www.eso.net n° 71 March / April 2016

Pulling together the case for prostate cancer units

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3 Editorial 37 Grandround Founding Editor Kathy Redmond Personalising treatments: Endoscopy in gastro- Editor Alberto Costa lessons from history intestinal oncology Associate Editor Anna Wagstaff 4 Cover Story 44 Our World Editorial Coordinator Corinne Hall Pulling together: Affordable cancer care: Editorial Advisors the case for prostate a global mirage? Matti Aapro, Felipe A. Calvo Fatima Cardoso, Franco Cavalli cancer units Fedro Peccatori, David Zaridze 48 Systems & Services Contributing Writers Simon Crompton, Marc Beishon 14 Spotlight Improving care for Maria Delaney, Janet Fricker Susan Mayor, Peter McIntyre, Is this the end patients with rare Vlad Mixich, Ken Murray Richard Sulliva, Anna Wagstaff for the microscope? cancers: are ERNs Publishing Advisor the answer? Jacopo C. Buranelli 22 Profile Graphic Concept and Design Studio TheValentino, www.thevalentino.it Ana Maria Forsea: 54 Impact Factor Printed by getting from here to Novel approaches Grafiche Ambert, Verolengo (TO) where we want to be to pancreatic cancer Cover by Lorenzo Gritti Illustrations by 29 Cutting Edge 60 Focus Nicolò Assirelli, Maddalena Carrai Elisa Macellari Accelerating progress How doctors die: it’s Published by in immunotherapy not like the rest of us, European School of Oncology Direttore responsabile but it should be Alberto Costa

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Editorial

Personalising treatments: lessons from history

Stephan Tanneberger, Guest editor

ifty years ago, when I was just starting out in progress. Given the biological diversity and continuing cancer medicine, our team at the cancer centre evolution of tumours, it is perhaps not surprising that Stephan Fattached to Berlin’s Academy of Sciences began patients cannot be cured using a single targeted thera- Tanneberger our attempts to individualise chemotherapy treatments. py. Even today’s sophisticated technologies still give us was Director We knew that response to different drugs varied enor- only a snapshot of the dynamic carcinogenic process. of the Central mously between patients, so we invented the ‘oncobio- Cancer is an error of cell division induced by avoid- Institute of gram’ to try to select, in advance, the best treatment able carcinogens or unavoidable body aging. It is an in- Cancer Research for each one. Modelled on the ‘antibiogram’ for select- herent part of our biology. Targeted treatment remains of the Academy ing antibiotics, we cultivated biopsies (cell culture/ a concept continually pursued, rather than realised, of Sciences of organ culture), which we then treated with the differ- and realistically speaking, we may never see a defini- the German ent drugs in vitro. We evaluated the efficacy of this se- tive breakthrough. Democratic lection procedure in clinical trials, and the results were Yes, the immune system is intriguing and a new gen- Republic from encouraging. eration of immune checkpoint inhibitors hold interest- 1974 until 1990. Less encouraging was what we learnt about the ex- ing potential. However, it has not evolved to eliminate He spent much treme heterogeneity of tumours in space and time. Our tumours, but rather to control ‘minimal deviations’ of of his later collection of more than a thousand of these cultures of cell division at the start of carcinogenesis. There are career with the human tumours showed individuality with respect to other interesting approaches that also need to be ex- Bologna-based detailed histology, mitotic index, DNA synthesis, drug plored, and in a time of great dreams of cancer thera- Associazione sensitivity and more. In a programme that spanned ten peutics, we should not forget cancer prevention. Nazionale years, we realised then that the existence of a single Oncology does need personalised medicine. But a Tumori, ‘cancer state-specific cell defect’ is nothing more than renewed focus on the patient, their needs and feelings, developing a scientific illusion. must be central to that personalisation. Our patients, their local and ‘Personalised’ or ‘precision’ medicine is often seen as many of whom are old, may have other needs more international a purely 21st century concept that is just in its infancy. important than access to highly sophisticated drugs. work supporting A better understanding of the historic context could My plea, particularly to the new generation of col- home-based help inform more realistic expectations about what it leagues, is: when you look at someone’s tumour to un- palliative will be able to deliver. derstand its driver mutations, don’t forget to also look care services. The annual rate of publications on cancer chemo- in their eyes, understand the person, and ‘personalise’ h.s.tanneberger therapy doubled between 1997 and 2014, alongside that human being in the room with you. This we call @gmx.de an expansion in expensive new anticancer drugs. But eubiosia – a ‘good life’, a human right for all, including the reported results do not show convincing clinical those of us suffering from cancer. March / April 2016 3 Cover Story

Pulling together: the case for prostate cancer units

People with cancer need their care managed by a team of specialists who work together and learn and improve together. Simon Crompton reports on efforts to achieve such a collaborative approach in delivering prostate cancer care.

4 March / April 2016 Cover Story

here are few easy decisions its database shows that more than Specialist, multidisciplinary, in prostate cancer. Many nine in ten of its patients are fully audited units Tmen’s experience of diagnosis, continent after treatment, compared treatment and beyond is characterised to a German average of between five What distinguishes the Martini by lack of clarity about the best and six in every ten (Harvard Business Clinic, and 96 other centres in management options, worry about Case Collection 2014, case 714-471). Germany, from the vast majority potentially life-changing side effects, Less aggressive approaches such of units treating cancer in Europe and enduring uncertainty about as active surveillance, which rely on is that they are certified prostate prognosis. A 2014 review in BMJ careful monitoring, reduce the risk of cancer units – centres characterised Open Oncology found that anxiety side effects and overtreatment – but by specialisation, multidisciplinary reached clinical levels in more than leave the risk of cancers growing and collaboration and independent audit. one in four men on diagnosis, one becoming harder to treat. It is a model that a range of opinion in seven during treatment, and more Whichever way you look at it, leaders, led by the European School than one in six after treatment. patients can often be left with an of Oncology and Europa Uomo – a But it wasn’t like that for Jobst anxiety-inducing gamble. Finding coalition of prostate cancer patients’ Plog, a 74-year-old retired director the right option for them requires groups – see as the future of prostate of a broadcasting company, who has clear understanding and impartial cancer care in Europe. Its over-riding little bad to say about his cancer principle is that no surgeon, radiation journey while at the Martini Clinic in oncologist or other professional Hamburg, Germany. Before having a Finding the right should treat prostate cancer unless nerve-sparing radical prostatectomy, they specialise in it, and no single he was advised about options, offered option requires professional should be directing his choice of treating physician and treatment on their own. The patient treatments, and was then given the impartial expert should be informed, involved and opportunity to attend a pre-treatment advice from all supported. multidisciplinary conference. It is the logical way to go, according “Physicians and the entire staff at the professionals to Riccardo Valdagni, Director of the the clinic work as a team, using their Radiation Oncology 1 and the Prostate range of experience and specialisations involved Cancer Programme at Milan’s Istituto in an organised process,” he says. Nazionale Tumori and also coordinator A diagnosis of prostate cancer of ESO’s Prostate Cancer Programme. brings choices, which take careful expert advice from the sum of the “If we look at the experience with explanation because each option is professionals involved in their breast cancer, it is clear that our based on uncertainty and involves care – not just a single urologist or evolution will be towards a system a complex risk–benefit analysis. radiation oncologist. And it was the of certified and accredited prostate Treatments such as surgery and multidisciplinary pooling of expertise cancer units,” he says. “That means radiotherapy may bring a greater at the Martini Clinic that helped Plog independent bodies checking the likelihood of cure, but they produce weigh the pros and cons, and left quality of services.” hugely varied side effects from patient him confident he was doing the right As Valdagni suggests, the idea of to patient. Some men are left with thing. the prostate cancer unit hasn’t come life-changing complications such as He was told about the treatment out of the blue. A similar model incontinence and impotence. options and also provided with has been promoted – and gradually Around two in ten men have long- detailed printed information. And he implemented – for breast cancer care term urinary incontinence following was involved in all the joint decision- across Europe. Responding to evidence prostatectomy, but the likelihood making about the type of treatment of widely varying survival rates, two varies according to age, physical he should receive. European Parliament resolutions in fitness, surgical technique and “There were no surprises during 2003 and 2006, and declarations where the surgery is conducted. The my treatment because I was well on the fight against breast cancer in Martini Clinic, for example, claims informed and prepared,” he says. 2010 and 2015, called on member March / April 2016 5 Cover Story

Exploring all the options. Patients seen by the Prostate Cancer Unit at Milan’s Istituto Nazionale Tumori have an initial consultation with the full range of specialists, including a urologist, radiation oncologist, medical oncologist, psychologist and nurse

states to ensure that all women in care brings quicker treatment, better and drawbacks of different diagnostic the European Union have access to individualised care and support, and tests; the relative merits of surgery, treatment in specialist breast units, better adherence to evidence-based brachytherapy, radiotherapy and certified according to quality criteria guidelines. surgery; the right time for active set down by the European Society of surveillance and watchful waiting; the Breast Cancer Specialists. The case for prostate role and timing of new drugs. All need There is evidence that five- cancer units to be carefully balanced to meet each year survival is around 18% higher individual’s needs and priorities. among women treated in a specialist Multidisciplinary specialist manage­ Multidisciplinary prostate cancer breast unit (BMJ 2012, 344:1e9). ment has become widely accepted as units provide a structure where Indeed, research in breast and other the best means to optimise experience urologists, radiation oncologists, cancers shows that such specialist and outcomes for patients for many medical oncologists and psychologists multidisciplinary centres produce years. But the argument to have it at specialising in prostate cancer the highest treatment success rates the heart of prostate cancer care is collaborate to decide the best and best patient experience. High particularly strong. treatment and care options. concentrations of specialists and a Here, the ‘best’ means of diagnosing Germany has been encouraging high volume of patients develop skills and treating localised disease can cancer centres with this specialist and quality. And multidisciplinary attract intense debate: the benefits multidisciplinary approach since 2003. 6 March / April 2016 Cover Story

Requirements for a European Prostate Cancer Unit

A multiprofessional task force of internationally Education and research recognised opinion leaders, representatives of European □□ Prostate cancer units should provide interdisciplinary scientific societies and patient advocates gathered to and multiprofessional­ continuous education on all set criteria and standards for prostate cancer units. The aspects of prostate cancer care, including research. result, published as a position paper in Critical Reviews □□ They should actively aim to enrol patients in clinical in Haematology & Oncology last year, describes the trials and research. relevant, feasible and applicable core criteria for defining prostate cancer units, and represented a consensus on Guidelines/protocols 40 mandatory and recommended standards and items, □□ Evidence-based written guidelines used for including the following: diagnosis and management of prostate cancer at all stages should be clearly identified. European Prostate Cancer Units □□ Protocols should be agreed by the core team □□ are structures, with on-site interdisciplinary and members; new protocols and protocol amendments multiprofessional teams and infrastructures, should be discussed in the core team. that are able to provide interdisciplinary and multiprofessional curative and supportive care for Documentation and audit patients from newly diagnosed through to follow- □□ A minimum set of variables should be recorded up, rehabilitation and care of patients with advanced electronically in a database: diagnosis, pathology, disease surgical treatments, radiotherapy, brachytherapy, □□ must manage a minimum volume of patients adjuvant treatments, observational strategies, (set at 100 patients/year for the unit, 50 radical palliative treatments, clinical outcomes and follow prostatectomies/year for surgeons, 50 radical or up, including side effects and complications. adjuvant treatments for radiation oncologists and a □□ Data must be available for audit. patient load of 50 for medical oncologists) □□ Minimum outcomes for mandatory quality indicators □□ need not be a geographically single entity, but should be achieved. patients must be managed and followed up under □□ Performance and audit figures must be produced the guidance of a single interdisciplinary and yearly and set alongside defined quality objectives multiprofessional team, for all immediate and and outcome measures. deferred treatments and observational protocols □□ Internal audit meetings should be held at least (active surveillance, watchful waiting) twice a year to review quality indicators and amend □□ should be allowed to network and outsource protocols as necessary. services, including adjuvant and palliative therapies as well as psychological support, to entities formally The full list of standards and requirements can be seen collaborating with the prostate cancer unit, to in Critical Reviews in Haematology & Oncology vol 95, complete the path of care. pp 133–143.

It has done it through a system of Each centre needs to fulfil a when ESO’s Prostate Cancer Units certification administered by Deutsche catalogue of requirements and Initiative in Europe developed 40 Krebsgesellschaft, the German Cancer publish quality indicators to receive new standards for prostate cancer Society – first for breast cancer, then certification. The requirementsunits, which were published last year for colorectal cancer and then, in 2008, were developed by a commission in Critical Reviews in Haematology & for prostate cancer. By 2014, one- of experts from professions and Oncology (see box). third of all prostate cancer patients in disciplines specialising in prostate The German framework, then, Germany were treated at a certified cancer and German patient advocacy is providing inspiration for the new prostate cancer centre. groups. They were taken into account European evolution of prostate March / April 2016 7 Cover Story

cancer treatment. But what insights a basis for national and international organisation Bundesverbandes Prostata­­­­ does it provide into the experience comparison. The main criterion for krebs Selbsthilfe, is also a member and effectiveness of specialist, comparing centres will never be of the certification commission for multidisciplinary units? length of survival, says Wesselmann, German prostate cancer centres. He An analysis of the German Cancer even if it were possible to measure. says that around a quarter of the total Society’s 2014 annual report of 92 “That’s not the aim of number of hospitals treating prostate urology departments certified as certification,”she says. “If you want cancer in Germany are now certified. prostate cancer centres shows that to gain the trust of the patient, you The important differences between all treat more than 100 primary must be able to say that within this the certified and non-certified centres, cases of prostate cancer each year: year, this doctor achieved these high- says Feick, lie in management systems, throughput is an important quality quality standards. structural requirements, audit, and indicator. The number of radical “You cannot say that if one patient collaboration with prostate cancer prostatectomies has decreased over dies after 13 years and another dies patient groups. time, indicating that approaches after 15 then the difference is down “The multidisciplinary organisation aiming to minimise overtreatment are to the quality of their surgery, or is very important to us,” he says. “The increasingly valued. the care they received. For certified patient always has the oncologist, the Between 2010 and 2013, the centres that would be a superficial urologist, the radiation oncologist, proportion of patients on active measure. We want to be trusted by the pathologist, the psychological surveillance increased more than the patient – to be able to tell him team, the social management team all six-fold, from 2.5% to more than that we know what this doctor did last together as one organisational unit, all 16%. And the proportion of patients year, that he’s had so many re-sections following a certain path of treatment receiving psycho-oncologic care more for a particular operation, or so many and communication together, in a than doubled, from 8% to 17%. critical events.” procedural flow described in the “We defined our measures to reflect These are the things that matter requirements. quality,” says Simone Wesselmann, for patients, says Wesselman. “It’s “It’s important that, three years head of the certification department about being totally transparent.” after their initial certification, of the German Cancer Society. No one claims that the German centres are visited by an independent “An auditor from the independent system is perfect. Wesselmann team of experts, including a patient acknowledges that patients’ own representative, to see on-site whether It is this constant reports of outcomes for different what they are doing still fulfils the therapies could be included in the initial requirement. measurement and indicators: the German Cancer “Each of the centres is required Society is investigating this as part to be in cooperation with a prostate reporting that of a new study into the patient cancer patient support group. experience, which will be funded by Because of this, not only are we part most distinguishes the men’s health charity Movember. of the certification process, but we And a recent paper in Der Urologe also have representatives within the prostate cancer reviewing the 2014 report of German centres. prostate cancer centres noted that “Patient representatives are also centres data about potency and continence involved in the annual audit. So this following all treatments was lacking. is a system where the patient has OnkoZert institute visits each centre, Patient groups have, however, been maximum influence, where the patient examines processes there, speaks to a driving force behind certification of is treated in a structure, process and all the people involved and discusses German prostate cancer centres, and reporting system which you find in no the results of the quality indicators. representatives do believe that the other clinical organisation.” This gives you a means of judging.” patient experience is improving as a It is this constant measurement Certification, she says, is all about result of certification. and reporting that most distinguishes transparency for the patient – making Günter Feick, chairman of the prostate cancer centres from the rest, quality of care visible, and providing German prostate cancer patients’ according to those involved with the 8 March / April 2016 Cover Story

“What’s measured improves”

The German Cancer Society certifies prostate cancer □□ Participation of core disciplines in post-therapy units on the basis of their performance, on a wide conferences — pathology range of indicators, including the following measures □□ Presentation at post-therapy conference — of interdisciplinary collaboration: primary cases □□ Presentation at post-therapy conference — all □□ Case presentation in pre-treatment conference — patients with initial manifestation of a recurrence through urology (primary cases) and/or distant metastasis □□ Case presentation in pre-treatment conference — □□ Psycho-oncologic care (at least 30 minutes) through radiotherapy (primary cases) (primary cases) □□ Participation of core disciplines in post-therapy □□ Social service counselling (primary cases) conferences — urology (diagnostic + surgical) □□ Participation in research study □□ Participation of core disciplines in post-therapy conferences — radiotherapy The full list includes indicators of interdisciplinary □□ Participation of core disciplines in post-therapy collaboration, specialism and adherence to clinical conferences — urologist or medical oncologist guidelines.

