oncology organisations, however, it faces the tricky problem of whether and how to extend terms to national radiation oncology societies. Representing more of the various sub-specialties at board level is another issue, as is forging ethical collaboration with industry – the society has recently expanded its corporate membership programme, and now offers a ‘gold level’ whereby companies can participate in an advisory corporate council for promoting research and education. ESTRO has certainly made a concerted effort to increase its profile and professional presentation, with the 30th conference being a flagship, and has engaged top-level public relations support, produced the anniversary book, created the new fellowship and started additional activities. With a solid platform in conferences and education, the emphasis is now on pushing forward its standards and guidelines in the multidisciplinary context, which will need both consistent engagement of activists at local level and higher-level European networking. To help finance this ambitious programme, the ESTRO Cancer Foundation was launched at the anniversary conference, which should help ensure ESTRO can continue to play a dynamic and leading role in pushing forward the boundaries of cancer care in decades to come.
A minimum acceptable standard of care for every patient ➜ Anna Wagstaff A great deal is already known about why cancer patients do better in some countries or some parts of a country than in others. But how can that knowledge be transmitted to the people who have the power to act, in a way they can quickly and easily understand?
aximising survival and minimising the sideeffects, the long-term effects and the impact of the disease and its treatment on patients’ quality of life are what good cancer care is all about. But when funds are limited, and diagnostic or management tools are expensive, distinctions must be made between what is essential and what is desirable, with a view to ensuring that every citizen diagnosed with cancer has access to the basic essentials of care. This is the philosophy behind one of the latest EUROCHIP projects, which has been piloting a new approach to closing the survival gaps between the best and the worst in Europe. The idea is simple. First, select a disease setting. Priority should be given to those with curative potential and those affecting large populations – low-risk childhoodALL (acute lymphoblastic leukaemia)
and early and advanced breast cancer were selected for the pilot studies. Next, ask a group of experts to agree on the gold-standard evidence-based protocol for diagnosing and managing the disease. Then, separate out the ‘minimum requirements for acceptable treatment’ from the ‘additional [desirable] tools’– things that might, for instance, offer an extra little bit of certainty, or make the patient feel less unwell. This list of minimum requirements will represent the basic standard of treatment that every cancer patient in Europe should have the right to expect. It can be scanned to identify which elements are affordable even in the poorest areas in Europe, and which are sufficiently costly to pose a problem where health budgets are very tight. By narrowing the focus onto diagnostic and management tools that are both essential and potentially unaffordable, it becomes possible to concentrate efforts on problem areas and look for alternative options that
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are more affordable but equally effective (if perhaps less desirable), or explore cheaper ways of getting access to essential tools – greater sharing of expensive diagnostic testing facilities, for example. This pilot project, one of many initiatives of the European Cancer Health Indicator Project (EUROCHIP) programme run from the Istituto Nazionale dei Tumori in Milan, focuses on reducing inequalities in cancer incidence and cancer care across Europe. (EUROCHIP’s work on improving cervical cancer screening in six countries was profiled in the May–June 2011 issue of Cancer World.) The pilot tackles an aspect of cancer control that almost all of Europe’s richer countries are now struggling with, and that is even more essential for the poorer ones: cost–effectiveness, how to do the best for cancer patients with the money available. Where this approach differs from that of existing bodies set up to perform health
COMITATO MARIA LETIZIA VERGA/ATTILIO ROSSETTI
technology assessment (HTA) and valuefor-money analyses, such as the UK’s NICE (National Institute for Health and Clinical Excellence) and Sweden’s Dental and Pharmaceutical Benefits Agency, is that rather than taking costs and benefits as its starting point, it tries to identify where cost constraints could be a significant factor explaining why patients do so much worse in some countries or regions than in others. And it tries to suggest solutions.