German certification system. Once The challenge of change There is as yet no authoritative you do that, how good (or bad) you evidence that abiding by the are becomes transparent – and the Specialist centres where men with requirements outlined in the ESO force to improve becomes irresistible. prostate cancer are managed through initiative (Crit Rev Haematol Oncol As Feick says: “What’s measured a multidisciplinary team have been 95:133–143) improves patient improves.” established in some countries besides experience or outcomes, says Chris This amounts to much more than Germany, and some are now applying Bangma, Professor and Chairman the vague commitment to involving the ESO criteria. Their experiences at the Department of Urology at the and informing patients that might are pointing to some of the challenges, Erasmus Medical Centre. “Of course, come from non-certified centres, he as well as some of the opportunities, our questionnaires show we have high says. The certification requirement that come with introducing prostate patient satisfaction,” he says. “We also that patients should be present, cancer units. know that we are reducing unnecessary if they wish, at the pre- and post- In the Netherlands, for example, biopsy by 30% because of risk-reducing treatment conferences with the the official ending of national protocols agreed between specialists. entire multidisciplinary team, makes health insurance in 2006 enabled It’s the result of close collaboration decision-making without patient insurance companies to centralise and agreed procedures. But there is as involvement virtually impossible. treatments in specialised centres to yet is no comparable data to show that The German Cancer Society’s increase efficacy and quality. The it is better.” report of indicators from all prostate Prostate Centre at the Erasmus What is clear, says Bangma, is that cancer centres shows that 98% of Medical Centre in Rotterdam started setting up a truly multidisciplinary patients who initially presented to a in October 2010, and is the first expert system is no minor undertaking. urologist attended a pre-treatment organised multidisciplinary prostate Re-organising structures, funding, conference in 2013. cancer unit in the Netherlands. working methods and professional March / April 2016 9 Cover Story

hierarchies, takes time. For some “If prostate cancer units are to be UK, Ireland, Scandinavian countries professionals, it involves letting go. a reality throughout Europe,” he and the Netherlands, specialist nurses “It’s all about creating trust,” says says, “there has to be a recognition have clinical autonomy and work Bangma. “Some people think they’re from urologists that there needs to alongside urologists. In others, their working towards something, other be investment in specialist urology clinical input is virtually zero. In the people want their income or salaries nurses – and an agreed skill mix where absence of any European directives or patients or whatever. That is what nurses are not just part of a support for standards in urological cancers – you have to avoid.” team, but actively, clinically involved as there have been for breast cancer Elsewhere, there have been in patient care. It’s about a change of – it is hard to see nurse specialists in concerns that traditional urology attitude, realising that nurses have to urological cancers becoming widely structures in some countries are a be engaged on an equal level.” available, says Drudge-Coates. barrier to the multidisciplinary outlook In the UK, specially trained urology “Prostate cancer units may be able nurse specialists form part of a to function without them, but in multidisciplinary urology cancer team, those countries that don’t have nurses Re-organising and see all newly diagnosed patients. working at that level, you have to ask This is a mandatory requirement, what can we can do to raise skill levels structures, funding, laid down by the standard-setting so that centres can call themselves National Institute for Health and prostate cancer centres.” working methods Care Excellence (NICE). The NICE In setting down its 40 requirements and professional requirements, concentrating prostate- for prostate cancer units, ESO’s specialist professions, means that the Prostate Cancer Units Initiative in hierarchies takes UK effectively has a system of prostate Europe acknowledged the need to set cancer units. standards at an “attainable medium time For the patient, says Drudge- level” to make them applicable across Coates, there are enormous benefits. Europe. “In the UK model, nurses are pivotal The prostate cancer unit skill of prostate cancer units. Last year, in ensuring continuity in patient care, mix requirements specify, as part of the long-serving Secretary General of from the point of referral when prostate the core team, “one or more nurses the European Association of Urology cancer is first suspected, and then all dedicated to or specialised in urology”, (EAU), Per Anders Abrahamsson, along that patient pathway. They have where “dedicated to” is defined as told Cancer World that urologists more contact with the patient than any devoting at least 75% of their working – traditionally surgeons – could no other individual in the team, and have time to genito-urological oncology. longer work independently of other the skills to tackle many aspects of Among their specified roles, they are specialists in the cancer field and had patient care, patient questions, follow- required to be available at clinics for to work as part of multidisciplinary up, and also providing key clinical people who are newly diagnosed, “to teams. He expressed EAU support for input.” provide additional information and the concept of prostate cancer units. Research conducted at King’s support as required”. Candidates College Hospital found that a nurse-led for accreditation as Prostate Cancer Investing in nurses assessment clinic for suspected cases Units will therefore have to show of prostate cancer cut waiting times to their nurses have the knowledge and But the concept of true multi­ further tests from eight to four days. skills to fulfil that role. disciplinary working, with skilled And nine out of 10 men said they were and specialist nurses at the heart of very satisfied at having nurses involved Making it happen clinical care, is still a challenge to at this early point of contact, saying some, according to Lawrence Drudge- they gained a clear understanding of The example of breast units Coates, a urological oncology nurse the diagnosis process. in Europe, though inspiring for specialist at King’s Hospital London However, there are huge variations in prostate cancer, is not necessarily and Chair of the European Association nursing skills, status and autonomy in encouraging. The target set by the of Urology Nurses. Europe. In some countries, such as the European Parliament was that all 10 March / April 2016 Cover Story women in Europe should have access to a specialist breast centre by the year 2016. But according to Europa Donna, the European breast cancer patients coalition, Prostate Cancer Units Network that was instrumental in gaining EU guidelines on specialist breast units, progress has been slow. And the need to improve breast cancer services through specialist units has not been In January 2016, ESO and the patient advocacy coalition Europa Uomo accepted by all stakeholders. launched a new network designed to help those centres working on the “There are still many countries prostate cancer unit model share information and spread understanding. where no breast units exist that in The objective is to gather a European consensus about the need for any way conform to the guidelines prostate cancer units, and then build an international system to accredit and there is a risk that there are now them. More information about its aims and how to join can be found at entities calling themselves breast www.prostatecancerunits.org. units without meeting many of the standards outlined in the guidelines,” said Susan Knox, Europa Donna Chief Executive Officer, in an article way to go will be someone independent we break down that kind of barrier to in Breast last year. accrediting prostate cancer units.” a multidisciplinary approach. At the She told Cancer World: “We The prostate patients’ coalition same time, you have to recognise that continue to advocate for the Europa Uomo, which has supported the gold standard may not be easily implementation of specialist breast ESO’s European prostate cancer unit achievable for the next five to ten units across Europe. We are now initiative from the start, now sees years.” working on highlighting the need for the main challenge as inequalities Following the example of breast specialist breast unit implementation in Europe. “We absolutely support cancer, Mastris believes that EU at the upcoming European Breast prostate cancer units as the gold guidelines for prostate cancer services Cancer Conference, where a survey standard,” says current chairman Ken are essential. Europa Uomo’s Call will be presented indicating the Mastris. to Action on prostate cancer across status of implementation today and a “From the patient point of view, Europe, published in 2013, called for manifesto addressing this issue will be the current experience is that the prostate cancer care to be coordinated released.” and managed by a multiprofessional The next steps for the Prostate “In some countries team within a certified centre or Cancer Unit Initiative in Europe, network of excellence. Europa Uomo then, look to be deliberate ones. the urologist is still sent a copy to every Member of the Gathering support for the concept, European Parliament, asking for gaining wide agreement for the God. We need to support. So far, the response has been quality indicators, and establishing an thin. independent accrediting body won’t break that barrier to “We want to see the issue addressed happen overnight. more in the European Parliament,” “Putting together the actors could a multidisciplinary says Mastris. “The priority should be: take a while,” says the Chair of the don’t treat the cancer but treat the Prostate Cancer Unit at Milan’s approach” patient. We need more personalised Istituto Nazionale Tumori, Riccardo medicine, more communication, Valdagni. “But we understand the professional you first see is the person patients being guided through their process and the nature of our evolution who controls your treatment. And in journey – before, through and after is that, if people support the idea of some countries the urologist is still treatment. Communication between multidisciplinary working, the rational regarded as God. It’s important that professionals is so important for that.” March / April 2016 11

Spotlight

Is this the end for the microscope?

New generations of precision digital scanners are threatening to replace the tool that has been the iconic symbol of pathology for so long. Maria Delaney reports.

lass slides containing tissues Three years ago all of the histology One of the biggest benefits to working and cells are sitting in piles on samples at Linköping were digitised, digitally, says Capitanio, is that he can Ga shelf in the pathology lab. and they now scan just under 200,000 “ask a colleague in New York by email They wait here until the consultant slides every year. Instead of looking at or Skype to look at the slide and discuss picks up a stack and carries them to slides through a microscope, Arrigo the case”. This means pathologists a microscope for analysis. An analogue Capitanio, consultant pathologist at can get much greater access to expert system in a digital world. the hospital, analyses scans of the opinion without having to delay their Well that’s how Michael McKenna slides on a high-resolution screen. report. sees it. He is clinical lead for pathology He notes that many fields have services in Altnagelvin Hospital, improved with digitisation and feels Pathologists can get Northern Ireland, and wants to move that the same is true for pathology. “A their system from slides to screens. trainee in radiology can’t imagine that much greater access “We want to report off the screen all the instruments they are currently because this makes it more efficient using didn’t exist just 30 years ago,” to expert opinion and productive,” says McKenna, who he says. is currently trying to find a mechanism Linköping has six slide scanners: without having to to scan slides and report them through four for clinical slides, one for their existing picture archiving and large histological sections, and one delay their report communication (PAC) system. dedicated to research. They run day There are a number of pathology and night to allow almost real-time Without a scanner, obtaining a labs in Europe that have already gone scanning. A variety of suppliers are second opinion takes much longer. digital. LabPON, a large pathology lab involved, including Hamamatsu and First you write an email or letter to the in the Netherlands, is one such early Aperio for the scanners, as well as relevant colleague, then you post the adopter. Linköping Hospital in central SECTRA for the digital platform/ slides. Capitanio remembers hoping Sweden is another. viewer. that the slides would not be broken 14 March / April 2016 Spotlight © Maddalena Carrai

when they arrived. Other hazards colleague in a hospital 100 kilometres Closer scrutiny include the slide being delayed en- away. “He was asking me to give a route or sometimes disappearing on second opinion on a CT liver and since When pathology joins radiology on its return journey. “It’s quite a big the message is automatically linked to NIPACS in Altnagelvin, Devlin feels difference,” he says. the examination, within a few minutes it will be the quality of scrutiny the At Altnagelvin Hospital, the PACS I was able to send a message back.” report receives at the multidisciplinary system for radiology was implemented Before NIPACS this type of request team meeting where the real impact as part of a huge project that involved would have taken days or weeks, will be felt. “It revolutionises them two datacentres and 27 hospitals says Devlin. “It’s all to do with speed, in terms of an effective discussion of across Northern Ireland (NI). Known efficiency and quality.” the patient’s case,” he says, because, if as NIPACS, and using a platform Devlin, who now also works with all the images are available, the team developed by SECTRA, the system not SECTRA to promote digital platforms, gets the opportunity to interrogate and only digitised radiology requests and believes that “all medical images confront. consultations within each hospital, but should be treated with the same Devlin himself likes to be challenged also linked all the hospitals within the robust storage and sharing facilities,” and forced to justify what he’s written, system. Brendan Devlin, radiologist and says NIPACS can offer that. which he sees as a matter of quality at Altnagelvin, was one of the driving As he points out, pathology is just assurance. “It’s not just a question of forces behind its implementation. one area producing images. Others reading my report,” he says. Shortly after getting the system, include medical photography, diabetic This has certainly been the Devlin remembers sitting at his desk retinopathy, dermatology, cardiology, experience at the LabPON pathology and receiving a message from his and ultrasound. labs in the Netherlands, according March / April 2016 15 Spotlight

more than 1.4 million patient examinations a year. All radiology images captured in the participating

Maria Delaney hospitals are stored in a central archive in Belfast.

The vision of NIPACS includes a virtual radiology department across Northern Ireland, full availability of images and reports, a system to revolutionise dispersed networked care and minimisation of training issues and clinical risk.

Brendan Devlin at his The assignment of a unique “Health & Care” number workstation in Altnagelvin to every individual in Northern Ireland was a key factor supporting its implementation, says Brendan NIPACS: a national virtual department Devlin, former lead radiologist of NIPACS. “Robust identification is the cornerstone of these integrated One of the largest RIS/PACS (radiology information systems because you can’t afford to put the wrong system/picture archive and communication system) images in the wrong place,” he says, pointing in projects ever undertaken worldwide was conducted in particular to the huge medico-legal implications. Northern Ireland, where 27 hospitals were connected by a system called NIPACS. The NIPACS service was launched in 2009 after many years’ preparation. The new technology costs £31mn Provided by SECTRA, this digital platform caters for (€40mn) over 10 years.

to Alexi Baidoshvili, pathologist and Campbell as examples, asking whether became quite enthusiastic,” he says, project director of the digital pathology it is easier to recognise them in person though he adds that some are sticking team. Multidisciplinary team meetings, or by looking at a photo. with the “glasses” (glass slides). he says, work much better when digital The tissues and the changes present This works in Linköping, as the files are used. Other advantages he in the histological preparation can be pathologists receive both the digital lists include faster consultation, the recognised perfectly in a good-quality and glass slides for analysis, which ability to compare a number of slides, scan, he says. “In other words: it is Capitanio says is needed, because a cleaner work environment, and better diagnostic.” in around 3% of digital slides the logistics. scan is not perfectly in focus, Notable by its absence from that list, Making the change despite the quality control. “Rather however, is the quality of the images than send everything back, I look at themselves, which Baidoshvili argues Implementing major change to the microscope, because there is a is not quite as good as microscopy. complex procedures rarely goes turnaround time to respect,” he says. “It’s always a choice,” he says, arguing smoothly, particularly when IT systems At his hospital, the change to digital that the marginally poorer quality is are involved. Capitanio, in Sweden, also required a major reorganisation of more than compensated for by the says the main problem in his lab was the whole histology lab to standardise improvements in the diagnosis process the transition from the microscope the method of production needed to and logistics. The problem will be to the computer for the pathologists. produce high-quality scanned images. solved in the near future, he says, as “Some simply don’t want to do it.” Some of the practical problems “scanners become better every year.” The turning point for many came Linköping encountered were coverslip Capitanio denies there is a problem when they experimented with the precision, drying of the slides before at all. The important point is to be digital system. “Colleagues who were scanning and, for smaller histology able to recognise the subject, he says. sceptical at the beginning now work blocks, correct positioning of the He uses George Clooney and Naomi very well digitally, and some also section on the slide. 16 March / April 2016 Spotlight