GOAL ORIENTED For Andrea Micheli, the EUROCHIP leader, this project is all about results on the ground, and that means it is heavily geared toward Europe’s political leaders. “The problem is that individual specialists know
We can do this. Not all ALL patients can receive the same level of care as this young girl at the San Gerardo Hospital in Monza, Italy, but Momcilo Jankovic, pictured here, hopes that simple messages designed to address the main factors behind variations in survival will ensure greater access to minimum acceptable standards of care across Europe
what has to be done, but this is not information known to politicians. What EUROCHIP does is to extract from these people some key proposals and to pass them on to the politicians. We need to send simple messages to the European Commission: in this way we can quickly improve the situation in poorer countries.” ChildhoodALL was an obvious choice for a pilot study. Thanks to decades of cooperative clinical studies by paediatric oncologists in the US and Europe (notably Germany), childhood ALL is now cur-
able in around 80% of cases.Yet many children continue to die unnecessarily in some countries and regions of Europe. Furthermore, the high level of collaboration in this area means that, while many questions remain to be answered, there is a strong consensus over the current gold-standard protocol for managing the disease. The rationale behind choosing breast cancer, both early and advanced, for the other pilot studies was that it is the most common cancer among women in Europe, and the number of new cases is growing.
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“Individual specialists know what has to be done, but this is not informatoion that is known to politicians”’ “In this case, new drugs are proposed, and differences in survival may be related to the availability of these drugs or to other things,” says Micheli.
A CHANCE TO HELP Momcilo Jankovic, a paediatric oncologist at San Gerardo Hospital in Monza, Italy, was delighted to be asked to participate in the ALL pilot, alongside Kathy PritchardJones, professor of paediatric oncology at University College London and Nick Goulden, consultant haematologist at Great Ormond Street Children’s Hospital, London. “When they asked me to cooperate to define what the child needs in order to be treated according to local resources and to reduce the cost of this treatment, I thought, this is not widely reported in the literature, so it seemed to be a very good opportunity to help with my experience.” Jankovic’s experience in this field is considerable. Not only does he have a long track record treating young ALL patients – including collaborating in international clinical studies led by the Italian Association of Paediatric Haematology and Oncology (AIEOP) and the BerlinFrankfurt-Munich (BFM) ALL group – but he also has experience helping improve results in countries where costs pose a real problem, including a collaboration with Nicaraguan paediatric oncologists, which raised survival rates for childhood ALL from 10% to an impressive 50%. Closer to home, Jankovic and his colleagues also built up a long-term collaboration with doctors in Serbia after years of isolation during the Balkan war left them trailing behind much of Europe. He mentions, as one important outcome, the interest and support these paediatric
oncologists received from the politicians once they saw what was being achieved. “The government looked at the results they obtained and wanted to promote a national network. They now pay for equipment, and they pay for doctors to attend meetings or to visit outside the country. They are much more positive about responding to the request of doctors.” Jankovic hopes that the EUROCHIP project will help achieve similar improvements across Europe.
A BRIDGE TO POLITICIANS Micheli describes the project as essentially an intellectual exercise, “using a methodology derived from our experience over 10 years” to facilitate discussion between experts coming from different fields, to extract key messages, check whether these are widely accepted by others, and then pass them on to the people who can deliver change. “We are trying to build a bridge and to find a common language with the politicians.” In the ALL pilot, as well as Jankovic and his fellow physicians, the group of experts included researchers, epidemiologists, health economists and health technology analysts. The final report has yet to be written and validated among a wider group of experts, but findings so far indicate that the cost of providing therapies is less of an issue than the cost of tests that can guide physicians in tailoring treatments. The only exception to this may be PEG-asparaginase, a less toxic, but more expensive, variation of L-asparaginase. However, as affordable methods exist for managing the side-effects of the unpegylated version, PEG-asparaginase was put under the ‘desirable’ rather than
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the ‘minimum requirement’ heading. More important, perhaps, are the methods used to stratify patients into risk levels as a guide to treatment, key among which are measurements of minimal residual disease, showing how well the patient has responded to the initial induction treatment (day 33) and the second induction treatment (day 72). The gold standard here is using quantitative PCR (polymerase chain reaction). “This is a very expensive methodology and is not possible to adopt in every country,” says Jankovic. However, PCR was listed under the heading ‘desirable’, because an alternative method for measuring minimal residual disease does exist, in the form of cytofluorometry. Though less accurate than PCR, the team considered it to be an ‘acceptable’alternative. While it is cheaper than PCR, cytofluorometry equipment nonetheless requires a hefty investment, and it was therefore flagged as a ‘minimum requirement where cost constraints could limit access’.