McKenna in Northern Ireland says he does not expect such a major reorganisation will be needed at the Philips Altnagelvin pathology lab, because it already functions in a very linear fashion, so it should be simple to add a scanning step at the end of their current method. The lab is also based in a new building within the hospital, which has space for new machines. When it was originally designed, the pathologist explains, “they already knew that technology was advancing and a lot of the things that we normally did manually would be replaced by technology platforms, which tend to have quite a substantial footprint compared to a human.” Scrutiny: The ability to share images across the Internet, compare different slides, McKenna points to a corner of and magnify particular areas – as Alexi Baidoshvili from LabPON in the Netherlands is pictured doing here – all contribute to raising the quality of discussion at the lab where the slides are currently multidisciplinary team meetings stacked, to show where he intends to locate the machines he will need. But developing repetitive strain injury – says ergonomics was also an important he recognises that not all labs have been inflammation in the arm and shoulder issue in the Northern Ireland project. built with new technology in mind, and – from spending all day moving images He sits at a work station that can tilt and this could pose a problem. “Some labs around with a mouse. be raised or lowered to suit him, and he will need to invest in infrastructure if Baidoshvili notes that using a uses an ergonomic multi-button mouse their building is too small,” he says, microscope all day is also known to to control the PACS and minimise use in which case, “it’s not just about cause problems, but he didn’t want to of the keyboard. procuring a piece of equipment, it’s also create new problems with digitisation. “You’re not uncomfortable, you’re about knocking down a wall or building Working in partnership with Philips, not distracted,” says Devlin. His own an extension.” they created additional user interfaces, work station is in a dark room with Getting to grips with the require­ such as a touchpad, and Baidoshvili wall panels to muffle sound. A number ments of digital technology can also of work stations are also housed in a be a bit of a learning curve, according “Colleagues who communal reporting room for easier Baidoshvili, who says they have had communication with colleagues and to to change the server at LabPON were sceptical at the facilitate second opinions. “It’s all part three times since the system went of better quality,” he says. live last July. “Every time we use beginning now work As far as McKenna is concerned, more scanners, or more pathologists the switch to digital can’t come fast start with digital diagnosis, the server very well digitally, enough. He is looking forward, above becomes slow,” he says. all, to moving from Vernier scales on Currently they use four scanners, and some became a microscope to clicking a mouse. as well as two backup scanners, and Measurement is really “tiresome and process 300,000 slides per year. They quite enthusiastic” cumbersome” at the moment, he are using the Philips Digital Pathology explains. “With a digital image, the Solution for both their scanners and says that he now protects himself from ruler is there and you just pull it from digital platform/viewer. RSI by alternating between devices point to point.” This is not only easier, The changes in working practices over the course of a day and also using he says, but also improves accuracy and also brought new work-related health both hands. enables pathologists to leave a record of hazards, with some pathologists Devlin recognises the problem and the measurement. March / April 2016 17 Spotlight

Arguments for cost saving with digitisation mainly involve process improvements for the pathologists, rather than reducing workload in the lab. In fact scanning is an extra step on top of the normal slide-making process. This is in contrast to radiology, which can remove the film-making process and associated costs when moving to digital images. One cost saving that falls outside of A resource for research the norm is storage. “You don’t have to store the glass slide because, if you scan In addition to the clinical applications of digital pathology, slides the image, the image is stored for as long are currently being scanned for research purposes. The European as legally required,” says McKenna. This Organisation for Research and Treatment of Cancer (EORTC) has a means the glass slide could be disposed of number of projects which are doing just that. after a shorter period of time. This saves money, as the cost to store Pathology review for the INNOVATION trial (http://tinyurl.com/eortc- the glass slides “is increasing every innovation), includes scoring tumour regression after neoadjuvant day,” according to Capitanio, whereas treatment of HER-2 positive, resectable gastric cancer. This will be done digital storage costs are reducing. In using scanned slides which will be viewable by the review panel members his previous job at University College via the Internet. London Hospitals, costs for storage were so high that the slides were sent on a The EVIDENCE trial (http://tinyurl.com/eortc-evidence) will scan the lorry to Wales. slides for quantitative, digital assessment to calculate the percentage There are many arguments and lines of of residual viable tumour cells at the site of the primary lesion in early- thought about the future of pathology, but stage non-small-cell lung cancer. why should labs move from microscopes to screens? Capitanio has a simple answer. The EORTC is also planning to set up a digital platform for review of “Why not? We’re in the digital era.” scanned slides as part of their new Screening Patients for Efficient For Baidoshvili, the question is Clinical Trial Access (SPECTA) programme. Edit Szepessy, a translational already out of date. His focus is on where researcher at the EORTC, says this will be particularly valuable for their digital pathology is going next. His first thoracic and rare cancers projects: SPECTAlung and SPECTArare. goal is to become completely digital, including cytology, he says. When that is accomplished, the plan is to focus on Digital futures involves changing the focus level, second image analysis, which Baidoshvili says is by second, to see different levels in the the future of pathology. Digital pathology in Linköping and slides. “To do this digitally, it is necessary He is collaborating with other labs in the LabPON is only for histology to date. to scan several levels and then to use Netherlands, as well academic hospitals As Capitanio explains, this is because software to see all these levels,” says and Philips, to create software to use in the tissue or tumour section lies on the Capitanio. This consumes a lot of time their daily diagnostics. This will make glass, so single-level scanning with a focus and data, so it cannot be used for routine their work much faster and more accurate, depth of about one micron is enough for diagnosis with current technology. according to the digital enthusiast. this type of specimen. Cytology samples are, however, Back in Northern Ireland, McKenna Cytology samples, by contrast, are already being scanned at Linköping for sits back at his desk with a microscope made up of cells from fluids such as urine the purposes of teaching, documentation on one side and a computer on the other. or sputum, or from the abdominal cavity and research. A number of companies are Glass slides in position and ruler in hand, or around the lungs. Micro-focusing is working on new types of scanners that can he turns to the analogue machine. Perhaps needed to analyse these cells, which do this automatically. not for much longer. 18 March / April 2016

Profile

Ana Maria Forsea: getting from here to where we want to be

With no data from a reliable registry, and no functional national cancer plan, Romania is destined to continue suffering some of the worst cancer rates in Europe. Vlad Mixich tells the story of one dermatologist who is doing her best to break her country from endlessly re-living the same crisis.

n her tenth birthday, Ana Maria Forsea told her got into the best school of medicine in the country, and this parents that she wanted to be a scuba diver when was the starting point in the journey of one of the pioneers Oshe grew up. She was told that she would have to in European dermato-oncology. give up on this dream because there was nowhere in the Even locals find it difficult to make any sense of the country for her to learn. Romania was a communist country Eastern European dynamics in the ’90s, but all locals, be at the time – all borders were closed, people bought their they Polish, Romanian or Hungarian, will summarise those daily bread ration with food coupons, hospitals had no days in two words: openness and transition. Forsea had heating, and power cuts could hit at any time, even during her full share of both. But in 1994, the Romanian medical surgery. At Forsea’s school, like all other schools, a portrait of studies tradition was still strongly influenced by communist President Ceaușescu hung on the walls of every classroom, mentalities. The first health ministers after 1989 had also and children could be punished if they said what they were held important positions under the communist regime. thinking out loud. Of all the sectors that needed to be reformed in Eastern Then in 1989 the Berlin Wall fell, and everything changed Europe, the health system was and still is the hardest to overnight. Every single thing. The country where Forsea change. lived her teenage years had become chaotic but fascinating: What made a difference was that Western European no rules, no borders, no more parents telling their kids that countries provided a lot of scholarships to young people on they had to give up on their childhood dreams. “When the other side of the continent. One of these gave Forsea the I turned 18” – four years after the fall of the communist chance to spend her first student summer doing practical regime – “I wanted to be the best at whatever I would be training at the Saint-Luc hospital in Brussels, Belgium. doing and I wanted to be needed,” says Forsea. “I wanted “That was the place that set the paradigm for me of what my actions to matter, to have meaning to other people.” She caring for patients and nursing means,” Forsea reminisces. 22 March / April 2016 Profile All photos: Ioana Moldovan

“The way that nurses cared for the patients, the way that But when she returned to Romania to start practising as a patients were greeted with smiles, and supported all the way dermatologist, she found that the realities of everyday life to get better. It was a mind-setting experience.” were brutally different. “I kept seeing advanced tumours, As a student, Forsea spent additional elective semesters discovered late in the process, and people who died useless in Bristol, UK, and Lyon, France, and says these experiences deaths. So that was when the concept of early detection in reinforced her conviction that she needed to go to learn cancer became crucial. It stopped being a mere slogan and it from the best, where she could learn most. “In places where became a necessity, a matter of practical urgency.” they let you learn, they support you in your learning and they encourage you to practise. A place where knowledge “That was when the concept and information are not personal assets to be locked away safely somewhere, but things that you have to share.” This of early detection in cancer approach to gaining and sharing information was to be a defining aspect of her future life. stopped being a mere slogan On graduating from the Bucharest School of Medicine, the second top student of her year, Forsea started a PhD and became a practical urgency” at the Dermatology Department of the Freie Universität in Berlin, emerging two years later with a summa cum laude It is estimated that melanoma kills more than 20,000 thesis on melanoma. The time she spent there, under the Europeans yearly. But there are significant differences mentorship of Constantin Orfanos and Christoph Geilen, between Western and Eastern Europe. In the West, up to were decisive, she says, in her development as a passionate 70% of newly diagnosed melanomas are less than 1 mm dermatologist and a committed researcher. thick, whereas in countries like Romania or Bulgaria, that is March / April 2016 23 Profile

true in less than 25% of cases. One reason is that, in many similar things everywhere, from the North to the South, Eastern European countries, the density of doctors in city from the East to the West. I kept hearing that many hospitals is twice as high as the national average, while large doctors are not sufficiently trained to detect melanoma rural areas lack physicians and diagnostic facilities. Another early on and to take preventive measures. That people are reason, says Forsea, is the lack of awareness about skin not educated enough to know when they need to go to cancer. “And there is a wide gap between what people know the doctor. I was already familiar with such problems in they should do and what they actually do in practice. Most Eastern Europe, but I was less prepared to hear this in the people don’t know what they have to do in the first place, but UK for example. That cases of melanoma are diagnosed even the few who do know still don’t do it.” late, that the doctor did not pay enough attention to a Forsea understood that to improve early detection rates mole that their patient was pointing out.” in skin cancer, a lot of things had to be done right. “People need to become aware that they have a problem, then they Looking for data must get out of their homes and go to the doctor, then they must be scheduled for a medical consultation, the doctor in Forsea started to ask herself some questions, “It was a question must understand what the issue is, must be able researcher’s knee-jerk reaction.” She tried to identify the to make a diagnosis and then, once diagnosed, the patient obstacles that block the prevention and early detection must be sent where treatment is available.” process. This, as she emphasises, meant looking for data. In Eastern European countries like Romania, this flow is “No data, no research. You are left with a crystal ball.” often broken. This is partly because the healthcare budgets The search for data led to the Harvard School of Public in eastern countries are much smaller than on the other Health in the United States, where Alan Geller, one of the side of the continent, but it is also because of management leading experts on early detection and prevention of skin cancer, is based. So in 2011, that is where Forsea went. She spent a year there, researching with Geller and his team how “Then I discovered that there to build an adapted strategy to improve early detection of simply was no data, that I melanoma in Eastern Europe. “He said to me, ‘OK, we’re building strategies that need to be adapted to Eastern Europe, couldn’t provide any statistics” but let’s see first where we are and where we want to go from here,’” remembers Forsea from their first encounters. Based on her practice experience, she thought it would be shortcomngs and cultural differences, which Forsea believes easy to collect the baseline data on skin cancer. “But then I need more attention. “In Romania, there are popular beliefs discovered that there simply was no reliable data for Eastern that may not exist in other countries. People are afraid to Europe, that I couldn’t provide any statistics matching what have a suspicious-looking mole removed because they know I knew from practice. In my career as both researcher and of an uncle who died after doing so. But this belief is actually practitioner, that was the moment when I stumbled upon lethal, because the removal of the mole would have saved a the problem of cancer registries for the first time.” life,” Forsea explains. Cancer registries collect and statistically analyse data on So 10 years ago, Forsea set about establishing a cancer cases. The more complex the data, the more valuable foundation that aimed at challenging these misperceptions the resulting statistics are. But in the absence of objective and improving skin cancer awareness. But in looking for and complete data from these registries, “One simply cannot office space she came up against another cultural barrier: develop any strategy, any plan or intervention to reduce the stigma and taboo. “The owner of one building said ‘Oh no! cancer burden in a specific geographical area,” says Forsea, No cancer in my building, it gives off negative vibes.’ These adding that the data are also needed to assess whether a beliefs and customs vary from one country to another. So strategy is useful, whether it should be a priority and, most when I set up this foundation, I did it precisely because importantly, to assess retrospectively whether or not it people died in vain, out of ignorance.” worked. Forsea used to believe that this low level of medical Yet, so far, only 29 out of the 41 European countries have awareness was part of the Eastern European specificity, quality population-based cancer registries. Some countries, but what she heard from European patients’ conferences such as Poland, only have local registries that cover about taught her differently. “It was mind-blowing for me to hear 10% of the population. In nine countries, located in Europe’s 24 March / April 2016 Profile eastern half (Romania, Hungary and Greece included), the national cancer registries might exist legally, but do not function at a sufficient quality, so that in international statistics the data from these countries are only estimates. “We do not know what our melanoma patients look like,” says Forsea. “We don’t know how many they are. We don’t know how late they are diagnosed. We don’t know if their risk factors are the same as in Germany, or how long they survive. We do know that in neighbouring Bulgaria, melanoma survival is 49% compared with 87% in Western Europe.” A 2014 report addressed by the European Commission to the European Parliament underlines that “at present, these registries supply the majority of epidemiological data on cancer but, most of the time, they are not managed by sufficient staff or they are not adequately planned.” The problem sticks out immediately from a glance at current statistics. While death rates from melanoma are comparable in Western and Eastern Europe, the rate of registered new diagnoses in Central and Eastern Europe is less than half that in the western part of the continent. Such anomalies persist when looking at data from some neighbouring countries: Germany reports four times the incidence of melanoma compared to Poland, and the same difference is reported for Romania and Hungary. “It is obviously a question of diagnosing and reporting the data,” Forsea concludes. This has serious consequences, all the more so for Eastern Romania has had no fewer than 25 health ministers, and the European countries, where the need for accurate data to ministerial orders that regulate these registries have been maximise the impact of health policies is all the greater amended several times in recent years. Very often, these because financial resources are so limited. amendments are inconsistent and result in discontinuities Remembering a conference of South-Eastern European in organisation, financing and information. For instance, cancer registries, Forsea describes the situation as an Alice it is not yet very clear who coordinates the registration at in Wonderland stance: national level or how institutions that are responsible for organising these registries can be made to implement the “Would you tell me, please, which way I ought to go from necessary actions. here?” “That depends a good deal on where you want to get to,” said Looking for allies the Cat. “I don’t much care where…” said Alice. Forsea emphasises that the European Union did make “Then it doesn’t matter which way you go,” said the Cat. a considerable effort to provide member states with a set “…so long as I get somewhere,” Alice added as an explanation. of detailed guidelines on how to design their cancer control “Oh, you’re sure to do that,” said the Cat, “if you only walk planning and set up quality cancer registries. She also long enough.” commends the vision of Vytenis Andriukaitis, the European Health Commissioner, that “investment, investment, and In Romania, there are eight regional cancer registries, but once again investment is the way to fight against cancer” only one provides data that are of sufficiently quality to be (Cancer World Sept–Oct 2015). Yet, the EU itself also lacks taken into consideration in European statistics. There are political consistency. Countries such as the Netherlands, many reasons for this – first and foremost the high degree who now hold the EU presidency, frequently cite healthcare of legislative and political instability. In the past 25 years, as an example of where the subsidiarity principle should March / April 2016 25 Profile

apply, as they claim this is an area that member states can – that they die in vain, without their case being counted. organise perfectly well themselves. Yet, as Forsea remarks, Their suffering is not at the moment quantified in data the disparities signalled by all European statistics and that could contribute to the prevention of similar cases in mapping clearly point to the fact that not all member states the future.” are perfectly capable of organising their healthcare. Forsea speaks with passion, which shows from the “We must take a step forward and move from mapping lively sparkle in her eyes, and the determined set of her to benchmarking. Starting from the indicators already jaw. She is a product of the European medical school: put forward by the Commission, there should be a set of Bucharest, Brussels, Bristol, Lyon and Berlin. At present, measurable minimum standards to allow us to concretely Forsea runs the largest survey conducted among European monitor the progress made. An external audit system would dermatologists. More than 8000 doctors have responded also be useful. The mapping and the analyses done so far – to questions about their practice of dermoscopy for skin and they do represent a huge effort – rely mostly on the self- cancer early detection. Her quest to bring data to the light evaluation of member states. Objective and independent and to improve the prevention of melanoma and the care of control mechanisms are crucial to improving the status patients is one she will not give up easily, but she needs more quo. This type of control is not an intrusion or a coercion, allies, more support. it is a way to identify the problem, help allocate resources “Cancer registries are not an isolated issue”, she says. to the highest priorities, and support member states to take “They are part of a cancer control continuum that needs to necessary action where they most need it.” be planned in the long run. Otherwise it’s always yet another Making people aware of the problems and empowering Groundhog Day. We keep re-living in the same present over them to take action on them is also crucial, says Forsea. and over again, the same crisis, the same desperate urgency “People are unaware of the threat that lack of data means to do something right here, right now.” 26 March / April 2016

Cutting Edge © Maddalena Carrai Accelerating progress in immunotherapy

The concept is attractive, the results in some patients have been stunning, but what will it take to extend these impressive responses to wider groups of patients? Peter McIntyre reports.

here is a growing sense of confi- inhibitors that combat the ability ipilimumab, and the newer anti-PD1 dence that immunotherapy will of tumours to switch off the T-cell and anti-PD-L1 therapies are expected Tdeliver long-term survival to an response. Early data from patients with to extend this still further. increasing number of cancer patients, other tumours, such as non-small-cell For patients who do respond, the including some people with advanced lung cancer (NSCLC) and bladder impact on quality of life can also be and metastatic disease. cancer, also indicate important survival dramatic. One study showed quality of The percentage of cancer patients benefit among patients who respond. life for patients with advanced NSCLC with advanced melanoma who have a Trials and clinical use suggest that a even rising above the levels for the prospect of long-term survival roughly percentage of patients can be kept alive general population. doubled from around one in five on in the long term. Some patients with It is predicted that combinations ipilimumab to more like two in five advanced melanoma are still alive ten of more than one immunotherapy, on the newer range of checkpoint years after they started treatment with and combinations of immunotherapies March / April 2016 29 Cutting Edge

Not just for melanoma

Head & neck cancer Glioblastoma

Lung cancer Breast cancer

Liver cancer Pancreatic cancer

Melanoma Gastric cancer

Renal cancer Ovarian cancer

Colorectal cancer

Bladder cancer

Immunotherapies work across a wide range of cancers, but only for a minority of patients

with chemotherapy, targeted therapy researchers, clinicians and patient being driven largely by clinical data, or radiotherapy will improve survival representatives, from Europe and North which has outpaced basic scientific in an ever wider number of cancers, America, with strong representation understanding of how these therapies though potentially at the cost of serious from pharmaceutical companies and work. toxicity. the participation of the US regulators, “Exciting as these agents are, they The sense of excitement is palpable. the FDA. really only benefit a small minority of There are currently more than 1,200 Much of the current excitement is patients in all but the most responsive trials for cancer immunotherapies focused on a class of drugs that inhibit indications such as melanoma, which listed on clinicaltrials.gov, mainly for PD-L1 (programmed death ligand 1), can be 30–40%. Almost all the other therapies that seek to block the tumours’ which plays a key role in protecting indications are in the order of 10–20% defences, but also for chimeric antigen cancers from attack by the body’s as single agents. Well tolerated and receptor (CAR) therapies that engineer immune system. The protein, which is highly effective, but not everybody T cells to attack the tumour and are expressed by cancer cells, switches off benefits.” designed provide a memory effect and T cells by binding to the PD-1 marker long-term protection. on the cell’s surface. Fast and furious However, there are significant In a keynote address, Ira Mellman, obstacles to developing immuno­ Vice President of Research Oncology Paolo Ascierto from the Istituto therapies that work for more patients at Genentech, said that this new Nazionale Tumori in Milan argued in a wider range of cancers. class of drugs represents a paradigm for adopting a “fast and furious” The European Medicines Agency shift in treatment. “What you can approach to testing combinations and the Brussels-based Cancer Drug achieve, albeit as yet for a relatively and identifying the right sequencing, Development Forum convened an small number of patients, using dosage, and length of treatment for the international summit in February immunological approaches is unlike right patients to increase the response 2016, where leading global experts almost anything I have seen in the past rate and reduce the impact of side- in immunotherapy discussed how to with respect to other types of cancer effects. The potential prize, at least in amass the evidence that will convince therapies in major disease indications.” advanced melanoma, he says, could be regulators and health technology But he also emphasised how much a further doubling of the proportion assessment (HTA) bodies to approve there is still to learn about how these who survive for the long term, from these treatments for more indications therapies function and in whom. The 40% to 80%. and patients. The meeting attracted current excitement, he argued, is Traditional approaches to trial 30 March / April 2016 design, it was widely agreed, are simply too slow and inflexible. As Today, tomorrow and the future Samir Khleif, Director of the GRU Overall survival for advanced Cancer Center, in Augusta, Georgia, melanoma patients put it: “The elephant in the room is the 300 years and multi trillion dollars [it could take] to be able to reach where we want to reach.” For patients with advanced cancers, the “fast and furious” approach certainly resonates with their need for urgent progress. The challenge is how such an accelerated approach can deliver the level of evidence on efficacy and value required by regulators and payers.

Combinations of checkpoint inhibitors could see long-term survival rates of up to 60% Balancing ethics and in some cancers, while the hope is that clever combinations and sequencing could raise evidence this to 80% and beyond. However, this is not yet within grasp Adapted from Walter J Urba, ASCO 2013 Immunotherapy agents are already being trialled in combination with one another, and with chemotherapy, Vagn Erik Jesperson, a 13-year and dosages. “The biology is very radiation therapy and small molecules, survivor of NSCLC and co-founder complex when we start looking at with the potential for much higher of the Danish Lung Cancer Patients combinations. We need to find the response rates, especially in those who Association, posed a question to the relevant animal model that can help have low levels of PD-L1. meeting about the ethics of conducting us, so we don’t end up spending 300 Many early results continue to trials where early results had shown years trying to figure out which is the both excite and impress, despite such major differences between the right combination to take into the some serious toxicity issues. An trial arms. “How do you feel about that clinic.” ongoing combination study in patients when you make [such] clinical trials?” with non-small-cell lung cancer, for he asked. “The elephant in instance shows that almost 40% of Using adaptive designs that allow a patients who are PD-L1 negative trial arm that was proving to be inferior the room is the 300 respond, compared with just 5% on to be dropped was seen as one way to monotherapy. mitigate this problem. There would years ... [it could But these early indications of be a cost, however, in terms of losing success raise problems of their own, data that could help get approval and take] to reach where as Ramy Ibrahim, immunotherapy reimbursement for the novel therapy. clinical vice-president for AstraZeneca, Khleif suggested that learning from we want to reach” pointed out. pre-clinical research in the lab will “It will be very difficult to enrol to help rule out combinations that are But as Bernard Fox, from the a monotherapy arm when the early unlikely to work. “The biology is very Earle A. Chiles Research Institute in data is suggestive of limited activity of important. We need to think about Oregon, pointed out, mouse models monotherapy. When we start thinking of the optimum response before we put can only take you so far. “The biology a randomised trial with a monotherapy millions of dollars into what we need of the tumour in a mouse and its arm of a CTLA4 inhibitor, patients are to take it forward and invest.” interaction with the immune system is reluctant to consent to such a study Ibrahim agreed that animal models fundamentally different from what you design,” he said. can guide the search for combinations find in a human. I would encourage March / April 2016 31 Cutting Edge

regulatory agencies and companies to progression by monitoring the size of most important challenges we have as a be thinking about innovative clinical tumour lesions is of little use in these field,” says Dan Cheng, who leads work trials with small numbers of patients circumstances. Even experienced on immunotherapy at Genentech. studied aggressively and in depth to clinicians can be fooled, for instance, “These drugs have a powerful effect learn as much as you can about what when a head and neck cancer treated on overall survival, but probably all of happens.” with pembrolizumab appears to grow these studies will be confounded by More investment is also needed in alarmingly before an equally dramatic massive use of immunotherapies in basic science to better understand the regression. multiple lines.” mechanisms of the immune response, Current trials of immunotherapies He talked about the “immune- said Fox, singling out in particular the are therefore taking place without any modified RECIST criteria” Genentech need for a microbiome equivalent of agreement on what should be used as a has introduced into randomised trials The Cancer Genome Atlas (TCGA), surrogate for overall survival, at least in to study detailed efficacy patterns and which could help define the role advanced disease. get a sense of whether they predict played by the body’s microbiota. The story of ipilimumab is survival. “One of the big questions instructive. The anti CTLA4 antibody would be to work in partnership with Finding the right endpoints passed through three different health authorities to the point where companies and underwent six clinical we all feel confident enough with Choosing the best indicators, or trials over 10 years before it was shown a new endpoint like this to use it for ‘endpoints’, to demonstrate, within that it extended patients’ lives. The actual approval in the future,” he said. an acceptable timescale, that a novel problem was finding a clear parameter therapy is more effective and brings of response that could be documented. Quality of life more patient benefit than its comparator The pivotal study was expected to last David Cella, Director of the is always tricky. With immunotherapies, three years but Bristol-Myers Squibb Institute for Public Health and those problems seem to have become (BMS) had to extend it a further Medicine at Northwestern University, even tougher, because of the unique 1.5 years to gather enough data for Chicago, highlighted the importance way in which they kick in. marketing approval. of measuring quality of life endpoints. Overall survival – showing that As survival gets longer and harder to patients live longer – has traditionally Trials are taking measure, the focus will turn more to been the gold standard in pivotal clinical the quality of that survival. trials. However, as new therapies place without any Long-term successful treatment are trialled in different doses and carries its own quality of life challenges, combinations, and trials often allow agreement on what he added: “It is one thing to have short- patients on one arm to cross to another term horrible diarrhoea – it is quite if they progress, once survival times go should be used as another to have it for two or three beyond 18 months it becomes extremely years. Some of the long-term treatment difficult to demonstrate that differences a surrogate for can be intolerable.” in overall survival are attributable to a He also pointed to a potential particular treatment. overall survival correlation between quality of life To get around this problem, trials and survival. “In advanced disease, of other types of cancer therapy are Tai-Tsang Chen, Executive Director early change in quality of life scores increasingly using progression-free of Global Biometric Sciences (part of of just about anything you measure is survival as a surrogate for overall BMS), says it might be sufficient in predictive of survival. There is a case survival. This doesn’t work so well future to follow only the earliest trial there that patients know something with immunotherapies, as checkpoint entrants to get long-term follow up, – particularly the change. There have inhibitors often elicit an initially slow and use ‘milestone survival’ for the rest been a lot of studies in lung cancer, (or no) reaction followed by a long to indicate survival rates ‘x’ years after colon cancer, breast cancer, where survival curve for a percentage of treatment begins. patients who get better early on in patients. Finding effective endpoints for therapy live longer, and patients who The RECIST criteria for judging immunotherapies “presents one of the get worse early on don’t live as long.” 32 March / April 2016 Cutting Edge

Cella suggested that analysing how Quality of life changes in different symptoms and quality of life indicators, measured just before and shortly after progression, correlate with overall survival could help identify markers that can predict survival.

Finding the right patients Immunotherapies currently work well in only a small minority of patients. Finding biomarkers that can predict which patients will benefit is proving surprisingly challenging. Contrary to expectations, the presence of CTLA4 or PD-L1 in tumour cells – both targets for checkpoint inhibitors – does not seem to be a reliable guide to the immune response. A study of patients treated with nivolumab for advanced non-small-cell lung cancer One thing that is clear, according indicated that, among long-term responders, patient-reported quality of life scores re- to Genentech’s Mellman, is that, turned to population norms at 36–42 weeks (M Reck et al, ECCO-ESMO 2015, Abstract “Everyone who responds to PD-1/PD- 3011). The study was exploratory, and involved a very small number of patients Courtesy of Martin Reck, LungenClinic Grosshansdorf L1 therapies are individuals who have some level of pre-existing immunity which you can objectively measure with that, “Our healthcare systems will be says that they cannot ignore the increasing degrees of accuracy.” Patients in serious trouble if we cannot define complexities, but have to find a way to who do not respond to immunotherapy sub-populations of patients.” be able to compare data. “It is entirely either have dysfunctional responses The size of the problem can be seen plausible that the relationship does so that T cells never get beyond the in the striking difference between the not have a natural threshold telling periphery of the tumour or “an immune cut-off points used in different clinical us there is a single cut off where you desert” where no T cells at all confront trials to define ‘PD-L1 positive’, ranging can exclude or include patients in the the tumour, he said. from 1% in a trial of pembrolizumab label. It is perhaps a dynamic type of Resolving this issue will be for melanoma, to 5% for a trial of marker across different tumour sites or important, not least because the FDA nivolumab in non-small-cell lung tumour types. The relationship might and EMA are becoming increasingly cancer and 50% for pembrolizumab in be a linear one not a binary cut off.” insistent that new cancer therapies be non-small-cell lung cancer. Imposing an arbitrary cut-off accompanied by validated biomarker Mira Pavlovic-Ganascia, a derma­ point, he argued, would be seen as tests that indicate in whom they tologist who coordinated the European desperately unfair by patients whose should be used. Network of Health Technology Agencies PD-L1 marker falls on the wrong side Heinz Zwierzina, from the Early (EUnetHTA) for two years, says this of a dividing line, and could encourage Clinical Trials Unit at Innsbruck, who discordance makes it impossible for off-label use. On the other hand, chairs the Cancer Drug Development regulators and HTA bodies to compare leaving it to patients and clinicians Forum, argues that it is also an issue of biomarkers. “It is really frustrating that to decide could mean that everybody ethics and affordability. “If we treat the people use different expression cut-off ends up on the drug, regardless of ‘wrong’ patients with a drug that does levels and say it is positive. What are we benefit. “How much confidence is not work and may cause side effects, meant to do with this?” there across the European Union we may lose time in treating patients Francesco Pignatti, who leads about shared decision-making once it with the right drug,” he said, adding cancer drug evaluation for the EMA, ends up on the label?” March / April 2016 33 Cutting Edge