PART EVIDENCE PART EXPERIENCE As Micheli readily admits, the approach taken in this EUROCHIP project draws as much on the experience of the experts as it does on hard peer-reviewed evidence. This is partly a matter of necessity, as evidence on the cost–effectiveness of specific procedures or therapies in the context of a particular indication is often hard to come by. A thorough search of the literature on cost–effectiveness/cost–utility/cost– benefit/cost minimisation analyses of the ALL diagnostic/management tools flagged up as potentially unaffordable showed how little there is out there – at least in the academic literature. In the case of child-
Survivors. Miloš, Ajla and Hena are among the many young ALL patients to have benefited from an initiative to ensure all children have access to minimum acceptable treatment, which was spearheaded by Serbian paediatric oncologists in collaboration with a group of Italian specialists
hood ALL, the treatment protocol is so widely accepted that there may be few calls to carry out such analyses. “Basically we still don’t have the evidence in terms of the literature, economic statistics and data, so we must go on the basis of experience,” saysAnnalisa Trama, one of the epidemiologists involved in the ALL pilot study. But that experience, she argues, offers some crucial insights that will probably form the basis of the main recommendations of the pilot study. She cites, in particular, reports by participating oncologists of visits to hospitals where children being treated forALL were not losing their hair. “This is almost impossible if children get the appropriate dose of chemotherapy.And it raised the question of to what extent children were really receiving the dose recommended by the protocol.” In some cases, children were being treated in general haematology departments, and sharing wards with adults. As a result of this discussion, says
Trama, the experts group started looking at whether, and to what extent, issues of organisation – “how these well-known drugs and other interventions are actually provided” – might be responsible for the observed variations in survival. “In the case ofALL, we are not talking about a very expensive treatment. There are a few techniques that are important and are expensive, but these alone cannot really explain the difference we see in survival. So we said, probably this is an issue of quality and accessibility of these treatments.” That said, she adds, there are important cost implications in improving organisation and delivery of care through greater use of referrals to specialist centres, linked in to national and European networks, and this needs to be explicit in any recommendations coming out of the pilot. Micheli is conscious of the need for any set of recommendations to carry the backing of the leading voices in the field, and he will be circulating a draft of the final
report to bodies such as ECCO, ESMO (Europe’s medical oncologists), SIOPE (Europe’s paediatric oncologists) and the European Leukaemia Network for their comments and endorsement. Whatever the specific recommendations may be on ALL and on early and advanced breast cancer, Micheli hopes to send three simple messages to the Commission about closing cancer survival gaps across Europe. ■ Studies exploring the relationship between costs and outcomes for specific cancer indications can help identify and address the key issues that lie behind variations in survival between countries, to help ensure that all Europe’s cancer patients have access to the minimum requirements for acceptable treatment. ■ To facilitate such studies, member states should be encouraged to gather and share information relating to the costs and benefits of technologies used in specific cancer indications. ■ EU funding should be made available specifically for studies that explore the relation between cancer costs and cancer outcomes in the next call for proposals for public health or medical cancer science research. Jankovic, who has seen the way the Serbian government responded to the evidence of improved survival when their young ALL patients were treated effectively in accordance with minimum requirements, endorses Micheli’s messages. “If we give the Commission the correct information, they can help different countries achieve these minimum requirements. So I believe in this type of study, which is based on evidence for some aspects and experience for others. In this way we can offer the authorities a way to ensure patients can be adequately treated at the lowest cost.” Details of this and other EUROCHIP projects can be found at www.tumori.net/eurochip/
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