EMA to sponsors: Talk early marketing authorisation for nivolumab medicines are not built for this class talk often (Opdivo) in advanced squamous non- and type of therapy.” small-cell lung cancer. Catherine He said the willingness of the FDA The European Medicines Agency Weil, from BMS Belgium, said, “We and EMA to give accelerated approval and the Food and Drug Administration submitted the confirmatory study on the basis of early evidence was very have both adopted a proactive approach data during the review based on large encouraging, but there could be a to discussing the shape of trials with survival advantage. The boundaries had mismatch with the criteria HTA bodies pharmaceutical companies during the been clearly crossed and the result was required for their assessments. “Time is design stage and a willingness to accept positive. It was very, very collaborative of the essence if you are a lung cancer ‘breaking news’ evidence after a licence I would say. For squamous non-small- patient – 80% of patients are dying application has been submitted. cell cancer patients there has not been within 12 months.” The ‘breakthrough’ designation a new drug approved in the past 20 Mira Pavlovic-Ganascia, former introduced by the FDA in 2012, and years or so. The sense of urgency was coordinator of EUnetHTA, agreed the ‘adaptive pathways’ approach really shared.” that some of the mortality data from piloted by the EMA in 2014, both aim trials was “amazing”. She argued, to speed the development and review The reimbursement hurdle however, that HTA bodies want a of new drugs for serious diseases where broader set of data to evaluate “added preliminary data indicate they might Marketing approval is one thing clinical benefit”, with the main clinical be substantially better than what is – getting the therapy to patients is endpoints being how a patient “feels, currently available. another. Patrick Hopkinson, director functions or survives”. In both cases, the emphasis is on of health economics and outcomes They also need data that can early and frequent access to discussion research at BMS UK, said the average inform national policy on where and advice, and a ‘rolling review’ to time from approval to an agreement for the treatment fits within the overall help steer the drug (or combination) reimbursement for cancer therapies treatment pathway and how this through the most efficient development is just over 8 months in France, 9 in differs between patients according to pathway. Germany, 10 in Italy, almost 11 months whether their disease is progressing Pembrolizumab (Keytruda) was in England and just over a year in fast or slow. the first immunotherapy to be granted Spain. In some other EU countries it They are therefore looking for breakthrough designation by the FDA is even longer. something more meaningful than early in 2013, and was approved for use in Francesco De Lorenzo, President data on progression-free survival, and patients with advanced melanoma of the European Cancer Patient they become “extremely nervous”, for in September 2014. EU approval for Coalition (ECPC), said that delays instance, when asked to assess results the same patient group came in the in introducing treatment amount to a of a trial using a non-authorised dose summer of 2015. form of rationing. ECPC is calling for of pembrolizumab for NSCLC. Roger Dansey, head of oncology a strengthening of current efforts to Many countries are, however, clinical development at developers coordinate aspects of HTA assessments looking at various forms of managed Merck (MSD), said that the EMA and across member states by introducing a entry agreements and risk-sharing its human medicines committee had single assessment of relative clinical arrangements that can allow new demonstrated “enormous flexibility benefit that would be legally binding medicines to be marketed on the and willingness” to accommodate across Europe. basis of promising early data, while data as it emerged from a trial that Hopkinson argued that HTA additional data about its value in was simultaneously assessing clinical bodies need to take a broad view of actual clinical practice are being benefit and dosage. “We are in a hurry clinical benefit given the potential for collected. because patients are in a hurry. There immunotherapy to transform patient is an enormous unmet need. We were outcomes. “We are on the cusp of A wider horizon very appreciative of that degree of a revolution in terms of therapies flexibility.” launched or to be launched. Current Although it is checkpoint inhibitors Bristol-Myers Squibb reported frameworks for value assessment in causing the excitement today, other similar flexibility when they applied for many HTA bodies especially for cancer forms of immunotherapy could 34 March / April 2016 Cutting Edge

Accelerating progress in immunotherapy: the challenges

Ethics v evidence. Patients don’t want to be put on in diseases associated with a very high symptom lengthy trials where early data indicate big differences burden. However, combinations of immunotherapies between trial arms. Adaptive trial designs, and carry a high risk of serious toxicity. This needs to be investing resources up front to learn as much as overcome, particularly if immunotherapies are to be possible through many short exploratory trials with used long term or as adjuvant therapy. small numbers of patients, will be important. Personalisation. Finding biomarkers that predict Endpoints. Finding surrogates that can be measured who will benefit is turning out to be very difficult. early on and predict for survival is a priority. Currently More basic understanding is needed of exactly how there is no agreement on surrogate endpoints. immunotherapies work. Changes in specific and measurable aspects of how a patient feels is one area for exploration. Reaching patients. Working with HTA on managed entry and risk-sharing agreements to secure early Side effects. Monotherapy has shown impressive access to new treatments while gathering robust improvement in quality of life among responders information on value remains a challenge.

become significant tomorrow, building singly seeking access to the new wave seen in lymphoma, mesothelioma, on new and emerging techniques. of immunotherapies. Aleksandra patients with mismatched repair One under development is the use of Filipovic, a clinical fellow at Imperial deficient colorectal cancer and mRNA and peptide-based anti-cancer College London, said that the private melanoma. Responses of 20% or more vaccines based on antigen profiling sector there had started using the have also been reported in patients of the individual tumour. Another latest checkpoint inhibitors within with advanced NSCLC, heavily pre- uses CAR-modified T cells to attack weeks of FDA approval, with patients treated triple negative breast cancers the tumour. This seems to be highly treated on the NHS now also able to and gastric cancers. effective in leukaemias but can also use them through the early access Filipovic agrees that many be highly toxic. programme. questions remain about how to select One small study (so far “The way these drugs have moved the most suitable patients, how best unpublished) in February 2016 forward in the past year and a half – to combine therapies, how long to give reported 94% complete remission in the speed is absolutely staggering. The them for, how to best assess likelihood patients with acute lymphoblastic question we have answered is that the of response as early as possible and leukaemia, along with some very drugs work. Tumours that have been how costs can be met. The main story, severe side effects. A wave of very difficult to treat are now finding however, is that these treatments are immunotherapy trials will report at their answer in immunotherapies,” offering hope to patients in great ASCO in Chicago in June. she said. need. “It is a space that is exploding Meanwhile, patients are increa­ The greatest response rates had been at the moment.” March / April 2016 35 From evidence to practice in multidisciplinary cancer care ECCO2017 European Cancer Congress, 27–30 January 2017 Amsterdam

am pleased to introduce ECCO2017 – European will invite community care physicians, oncologists and Cancer Congress, the multidisciplinary evidence- patient advocates to discuss this evolution. based meeting for all cancer types, addressing all Regulatory sessions on newly approved drugs and Ioncology disciplines and related healthcare professions. innovation in local regional treatment will gather ECCO2017 will have a direct impact on daily clinical regulators, HTA bodies, academia, industry and patient practice. advocates. Focusing on phase III data, this scientific meeting will put ECCO2017 will shed light on ECCO policy initiatives, centred the new evidence into perspective for a multidisciplinary around the oncology workforce and quality cancer care, audience by critically reviewing it in expert panels. Leading making sure cancer is at the top of the EU public health oncologists will address the value of these potentially agenda. practice-changing treatments by reviewing their clinical benefits and cost. Experts, patient advocates and the ECCO is an open forum for its members. The first day audience will determine whether the data really do support of ECCO2017 will feature societies’ meetings for their changes in clinical practice. members and the oncology community: the European Oncology Nursing Society (EONS), the European Recognising the discrepancies between what happens in Organisation for Research and Treatment of Cancer real life and in a clinical trial setting, the congress will (EORTC), the European School of Oncology (ESO), the give centre stage to real world data showing the impact of European Society of Surgical Oncology (ESSO), the treatment and care. European Society for Therapeutic Radiology and Oncology This focus on clinical practice will provide delegates with (ESTRO), and the European Society for Paediatric Oncology concrete, up-to-date knowledge through a multidisciplinary (SIOPE). tumour board format, and give them the opportunity to Reaching a global audience, ECCO2017 has an extensive Peter Naredi participate in identifying practice-changing developments. – President of media programme for scientific media worldwide. Submit the ECCO Board The Educational Committee has prepared a comprehensive your practice-changing data for global visibility: of Directors educational programme covering topics from using Abstract submission opens: 25 April 2016 (2016/2017) evidence-based information to guide decisions on and Professor treatment options to understanding health economics Registration opens: 15 April 2016 of Surgery and and outcome research. There will be strong focus on Early registration deadline: 27 June 2016 Chairman of the immunotherapy and personalised medicine. Department of I thank ECCO member societies, the ECCO Patient Advisory Surgery at the Based on ground-breaking research, the programme will Sahlgrenska Committee, and leading experts, for designing this also look at evolving healthcare systems and the future innovative scientific programme. Academy, of cancer treatment, with particular regard to access to University of ECCO2017 will change the paradigm of oncology, be part Gothenburg since innovation, disparities in cancer care and the diminishing 2013 oncology workforce. Given the increasing role that primary of this change! care looks set to play in secondary cancer care, ECCO2017 ecco-org.eu Grandround

Endoscopy in gastrointestinal oncology

Once used primarily to detect large polyps and tumours, endoscopy has now become an essential tool for early diagnosis, curative treatment and palliation for gastrointestinal cancer.

This is an edited version of a presentation delivered by Michael Häfner, from St. Elisabeth Hospital, Vienna, Austria, as a live webcast for the European School of Oncology. It is edited by Susan Mayor. The webcast of this and other e-sessions can be accessed at e-eso.net.

ndoscopy is used in gastro­ mostly large polyps and tumours at characterisation of minute lesions that intestinal (GI) oncology in an advanced stage. The development can otherwise be difficult to see. This is Ediagnostic, curative and palliative of more advanced technologies over crucial because mucosal cancer can be settings. In diagnosis, it is used to recent years has led to a paradigm cured by means of endoscopic resection detect lesions, facilitate macroscopic shift, and endoscopy has moved on in many cases. classification of tumours and enable to the detection of small, flat, early The figure overleaf shows an example biopsy and fine-needle aspiration to malignant or precancerous lesions. of real-time pathology using confocal collect tissue samples. In curative The benefit is that there are now endomicroscopy, which is typically treatment it is used to resect early several interventions to cure these carried out using a probe during cancer by endoscopic mucosal or conditions, including resecting early endoscopy, such as during endoscopic submucosal resection and thermal lesions by endoscopic techniques. retrograde cholangio-pancreatography ablation. In palliation it is used mainly Technological developments, inclu­ (ERCP) in the bile duct. In this for stent implantation, but also for ding high-resolution endoscopy and case the procedure was carried out percutaneous endoscopic gastrostomy. zoom endoscopy, enable clinicians during gastroscopy with a dedicated to examine lesions more closely, for endomicroscopy endoscope in a patient Endoscopy in diagnosis example assessing the vascular pattern in with Barrett’s oesophagus. The image dysplasia in Barrett’s oesophagus. Novel shows a leakage in the bright area, which In the early days endoscopy was technologies, such as confocal laser is the contrast agent given intravenously, used mostly for diagnostic procedures endomicroscopy and autofluorescence, and a distortion of the mucosal cells that with the goal of finding tumours – now allow the detection and indicates Barrett’s cancer. The benefit March / April 2016 37 Grandround

To actively find lesions it must be clear contrast and make blood vessels and Real-time pathology what we are looking for. Classifications surface patterns more visible, enabling are usually considered rather boring, but us to spot very discrete lesions. they can be very useful in endoscopy. The The figure on page 39 top( left) figure below shows the Paris endoscopic shows a completely flat lesion on virtual classification for superficial neoplasia, chromoendoscopy, which makes lesions which applies in all of the organs that easier to see by changing their colour. can be reached with an endoscope: the This was a squamous cell cancer of the oesophagus, stomach and colon. oesophagus that was extremely important to diagnose, because endoscopic sub­ Enhancing images mucosal resection cured this early There are several techniques for cancer with no need for surgery. Lugol’s enhancing endoscopic images. Flat staining shows the lesions much more lesions can be very difficult to detect, so clearly as the unstained areas. The case considerable knowledge of macroscopic illustrates that it is important to know features is needed. The endoscopic what you are looking for, or you may miss Confocal endomicroscopy reveals picture can be enhanced using optical or subtle lesions. leakage of contrast agent (bright area) and a distortion of the mucosal cells – electronic manipulation, with techniques If these technologies are not available, enough to diagnose a Barrett’s cancer such as virtual chromoendoscopy, or various dyes can be used to improve without the need for biopsy use of a dye in chromoendoscopy. The image visualisation throughout the Courtesy of Michael Häfner goal is to enhance contrast and improve gastrointestinal tract. This can facilitate the detection of lesions and allow detection and also characterisation of a of this technique is that it offers real- for their characterisation, including lesion. They include: time histopathology while examining a assessment of surface patterns. Virtual o Lugol’s staining. This is iodine patient, without taking a biopsy. Based chromoendoscopy makes use of the fact based (so it is important to be aware of on these findings, we were able to plan that modern endoscopes are basically the risk of allergy), and is used for the our therapeutic intervention. Only a computers that allow manipulation of detection of oesophageal squamous cell few centres in the world currently have colours, essentially providing ‘Photoshop’ cancer. It is also used for screening high- this technology, but it is an exciting for endoscopy. Other techniques risk patients, such as smokers or patients development for the future. use optical filters that enhance the with a history of alcohol abuse. o Acetic acid (vinegar). This reacts What to look for with the surface of the mucosa and makes the surface pattern, or pit pat- tern, of a lesion much more visible. It is applied to detect dysplasia in Bar- I I protuded rett’s oesophagus. o Indigo carmine. This can be con- lla lla superficial, elevated sidered the ‘Swiss Army knife’ of gastro- intestinal endoscopy, and is widely used llb llb flat throughout the gastrointestinal tract. The blue colour stains depressed areas llc llc superficial shallow, depressed and increases the contrast. It also makes surface structures, surface patterns and the margins of a lesion more visible (see lll lll excavated page 39 top right). The spread and sur- face pattern information can help distin- guish benign from malignant lesions. The Paris endoscopic classification of superficial neoplastic lesions. Source: Participants in the Paris workshop (2003) Gastrointest Endosc 58:S3–S43 Modern imaging technology makes Reprinted with permission from Elsevier it possible to reliably predict the 38 March / April 2016 Grandround

deeper layers, for example submucosal Enhancing images Macroscopic classification lesions, is usually unsuccessful with of lesions standard biopsies. Some lesions cannot be reached at all because of their nature or location, such as lesions in the lymph nodes or outside the gastrointestinal tract, such as the pancreas. In these situations, endoscopy-guided fine- needle aspiration is a relatively easy way to obtain tissue samples. It is ultrasonography based and enables operators to puncture tissue and obtain pathology specimens. However, results Staining with indigo carmine shows up can vary considerably depending on the margins of the lesion and its surface patterns well enough to reliably predict operator experience, the presence the histopathology – in this case a later- of a cytologist, who can advise when ally spreading tumour with granular type enough material has been obtained, pit pattern type IV and the choice of needle. Courtesy of Michael Häfner

Question: Would you consider taking a Endoscopy in curative biopsy in early malignant lesions? therapy Mid-oesophagus scan using virtual Answer: It is important to recognise early Use of endoscopy in curative chromoendoscopy (above) and Lugol’s lesions because taking a biopsy is not treatment of gastrointestinal oncology staining (below) in the same patient - generally recommended due to the risk is a very recent development. In the Courtesy of Michael Häfner of making resection more difficult. It is past, the standard treatment of gastric best to resect flat lesions immediately cancer was surgical, but endoscopic histopathology of lesions. Macroscopic or mark for a colleague who will resect techniques have been developed so classification, with the help of contrast them. You can biopsy any polypoid lesion that endoscopic mucosal resection enhancement, is important for making safely without having consequences for (EMR) of early cancers is now the decisions during endoscopy on whether endoscopic resection. standard approach. The first attempt to resect a lesion, take a biopsy, refer for surgery or leave a lesion because it has no risk of malignancy. Commonly, Kudo’s Pit Pattern classification classifications are used for (early) oesophageal cancer, (early) gastric cancer Type I Round pit (normal pit) non-neoplastic and lesions in the colon. The oldest and most widely used classification, Kudo’s Type II Asteroid pit non-neoplastic Pit Pattern (see figureright ), has been Type IIIS Tubular or round pit that is smaller neoplastic developed for colon polyps. Certain than the normal pit (Type I) types of patterns are clearly associated Type IIIL Tubular or round pit that is larger neoplastic with neoplastic lesions and others with than the normal pit (Type I) non-neoplastic lesions, providing further Type IV Dendritic or gyrus-like pit neoplastic information for decision-making during endoscopy without having to wait for Type VI Irregular arrangement and sizes of neoplastic L S pathology results. III , III , IV type pit pattern Type VN Loss or decrease of pits with neoplastic an amorphous structure Fine-needle aspiration

Not everything is accessible for Source: S Kudo et al. (1996) Gastrointest Endosc 44:8–14 direct biopsy. Tissue sampling from Reprinted with permission from Elsevier March / April 2016 39 Grandround

method is the limited size of specimens size and is expected to replace surgical Barrett’s cancer pre- and that can be resected en bloc; but, on resection, at least in well-defined post-EMR the positive side, it is fairly quick to indications (J Gastroenterol 2006, learn and is safe. A commonly used 41:929–942). However, it is associated technique is cap-EMR, in which saline, with a higher incidence of complications and sometimes dye, is injected into the than standard EMR procedures, is much submucosa. The artificial polyp created more complicated to perform than EMR is sucked into the endoscope cap and and requires a high level of endoscopic cut with a snare. Complications are rare skill. Courtesy of Michael Häfner and include bleeding (5%), perforation at endoscopic treatment was reported (very rare) and strictures, which are Indications for treatment in Japan in 1974, where it was used also rare but may occur, for example, in The most important indications for to treat a polypoid-type gastric cancer. circumferential EMR in the oesophagus. endoscopic treatment of early gastric Subsequently, EMR techniques The figuretop left shows a Barrett’s cancer are determined by considering have been developed to resect flat cancer pre- and post-EMR. the risk of lymph node metastasis, gastric lesions. You can usually resect Endoscopic submucosal resection technical problems and whether to resect lesions of up to 1.5–2 cm in one overcomes this limitation, allowing for en the tumour en bloc. The conventional piece. However, this technique is bloc resection of larger lesions if certain criteria for endoscopic resection of early unsuitable for larger lesions, which criteria are met. It is now considered the gastric cancers, which were proposed by have to be resected piecemeal or with treatment of choice for intramucosal the Japanese group, are: a newer technique called endoscopic gastric cancer and oesophageal cancer, □□ highly differentiated adenocarcinoma submucosal dissection (ESD). This especially for squamous cell cancers, □□ intramucosal cancer has, theoretically, no upper limit on the and is superior to conventional EMR □□ size of the lesion less than 20 mm size of the lesion that can be resected. in terms of the curative and recurrence □□ no endoscopic findings of ulceration Endoscopic mucosal resection was rates. □□ no lymph node involvement or developed initially for the treatment Endoscopic submucosal dissection metastasis seen on computed of mucosal gastric cancer in Japan. (ESD) is a new development in tomography. It is currently used for lesions in the therapeutic endoscopy, which allows Lesions that meet all these criteria should oesophagus, where it is used in Barrett’s the direct dissection of the submucosa be considered for en bloc resection by oesophagus, in the stomach and the and enables large lesions to be resected conventional EMR methods because of colorectum. The main drawback of this en bloc. ESD is not limited by resection the low risk of lymph node metastasis. Extended indications for EMR have recently been proposed, based on The risk for lymph node metastasis in gastric cancer surgical data. Gotoda et al. reported that lesions meeting the following extended Depth Mucosal cancer Submucosal cancer criteria have no, or minimal, risk of lymph node metastasis (J Gastroenterol UL(-) UL(+) SM1 SM2 2006, 41:929–942): Histology 20 20 30 30 30 any size □□ no size limitation for intramucosal differentiated cancers without ulcer­ Differentiated ation­ that have no lymphovascular invasion Undifferentiated □□ less than 3 cm in diameter for ulcerated differentiated intra­

Guideline criteria for EMR Surgery mucosal cancers without lympho­ vascular invasion Expanded criteria for ESD Consider surgery □□ less than 3 cm in diameter for differentiated cancers (extension Source: T Gotoda, H Yamamoto and RM Soetikno (2006) J Gastroenterol 41:929–942 Reprinted with permission of Springer into the submucosa <500 µm) 40 March / April 2016 Grandround

without lymphovascular invasion □□ less than 2 cm in diameter Endoscopic submucosal dissection of a for undifferentiated intramucosal gastric cancer cancers without ulceration. a) b) c)

EMR can be performed, sometimes in an outpatient setting, in patients meeting these criteria, and it provides a very effective way of treating patients. The figure at the base of page 40 presents a graphical representation of the criteria, d) e) f) illustrating that EMR and ESD can be used for small lesions, nonulcerated lesions, and lesions limited to the mucosa. Patients with other types of lesions should be considered for surgery.

Endoscopic submucosal Figure a) shows a clearly suspicious stage IIa–c lesion in the stomach, dissection technique which had been biopsied in the referring hospital and found to be a Endoscopic submucosal dissection gastric cancer. We marked the outer margins and administered a (ESD) involves applying a submucosal submucosal injection of hyaluronic acid (b), creating a cushion that gave injection, which can be with saline enough space to enable us to resect the lesion in the submucosal layer or glycerol, although we prefer to use and in one piece. The next step was to cut around the lesions (c), with hyaluronic acid for more complicated indigo carmine used to stain the lesion margins, before mounting the procedures because the cushion it cap (d) and continuing to resect in the submucosal layer and remove the forms in the submucosal layer is longer lesion (e). Pathology showed the tumour was limited to the lower third lasting. ESD knives are available in of the mucosal layer, was highly differentiated and there was no lymph different shapes, including the IT knife, node involvement (f). The patient was cured of her gastric cancer by this which is designed to reduce the risk endoscopic dissection procedure. of perforation. Haemostasis devices, such as the coagrasper that coagulates blood vessels in the submucosa, are The mean size of lesions treated was Palliation required because bleeding is common, 26 mm, with the largest being 150 mm. The goal of endoscopic palliation is to as for EMR. In addition, devices Most lesions were high-grade dysplasia offer minimally invasive therapy to reduce are needed for closing perforations. or mucosal cancer (71.2%). En bloc a patient’s suffering and to avoid surgical These may include conventional clips resection was performed in 77.1% of interventions. Common procedures or OTS clips, which can close larger cases, which was a little bit worse than include bile duct drainage, implantation perforations. figures from Japan, and the R0 resection of endoprostheses in other areas of the A 2011 study of ESD from the French rate was 72.9%. The mean duration was gastrointestinal tract, and endoscopic working group of 16 centres, each with 105 minutes and the complication rate feeding tubes (percutaneous endoscopic one endoscopist performing ESD, was 29.2% (34 perforations, which is gastrostomy, PEG). Although endoscopic analysed data from 188 consecutive high, and 21 cases of bleeding), with palliation is commonly performed, some patients (mean 6 per centre, range 1–43) most resolved conservatively. indications, such as colonic stenting, have (Endoscopy 2011, 43: 664-670). The number of ESD procedures to be chosen carefully. The cancers treated with ESD were: being carried out is increasing, and their stomach (n=75), oesophagus (n=27), duration and complication rates are Stenting duodenum (n=1), caecum (n=3), right- decreasing with growing experience. In Stenting is a very important method sided colon and transverse colon (n=8), my unit we performed 50 ESD and EMR for palliation in endoscopy. Stents are sigmoid (n=3), and rectum (n=72). procedures in 2014. most commonly used in the bile duct March / April 2016 41 Grandround

as a palliative measure in unresectable □□ oesophageal fistula and perforation. Take home messages tumours, such as tumours of the pancreas or cholangio-carcinoma. Plastic stents A PEG should be considered if prolonged “Seeing in endoscopy” has are cheap and widely available but suffer enteral feeding is required for a period of changed considerably over the from limited patency, for example biliary longer than three weeks. PEG placement last few years. Detection of stents last for about three months. Metal is generally considered to be relatively safe. premalignant lesions or early stents are expensive, but have much longer Complications such as infection occur cancer has become the pinnacle patency. However, in the case of covered quite frequently, but can be avoided by of diagnostic endoscopy. stents they can’t be removed. Other giving a single injection of an antibiotic. High- and low-tech image common indications for stenting include manipulation­ allows for precise oesophageal cancer, duodenal obstruction Question: In times of limited resources, characterisation of a lesion based due to pancreatic cancer and, in rare cases, which patients are best for endoscopic on its macroscopic appearance. colon cancer. palliative treatment? Endoscopic resection techniques Answer: As a rule of thumb, I would suggest Percutaneous endoscopic such as submucosal dissection patients who are fit enough to go home after gastrostomy (PEG) can replace surgery in carefully palliative interventions are good candidates. selected patients. Common oncological indications for endo­ Conservative methods may be preferred for Endoscopic palliation should scopically placed feeding tubes include: patients in their final days, because of the risk be considered as a minimally □□ oro-pharyngeal and oesophageal of complications and the limited potential invasive option in patients with malignancy with inability to eat for gains in quality of life and survival time. advanced oncologic diseases. □□ prolonged stomatitis after radiation We discuss options with the patient and their therapy for oropharyngeal cancer relatives and come to a decision together.

42 March / April 2016

Our world

Affordable cancer care: a global mirage?

ne of the great myths peddled about care, will cost low-income and emerging powers cancer control is that it is intrinsically $7 trillion of cumulative GDP losses by 2030. Oaffordable. Nothing could be further The Global Taskforce on Radiotherapy also from the truth. Preventing and treating cancer is estimates similar losses. The point is not the the pinnacle of the health system’s mountain. It huge figures, it’s that failure to invest in systems is the most demanding disease domain to address for cancer care is going to seriously impact in health systems planning, as well as being highly development. Yet we are faced with a range of sensitive to all the socio-cultural determinants serious paradoxes. of health. Those of us ‘inside’ the cancer tent The first is the cold hard fact that many take for granted these interdependencies, but countries are failing miserably to invest in basic to the ‘outside’, including most policy makers, healthcare. Affordable and equitable cancer Richard Sullivan cancer is a ‘black box’. This is a huge challenge care cannot be built on sand, and this is just is Director of to rational economic and fiscal policy-making. the situation facing many countries now. It’s the Institute of As the Institute of Medicine noted in its all very well to sign up to Universal Health Cancer Policy Delivering Affordable Cancer Care in the 21st Coverage, the Sustainable Development Goals and Conflict Century report, “cancer is such a prevalent set and National Cancer Control Plans, but in low- and Health of conditions and so costly, it magnifies what income and emerging powers only a handful Programme at we know to be true about the totality of health of countries have a total health expenditure Kings Health care systems. It exposes all of its strengths and above the threshold needed to build a cancer Partners weakness.” system (about 6% of GDP, and more than Comprehensive There are some eye-watering numbers $100 per capita). The economies of Asia Cancer Centre. around economic productivity losses due to typify the problems affecting many countries: He will address cancer, particularly premature mortality and low domestic healthcare spending that is a specific morbidity. Lung cancer costs Europe more than increasingly being backstopped by private challenge in €10 billion every year in premature mortality, health expenditure (Lancet 2011:377:863– global cancer far outstripping the costs of direct cancer care 872). In some Asian countries, such as Laos, care in each of around €4.5 billion. And we know from Philippines and Cambodia, the private sector issue of Cancer the Lancet Oncology Commission on Global now makes up more than two-thirds of total World. Cancer Surgery that a failure to deliver more health expenditure. surgical workforce, the backbone of cancer Should this matter though? The short answer 44 March / April 2016 Our world is yes it does. Only countries with dominant public sector financing, such as Thailand, can deliver equitable and Some cancer systems get more for sustainable economic policies to build cancer care. The sad their money than others fact is that the mantra from the World Bank and most of the overseas aid donors is that public fiscal policy in cancer is not that important, and gaps can be filled by business, contrary to the evidence from studies such as Global Health 2035 (Lancet 2013, 382:1898–1955). Economic sustainability in cancer control is also in serious doubt in many places. For example, take a stable African country like Uganda.

As it stands, around half of the Sustainable Development Case fatality risk Goal indicators are currently underperforming (World Bank Group. Country Diagnostics Jan. 2015). The other equally pressing issue is how to protect individuals and families from catastrophic health expenditure. Here too the picture is none too rosy. The Asean costs in oncology study (ACTION) looked at the economic impact of cancer on 9513 patients diagnosed Healthcare costs per incident case adjusted for price differentials with cancer between March 2012 and Sept 2013, who ( €, 2010 - 2011) were recruited from private and public hospitals and cancer This graph, which plots cancer patients’ risk of dying against centres across eight Asean countries. It found that, one the per patient spend, shows that some EU countries spend year after diagnosis, 29% had died and nearly half (48%) almost three times as much as others for comparable outcomes had suffered financial catastrophe, defined as having to (e.g. Belgium v Germany) pay more than 30% of their annual income in healthcare costs (BMC Medicine 2015, 13:190). The fact is that & Health 2014, 10:66). Development money today is being out-of-pocket expenditures are ruining families. In many traded off against economic losses in health tomorrow. countries social health insurance, such as AUGE in Chile If this all sounds depressingly familiar, it is. Talking about and RSBY in India, are also not keeping up with what it the cost of cancer is really a debate about how we are going to manage to pay for our healthcare. High-income countries Only countries with dominant like France are now having to spend more than €11 billion every year to achieve the outcomes their populations enjoy. public sector financing Yet the needs of the elderly and chronically ill are not being met (Value in Health 2010, 13:552–556). can deliver equitable and What we do know is that there is no straightforward investment–impact model. Increasing expenditure does sustainable cancer care not lead automatically to better outcomes without serious structural, organisational and cultural engineering (Nat Rev Clin Oncol 2016, 13:137). Irrespective of base funding, too actually costs to deliver good basic cancer care in the public much cancer care is poor value or the focus of corruption. sector. A radical overhaul is urgently needed, but with so However, just adopting high-income mechanisms for many competing needs, cancer’s place in universal health priority setting does not work. Context matters too much, coverage is not assured. and different ideological and normative values will need very The last paradox reflects a deep-seated failure to square different economic and fiscal strategies, as Thai colleagues trade and investment liberalisation with the needs of public have pointed out (Value in Health 2009, S26–S30). But this health. The evidence is overwhelming that these are serious is not an excuse for ignoring the basic building blocks. Fund drivers of the burden of non-communicable diseases, yet your health system properly. Invest in a strong public sector the proliferation of bilateral and regional preferential trade system for caring for cancer patients, and protecting them agreements, without any in-built public health protection, financially. And ruthlessly ensure the quality and fiscal will simply drive up cancer risk factor exposure (Globalisation probity of services from both public and private sector. March / April 2016 45

Systems & Services

Improving care for patients with rare cancers Are European reference networks the answer?

As the European Commission issues its first call for proposals to set up European reference networks, Anna Wagstaff asks: how can these cross-border healthcare structures improve the quality of care received by the almost half a million Europeans who are diagnosed with a rare cancer each year.

obody wants to be told that Tests revealed they were in the right area: been directed to a PAWS-GIST centre their 15-year-old daughter has a it was a rare form of GIST, known as a of excellence in the UK, or indeed Ncancer that cannot be removed paediatric-adolescent wild-type syndromic anywhere in Europe – somewhere that without cutting out her entire stomach. (PAWS) GIST – which was more a specialised in treating young people like But when the medical team – at one description than classification, being a her daughter, had experience caring for of the top children’s hospitals in the GIST that occurs in young people and similar patients, and was engaged in country – also tells you that they’ve never does not have either the KIT or PDGFRA research. But she found no such place. seen anything like it before and don’t mutation, which characterise 85% of all Happily, thanks to a tip-off from one know exactly how to treat it, that is a very GISTs. So an extremely rare cancer. of the doctors who’d been doing some lonely and frightening place to be. The advice was to agree to the research of his own, Jayne and her That is certainly how Jayne removal of her daughter’s stomach. daughter did find what they needed in Bressington felt six years ago. The Bleeding from the tumour was causing the US. The only PAWS-GIST clinic surgeons, who had aborted an operation severe anaemia that could be controlled in the world convened twice a year at to remove the growth after seeing how only through regular transfusions, and the National Institutes of Health in far it had invaded the young teenager’s would eventually be life threatening. It Bethesda, Washington DC, flying in stomach, had taken an informed guess had to come out. specialists from different disciplines that it could be a gastro-intestinal stromal Bressington was not keen. Like from all over the country to consult with tumour (GIST) – a rare type of sarcoma, many people in similar situations, she patients who found their way there. which is itself a rare cancer, and is most turned to the Internet. She would have Jayne Bressington brought two things commonly found in 50- to 70-year-olds. given anything at that point to have back with her from that clinic. The first 48 March / April 2016 Systems & Services was the confidence to say “no” to surgery. patients with rare diseases across Europe put in the hands of a ‘Board of Member The advice from “the most knowledgeable by building networks that link designated States’, which will deliberate on the people in the world,” had been categorical: centres of expertise within and between first round of proposals sometime “Resist at all costs having your stomach the member states. after the summer deadline, and make removed. You have to find every way its decision. Paolo Casali, chair of possible to stop the bleeding. You’ve got the campaigning group Rare Cancers to grow, you need your nutrition, you Europe (rarecancerseurope.org), need a stomach.” The second and a trail-blazer in rare cancer thing she brought home was networking, is waiting with a determination to see a equal measures of hope similar clinic set up in and trepidation. the UK.

Hopes and European fears Reference Networks When it comes to networking There are al- to improve the most 200 dif- care of people ferent types with rare can- of rare cancer © Maddalena Carrai cers, no-one (defined as does it better fewer than 6 than the pae- cases per year diatric oncolo- per 100,000 peo- gists. Every pae- ple), and every diatric cancer is a year, more than rare cancer, and for half a million peo- decades this group of ple in Europe will be specialist clinicians have diagnosed with one (EJC been collaborating on clini- 2011, 47:2493–2511). cal trials to learn how to get the Around 120,000 of these best possible results for their young will be cancers that are seen in fewer patients. than 1 person per 100,000. Many of In recent years, specialists in other those affected scour the internet, as Jayne The 12 groups of rare cancers. Research forms of rare cancers have begun to Bressington did, to find doctors and cen- by the EU-funded RareCare project follow their lead and have used EU tres with the expertise to give them the identified almost 200 types of rare cancer. funding to set up their own networking best possible chance of surviving with a A consensus exercise carried out by Rare projects. Casali himself played a key role Cancers Europe grouped these into 12 good quality of life. Many will not find families, each of which, they argue, needs in setting up the Concatinet network, what they are looking for. its own European reference network which linked teams in a number of Their chances of finding a specialist European countries with expertise centre may considerably improve, How these networks will work in in diagnosing and treating more than however, thanks to an EU policy practice remains to be seen. The first 25 types of connective tissue cancers promoting the setting up of European call for proposals was issued by the known as sarcomas. reference networks, which formed part European Commission in mid-March. Casali’s biggest hope for European of the 2011 cross-border healthcare As healthcare is beyond the competence reference networks is that they will directive. The idea is to harmonise and of the European Commission, power to dovetail with rare disease communities improve the standard of care available to approve or reject proposals has been like his that are already organising March / April 2016 49 Systems & Services

themselves and their work – his biggest community, but nowhere is this more the reality of the networking that the fear is that they won’t. important than for rare cancers, where oncology community has already built One serious concern is that the Board the evidence base for diagnosis and over recent decades?” asks Casali, “rather of Member States has failed to grasp management is sorely lacking, and the than acting as if oncology networking in how many people are affected by rare small size of patient populations makes it Europe is a blank slate.” cancers. “Using a conservative definition, imperative to recruit every patient possible rare cancers are 20% of new cancer into trials, or at least ensure that the details cases. Clearly they are at the heart of the from each patient’s history contributes to Making the networks work field of oncology. This must be properly building up new knowledge. Even in the worst case scenario, Casali understood or the networks will fail,” When pressed on this issue at a meeting recognises that the European reference Casali warns. on European reference networks called by networks will mark an important step A consensus exercise carried out the European Commission last October, forward, because centres joining the by Rare Cancers Europe succeeded in however, the Commission was very clear: networks will be endorsed by governments. sorting almost 200 types of rare cancer the primary purpose of reference networks This means that patients will have into a minimum of 12 family groups, is to provide care – they are not intended somewhere in Europe to turn to that has each with its own community of experts, for research. been endorsed by its government, and is reference institutions and patients. The But Casali argues that the two can and linked to a formal European network. signals coming from the Board of Member should go hand in hand: “Care can be well It also creates conditions for building States, however, is that they are looking accomplished without giving up the goal networks within countries, and promoting to keep the total number of rare cancers of research.” policies on referral or shared care to ensure networks very low – maybe two or three. that the diagnosis and care of patients with This might mean a single network for Linking care and rare cancers is handled by professionals paediatric cancers, as has already been set with the greatest expertise, and not by the up in the form of a three-year pilot project research has first doctor they encounter. “Clearly some (see box), and one for haematological health systems work better on rare cancers cancers, possibly grouped with other rare become a mantra than others,” says Casali, “This could diseases of the blood. The expectation lead to a kind of harmonisation, because seems to be that the entire spectrum of throughout the governments are involved.” adult solid rare cancers would be taken That said, the rare cancers community care of by a single network, even though cancer community is not intending to sit idly by to see how each involves different communities and these networks develop, says Casali. Rare institutions, requires different approaches – nowhere is this Cancers Europe has been instrumental in to diagnosis and management, and the getting agreement to set up a European specialists in Europe are already working more important than Joint Action on Rare Cancers, “with together within their specific communities. the overarching aim of helping shape Casali accepts that it might be possible for rare cancers European reference networks in the best to organise subnetworks within one big way possible for member states.” network, but argues that this would add The heavy focus on care is reflected in The Joint Action is going to have to move an unnecessary and bureaucratic layer of the structure of the networks, where pretty quickly, given that the networks complexity. Specialists in sarcomas already only healthcare institutions can join have already been defined and the first call work with one another and constantly as designated centres of expertise. for proposals has been issued. However, meet at conferences and other forums, as Professional bodies that develop clinical there is a lot still to play for in how these do people specialising in head and neck practice guidelines, such as ESMO, networks will operate in practice. cancers or endocrine tumours, and so and research organisations such as the Because the Joint Action group includes forth, he says, so it makes sense to set up EORTC – which is currently setting up a representatives from many member states, reference networks that mirror this reality. rare cancers screening platform to improve it should offer the chance to look at how The other big concern for Casali is access to trials – will probably be relegated European reference networks can meet research. Linking care and research has to operating on the fringes of the networks. varying needs and priorities in different become a mantra throughout the cancer “Why not acknowledge and build on countries. 50 March / April 2016 Systems & Services

Casali, for instance, based in Italy – population 60 million – sees European reference networks more in terms of “networks of [national] networks”. Italy The paediatric pilot records 2000 new sarcoma cases each year, so the role of its national hub will be to ensure that patients diagnosed Reference networks are being been piloted in paediatric oncology. The anywhere in the country benefit from three-year ExPO-r-Net project (European Expert Paediatric Oncology expert diagnostics and care planning, Reference Network for Diagnostics and Treatment – http://expornet. rather than discussing routine cases across siope.comsbox.com/), was launched in 2014 to build a European borders. Reference Network for Paediatric Oncology. Slovenia, by contrast, with its population It has started: of 2 million, can expect to see closer to □□ tackling technical and legal (privacy and medical liability) issues 100 cases a year, spread between many involved in conducting cross-border tumour boards different types of sarcoma, diagnosed □□ identifying the types of patient who need a particular concentration at different stages and in patients with of resources or expertise, where European networking could be different needs and priorities. Slovenian most valuable sarcoma specialists may well value the □□ setting up a partnering scheme to improve access to high-quality opportunity to discuss cases with experts healthcare in countries where that is not available due to low case in other countries. They may be less volumes and/or lack of local resources – the emphasis is on moving interested, however, in building a national information, not the patient, wherever possible. network, as care of complex or rare cases is largely concentrated in Ljubljana’s ExPO-r-Net involves 18 core partners and more than 50 collaborating Institute of Oncology. professional partners (professionals, hospitals, institutes) from 17 Tanja Čufer, Professor of Oncology at countries, as well as parents and patients. the University of Ljubljana, would like the Joint Action to raise the issue of access to clinical trials in other EU countries, which Chorym na Mięsaki Sarcoma, having disseminate (including information about she sees as crucial for people with rare a government-designated centre of clinical trials for those who can afford to cancers, and is not covered by the reference expertise is not the big issue. Poland pay). They could also give patients access networks’ remit. She points out that, does have an institution that acts as a to second opinions, and help harmonise “There are more and more small countries, reference centre – the problem is it has standards of care. and more and more rare cancers,” and says only one (for adult patients), serving a a solution must be found. population of almost 40 million spread “There is no routine She gives as an example, ROS-positive across a very large country. For her, the lung cancer, which makes up just 1% of major obstacles include late diagnosis care, so these non-small-cell lung cancers. “There is due to poor awareness among the public no routine care, so these patients need and GPs; lack of accurate information patients need access access to clinical trials in larger countries, for patients and poor doctor–patient because we don’t have clinical trials for all communication; and poverty, which to clinical trials in these rare cancers in such a small country.” limits access to best care. In Poland, she Winning the argument on cross-border says, many people can’t afford to travel larger countries ” access to trials, she hopes, may be easier for appointments within the country, let once you have accredited centres and alone across borders. In Belgium, the problem is almost the European networks to make the case. Gmaj believes that effective European reverse. Véronique de Graeve, President Patient advocacy groups have their networks could do a lot to address at of the NET & MEN advocacy group for own priorities. For Paulina Gmaj, who least some of these needs. They could, patients with neuroendocrine tumours is active in the Polish sarcoma patient for instance, develop patient friendly and multiple endocrine neoplasia, says advocacy group Stowarzyszenie Pomocy information for advocacy groups to that Belgium has several centres and March / April 2016 51 Systems & Services

Cambridge, saying he would be happy to lead the initiative. Four years of frenetic activity followed, raising funds, setting up a tissue bank, sorting out a registry and increasing the pool of patients from the three they started with to 70. They also set up a PAWS-GIST collaborative research initiative – a multidisciplinary team effort that aims to improve care and find innovative treatments for patients with this rare cancer. If you Google PAWS-GIST from anywhere in the world now, you will find your way to the world’s second PAWS- The world’s second PAWS-GIST clinic. Jayne Bressington (far right), who GIST clinic (www.pawsgistclinic.org.uk), was instrumental in making it happen, is pictured with (from right to left) which convenes four times a year, has so Dochka Davidson (sarcoma specialist nurse), Richard Hardwick, (upper far seen 40 patients, and is about to be GI tract surgeon), Ramesh Bulusu (clinical oncologist, and clinical lead written into the latest edition of the UK for the PAWS-GIST clinic), Palma Dileo (medical oncologist specialising national guidelines for diagnosing and in sarcoma) and Jason Bossert (formerly project manager). managing GIST. Patients across Europe European reference networks could help ensure patients with rare get in touch, and specialists approach cancers like PAWS-GIST have a government-accredited reference centre Balusu at conferences to talk about somewhere in Europe they can turn to. But their impact on boosting setting up something similar in their own research and spreading best practice will depend on how well they countries. A few weeks ago, PAWS-GIST dovetail with the way rare cancers communities already work together. received its first requests for seed funding to kickstart two research projects – “A dream come true,” says Bressington. professionals with expertise in NETs (less Room for manoeuvre? So what would Bressington look for so for MENs), but that patients often in a European reference network? “It don’t know where to find them. “Even There are, in short, plenty of views and would have to be able to help transform general practitioners don’t really know opinions about how European reference the situation from where we are now to where to refer their patients so the best networks should function. But will the where patients need to be,” she says, care can be given,” she says, “because we rare cancers community really be able to “ie a system that naturally facilitates still don’t have official national lists with influence how they develop in practice? research – a network of GIST registries, experienced or recognised NET doctors or If the PAWS-GIST story in the UK which includes mutational status; centres.” The government, she adds, is in is anything to go by, the answer is an mutational testing as standard; a network the process of setting up a patients’ portal unequivocal yes. On her return from of GIST tissue banks; a network of agreed to provide relevant information to both the US, Bressington started her quest specialist centres focusing on PAWS- patients and professionals. to found a similar specialist clinic in the GIST patients in collaboration with their de Graeve’s concerns are that the UK with a Google search for “Dr+GIST”, local physician.” European reference network model, with which came up with 33 names in the It doesn’t sound quite what the its emphasis on centres of expertise, could UK. Together with a patient advocate Commission has in mind. But as we lead to pressures for services to be more from GIST Support UK, she wrote to await the responses to the first call for centralised than they need to be. “An them all, saying, “We’re in this terrible proposals, there is still much to play for. isolated NET reference centre is not the situation. Nobody knows what’s ailing our With determined players like Bressington way we see it in Belgium,” she says. “I daughters, and there is no treatment. We on the field, there may still be a chance prefer the ‘shared care’ between reference want to set up a focus group in the UK.” to ensure that the reference networks centres and peripheral hospitals… you Eleven responded; one of them, provide what people with rare cancers need to respect what people are used to.” Ramesh Balusu at Addenbrookes in really need. 52 March / April 2016

Impact Factor

Novel approaches to pancreatic cancer

With a five-year overall survival of less than 5%, there is an urgent need to explore new treatment paradigms for pancreatic cancer, including targeting stroma cells, cancer stem cells and metabolic pathways. Ignacio Garrido-Laguna and Manuel Hidalgo outline the current standard of care and review promising novel treatments.

This is an abridged version of I Garrido-Laguna and M Hidalgo (2015) Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 12:319–334. It was edited by Janet Fricker and is published with permission ©2015 Nature Publishing Group. doi:10.1038/nrclinonc.2015.53

urgery is still the only curative plus gemcitabine, APACT trial) and 2011, which showed no R0 margin treatment for pancreatic cancer; FOLFIRINOX (PRODIGE study). differences between upfront resection Showever, therapeutic strategies and neoadjuvant treatment (World J based on initial resection have not Neoadjuvant therapy Surg 2014, 38:1184–95). substantially improved the survival of Potential advantages for neoadjuvant Meta-analyses have consistently patients with resectable disease over therapy include increasing negative failed to demonstrate neoadjuvant the past 25 years. Presently, more than margin (R0) resection rates, improving survival advantages. A lack of consensus 80% of patients suffer disease relapse surgical selection, earlier treatment of over which tumours are borderline after resection. micrometastatic disease, and enhancing resectable influenced results. chemoradiotherapy delivery. Predictive biomarkers of response to The state of the art Single-institution studies suggest gemcitabine or 5-fluorouracil (5-FU) neoadjuvant treatment increases the are urgently needed. Resectable disease rate of R0 resections. Such findings More effective chemotherapy back­ contrast with a retrospective analysis Unresectable disease bones are currently being tested in of resections of pancreatic ductal The ECOG 4201 trial demonstrated the adjuvant setting (nab-paclitaxel adenocarcinoma between 1992 and a modest improvement in survival 54 March / April 2016 Impact Factor for chemoradiotherapy compared Novel treatment opportunities than 90% of pancreatic ductal adeno- to gemcitabine, but with increased carcinomas. Inhibition of oncogenic toxicity (JCO 2011, 29:4105–12). Given the poor clinical outcomes RAS signalling might be achieved by The FFCD/ SFRO study, however, for pancreatic ductal adenocarcinoma, multiple mechanisms including block- suggested detrimental overall survival novel strategies are needed. ing RAS protein transport to the cell for chemoradiotherapy versus gemcita­ membrane, and inhibiting oncogenic bine therapy (Ann Oncol 2008, Drugs targeting pancreatic RAS activity directly or indirectly 19:1592–99). cancer cells through targeting downstream path- The rationale for the detrimental Cytotoxic agents. To tackle the way components. effects of chemoradiotherapy comes desmoplastic response in pancreatic Owing to the complexity of directly from a study showing enhanced ductal adenocarcinoma, where targeting KRAS, efforts have focused invasiveness for cancer cells co- dense fibrous tissue grows around on downstream components of the cultured with irradiated fibroblasts tumours, novel formulations of classic RAS pathway, such as MEK. Unfor- due to activation of MET and MAPK cytotoxic agents are currently under tunately, clinical trials with MEK in- signalling pathways (Cancer Res 2004, development. hibitors (trametinib or pimasertib) 64:3215–22). MM-398, a nanoliposomal formu­ have provided disappointing results. The SCALOP trial demonstrated lation of irinotecan, was recently Inhibition of ERK has shown prom- that capecitabine is superior to approved by the US FDA, in ising activity in preclinical models. A gemcitabine as a radiosensitiser combination with 5-FU, for patients phase 1b study will be testing BVD- (Lancet Oncol 2013, 14:317–326). with metastatic pancreatic cancer 523 (an ERK inhibitor) in combination Clinical trials are needed to refractory to gemcitabine. The with nab-paclitaxel and gemcitabine validate biomarkers to identify NAPOLI-1 study showed a modest (NCT02608229) in patients with ad- patients less likely to benefit from improvement in survival (8 weeks) with vanced pancreatic cancer. chemoradiotherapy. The RTOG 1201 the combination compared to 5-FU Janus kinase inhibitors. High trial is currently testing nab-paclitaxel alone (Ann Oncol 2014, 25:ii105– throughput gene-expression analysis plus gemcitabine followed by ii117). It is unclear whether MM-398 showed enrichment of the JAK–STAT chemoradiation. This study stratifies will provide any benefit to patients pathway in pancreatic cancer (Pancreas patients according to SMAD4 status. who have received first-line therapy 2014, 43:198–211). A randomised The hypothesis is that patients with with nab-paclitaxel and gemcitabine, phase II study failed to show survival preserved SMAD4 may benefit from as such patients were not included in benefit when ruxolitinib (a JAK intensification of local therapy. the study. inhibitor) was added to capecitabine. TH-302, a releasing DNA- In a small subset of patients with Advances in metastatic disease alkylating agent activated under markers of systemic inflammation, Over the past decade, single-agent hypoxic conditions, recently failed to a modest improvement in survival gemcitabine has been the standard of provide any added survival benefit to was identified. Two phase III trials care in metastatic pancreatic ductal gemcitabine in the MAESTRO trial evaluating capecitabine plus ruxoli­ adenocarcinoma, with multiple trials (Van Cutsem et al. Abstract #193 tinib in second-line advanced stage failing to show that adding targeted ASCO GI 2016). pancreatic ductal adenocarcinoma are therapies improves survival. The ‘synthetic lethality’ strategy ongoing. Two positive trials have been holds some promise in patients with Drugs targeting tumour me­ reported in advanced-stage pancreatic aberrations in DNA-repair pathways. tabolism. To survive hostile desmo- cancer. The PRODIGE-III trial A basket study tested olaparib plastic microenvironments, cancer showed better survival (HR 0.57) in patients with germline BRCA1/2 cells reprogramme metabolic path- with FOLFIRINOX over gemcitabine mutations in BRCA-associated ways to metabolise 10 times more (NEJM 2011, 364:1817–25), while the cancers. The response rate in patients glucose than normal. In addition, MPACT study showed nab-paclitaxel with pancreatic cancer (n=23) was cancer cells process glucose through plus gemcitabine delivered better 21%. high rates of glycolysis and anaero- survival (HR 0.72) than gemcitabine RAS pathway inhibitors. Activat- bic conversion of pyruvate to lactate (NEJM 2013, 369:1691–1703). ing KRAS mutations are found in more (Warburg effect). Nutrient deprivation March / April 2016 55 Impact Factor

also activates autophagy, enabling can- of hyaluronic acid might overcome and its ligand PD-L1 have proved effec- cer cells to utilise internal fuel sources. physical barriers, enhancing drug tive in non-small-cell lung cancer and Hydroxyl-chloroquine, an autophagy delivery. In a phase II study, the melanoma, responses have not been inhibitor approved for malaria, is being addition of PEGPH20 (a recombinant observed in pancreatic cancer. Fur- evaluated in a neoadjuvant setting and human hyaluronidase) to nab-paclitaxel thermore, ipilimumab, an anti-CTLA4 advanced-stage disease in combination and gemcitabine resulted in increased monoclonal antibody, failed to show sig- with nab-paclitaxel plus gemcitabine. response rate and progression-free nificant activity in advanced-stage pan- PI3K–mTOR pathway inhibi­ survival in post-hoc analysis (Hingorani creatic ductal adenocarcinoma. tors. Mutations in PIK3CA, encoding et al Abstract #4006 ASCO 2015). A different approach is through part of the PI3K subunit, have rarely activation of CD40, a member of been reported in pancreatic ductal ad- Drugs targeting cancer the tumour necrosis factor receptor enocarcinoma. While two phase II tri- stem cells superfamily present in tumour- als failed to demonstrate therapeutic The concept of cancer stem cells associated macrophages. Gemcitabine activity for rapalogues targeting mTOR driving tumour growth remains combined with a CD40 agonist (the downstream effector of PI3K–AKT controversial. Expression of cancer promoted accumulation of tumouricidal signalling), a case report in a patient stem cell markers in pancreatic macrophages, leading to stromal with STK11-positive pancreatic cancer ductal adenocarcinoma specimens collapse and tumour regression. showed a response to everolimus. In fu- was associated with shorter survival. Cancer vaccines. GVAX pancreas ture, next-generation DNA sequencing In patient-derived xenograft models, is an allogeneic whole-cell vaccine could identify patients most likely to re- treatment with drugs targeting cancer generated from pancreatic cancer spond to mTOR inhibitors. stem cells increased survival. However, cell lines that have been modified as cancer stem cells frequently represent to express granulocyte-macrophage Drugs targeting stromal less than 1% of total tumour cells, colony-stimulating factor (GM-CSF). compartments drugs targeting cancer stem cells are GM-CSF induces chemotaxis of A growing body of evidence suggests unlikely to result in objective responses. dendritic cells to the injection site, that crosstalk between malignant Nevertheless, in advanced-stage which phagocytose tumour cells and epithelial cells and surrounding stroma pancreatic ductal adenocarcinoma, subsequently present tumour antigens results in cancer cell proliferation, several drugs inhibiting signalling to T cells, eliciting an immune response survival and resistance. pathways associated with cancer stem against the tumour. Hedgehog inhibitors. A phase II cells are being tested in combination A phase II trial in metastatic trial did not observe progression- with chemotherapy. pancreatic cancer reported a two- free survival benefits when the SMO month improvement in overall survival inhibitor vismodegib was added to Immunotherapy for GVAX–cyclophosphamide and gemcitabine in patients with chemo- Pancreatic cancers are characterised CRS-207 (an attenuated Listeria naïve metastatic pancreatic cancer. by immune-suppressive microenviron­ monocytogenes strain given as a boost Vismodegib is currently being evaluated ments believed to be orchestrated by vaccine) compared with GVAX– in combination with nab-paclitaxel multiple cell types recruited to the tu- cyclophosphamide alone. In a different and gemcitabine. The clinical failure mour, including cancer-associated fi- study, increased expression of PD-1/ of HH pathway inhibitors in pancrea­ broblasts, myeloid-derived suppressor PD-L1 was noted following resection tic cancer may be better understood in cells, and tumour infiltrating lympho- in patients treated with GVAX. Such light of preclinical evidence suggesting cytes. Disrupting immunosuppressive studies suggest there may be roles pathway inhibition releases tumour networks might provide new treatment for combining GVAX and immune- restraining influences of the stroma. opportunities. checkpoint inhibitors. Enhancing drug delivery using Monoclonal antibody immuno­ Chimeric antigen receptor hyaluronidase. Hyaluronic acid, therapies. Cancer cells evade natural T cells. A first-in-man study examining a glycosaminoglycan extracellular immune responses by modulating T-cell the safety of genetically modified T cells matrix component, is enriched in the signalling and inducing immune toler- engineered to express chimeric antigen hypovascular stroma of pancreatic ance. While monoclonal antibodies receptors recognising tumour antigens ductal adenocarcinoma. Degradation targeting the checkpoint inhibitor PD-1 (CAR T cells) led to anaphylaxis and 56 March / April 2016 Impact Factor

Take home message from the authors

Ignacio Garrido-Laguna (left) is from the Department of Internal Medicine, Division of Oncology, and Center for Investigational Therapeutics, at the Huntsman Cancer Institute, University of Utah, USA. Manuel Hidalgo (right) is from the Gastrointestinal Cancer Clinical Research Unit, Clinical Research Programme, at the Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

ven in the early stages, pancreatic ductal adeno­ need to identify biomarkers to assist treatment decisions. carcinoma is a systemic disease. This is supported It is also critical to elucidate whether patients with “Eby in vivo models as well as clinical data showing that up grade 2 ECOG performance status (Karnofsky score 70) to 60% of patients relapse within six months of resection. benefit from nab-paclitaxel plus gemcitabine. The MPACT Better systemic treatments are needed in adjuvant study did not find a survival benefit in this subgroup, and settings, as well as different treatment strategies allowing there is a potential for harm with gemcitabine doublets in early treatment of systemic disease (neoadjuvant therapy). frail patients. For patients with locally advanced unresectable disease, For patients with advanced disease, early results from where the role of chemoradiation is controversial, more immunotherapy clinical trials enrolling pancreatic effective induction chemotherapy backbones must be cancer patients were disappointing. The stroma in this tested. For patients with more advanced disease, targeting disease is predominantly immunosuppressive leading to different tumour compartments, such as the stroma, exclusion of CD8+ effector T lymphocytes. Overall this seems critical. The growing field of immunotherapy could leads to a tumour phenotype characterised by immune open new treatment opportunities in this lethal disease. system ignorance. Work in preclinical models shows that, even when only premalignant lesions (PanIN) are Clinical implications identified, the immune response is impaired. Treatment We would like to see an increasing number of neoadjuvant strategies that increase T-cell infiltration of tumour trials to elucidate the role of early systemic treatment. At a sites have shown promising results in preclinical models time when the value of care is critical for the sustainability and are currently undergoing clinical testing in early- of health care systems across the world, we need to phase clinical trials. In addition, recent preclinical work consider whether drugs that provide modest survival demonstrates that loss of PTF1A, a regulator of acinar benefits (days for erlotinib and weeks for MM-398) deliver differentiation, is needed to facilitate oncogenic acinar any added value to patient care at current costs. to ductal reprogramming by KRAS. One could envision that the use of preclinical models such as Ptf1a cKO; G12D Future studies KRAS may facilitate the identification of neoepitopes In the adjuvant setting it will be interesting to follow up as new targets to develop immunotherapies in this the results of the APACT and PRODIGE studies to discover disease. whether more effective chemotherapy backbones impact Lastly, use of next-generation sequencing and liquid on survival in patients with resectable disease. We also biopsies need to be further investigated in this disease. ” cardiac arrest in one patient, although phan-catabolising enzyme indoleam- An ongoing phase Ib trial is testing the clinical activity was seen in a patient ine-2, 3-dioxygenase (IDO) is as- IDO inhibitor indoximod combined with pancreatic ductal adenocarcinoma. sociated with poor outcomes, with with nab-paclitaxel plus gemcitabine A phase I study is evaluating meso- expression increased in metastases. in advanced pancreatic ductal adeno- CAR T-cell therapy in advanced-stage Tryptophan metabolites are toxic to carcinoma. Preliminary results from pancreatic cancer. T cells and contribute to an immu- this study showed delayed and durable Indoleamine-2, 3-dioxygenase nosuppressive microenvironment by responses (Bahary et al. Abstract #452 inhibi­ tors.­­ Expression of the trypto- increasing regulatory T cell numbers. ASCO GI 2016). March / April 2016 57

Focus

How doctors die It’s not like the rest of us, but it should be

This hard-hitting blogpost by Ken Murray, a retired Los Angeles family doctor, helped open up discussions about why doctors routinely administer treatments to dying patients that they would adamantly refuse for themselves.

ears ago, Charlie, a highly respected all the time they spend fending off the deaths of orthopaedist and a mentor of mine, found a others, they tend to be fairly serene when faced with Ylump in his stomach. He had a surgeon explore death themselves. They know exactly what is going the area, and the diagnosis was pancreatic cancer. to happen, they know the choices, and they generally This surgeon was one of the best in the country. He have access to any sort of medical care they could had even invented a new procedure for this exact want. But they go gently. cancer that could triple a patient’s five-year-survival Of course, doctors don’t want to die; they want to odds – from 5% to 15% – albeit with a poor quality live. But they know enough about modern medicine of life. to know its limits. And they know enough about Charlie was uninterested. He went home the next death to know what all people fear most: dying in day, closed his practice, and never set foot in a hos- pain, and dying alone. They’ve talked about this with pital again. He focused on spending time with family their families. They want to be sure, when the time and feeling as good as possible. Several months later, comes, that no heroic measures will happen – that he died at home. He got no chemotherapy, radiation, they will never experience, during their last moments or surgical treatment. Medicare didn’t spend much on on earth, someone breaking their ribs in an attempt to him. resuscitate them with cardiopulmonary resuscitation It’s not a frequent topic of discussion, but doctors (that’s what happens if CPR is done right). die, too. And they don’t die like the rest of us. What’s Almost all medical professionals have seen what we unusual about them is not how much treatment they call “futile care” being performed on people. That’s get compared to most Americans, but how little. For when doctors bring the cutting edge of technology to 60 March / April 2016 Focus © Nicolò Assirelli

bear on a grievously ill person near the end of life. I know it’s one reason I stopped participating in The patient will get cut open, perforated with tubes, hospital care for the last 10 years of my practice. hooked up to machines, and assaulted with drugs. How has it come to this – that doctors administer so All of this occurs in the Intensive Care Unit at a much care that they wouldn’t want for themselves? cost of tens of thousands of dollars a day. What it buys The simple, or not-so-simple, answer is this: patients, is misery we would not inflict on a terrorist. I cannot doctors, and the system. count the number of times fellow physicians have told me, in words that vary only slightly, “Promise me What it buys is misery if you find me like this that you’ll kill me.” They mean it. Some medical personnel wear medallions stamped we would not inflict on “NO CODE” to tell physicians not to perform CPR on them. I have even seen it as a tattoo. a terrorist To administer medical care that makes people suffer is anguishing. Physicians are trained to gather information without revealing any of their To see how patients play a role, imagine a scenario own feelings, but in private, among fellow doctors, in which someone has lost consciousness and been they’ll vent. “How can anyone do that to their family admitted to an emergency room. As is so often the members?” they’ll ask. I suspect it’s one reason case, no one has made a plan for this situation, and physicians have higher rates of alcohol abuse and shocked and scared family members find themselves depression than professionals in most other fields. caught up in a maze of choices. They’re overwhelmed. March / April 2016 61 Focus

When doctors ask if they want “everything” done, they the pressures they all face are similar. When I faced answer yes. Then the nightmare begins. Sometimes, circumstances involving end-of-life choices, I adopted a family really means “do everything,” but often they the approach of laying out only the options that I just mean “do everything that’s reasonable.” The thought were reasonable (as I would in any situation) problem is that they may not know what’s reasonable, as early in the process as possible. When patients or nor, in their confusion and sorrow, will they ask about families brought up unreasonable choices, I would discuss the issue in layman’s terms that portrayed the downsides clearly. If patients or families still insisted When doctors ask if they on treatments I considered pointless or harmful, I would offer to transfer their care to another doctor want “everything done”, or hospital. Should I have been more forceful at times? I know they answer yes. Then the that some of those transfers still haunt me. One of the patients of whom I was most fond was an attorney nightmare begins from a famous political family. She had severe diabetes and terrible circulation, and, at one point, she developed a painful sore on her foot. Knowing it or hear what a physician may be telling them. For the hazards of hospitals, I did everything I could to their part, doctors told to do “everything” will do it, keep her from resorting to surgery. Still, she sought whether it is reasonable or not. out outside experts with whom I had no relationship. The above scenario is a common one. Feeding Not knowing as much about her as I did, they into the problem are unrealistic expectations of what decided to perform bypass surgery on her chronically doctors can accomplish. Many people think of CPR clogged blood vessels in both legs. This didn’t restore as a reliable lifesaver when, in fact, the results are her circulation, and the surgical wounds wouldn’t usually poor. I’ve had hundreds of people brought to heal. Her feet became gangrenous, and she endured me in the emergency room after getting CPR. Exactly bilateral leg amputations. Two weeks later, in the one, a healthy man who’d had no heart troubles famous medical center in which all this had occurred, (for those who want specifics, he had a ‘tension she died. pneumothorax’), walked out of the hospital. If a patient suffers from severe illness, old age, or a terminal disease, the odds of a good outcome from I adopted the approach of CPR are infinitesimal, while the odds of suffering are overwhelming. Poor knowledge and misguided laying out only the options expectations lead to a lot of bad decisions. that I thought were reasonable, But of course it’s not just patients making these things happen. Doctors play an enabling role, as early in the process as too. The trouble is that even doctors who hate to administer futile care must find a way to address the possible wishes of patients and families. Imagine, once again, the emergency room with those grieving, possibly hysterical, family members. They do not know the It’s easy to find fault with both doctors and patients doctor. Establishing trust and confidence under in such stories, but in many ways all the parties are such circumstances is a very delicate thing. People simply victims of a larger system that encourages are prepared to think the doctor is acting out of base excessive treatment. In some unfortunate cases, motives, trying to save time, or money, or effort, doctors use the fee-for-service model to do everything especially if the doctor is advising against further they can, no matter how pointless, to make money. treatment. More commonly, though, doctors are fearful of Some doctors are stronger communicators than litigation and do whatever they’re asked, with little others, and some doctors are more adamant, but feedback, to avoid getting in trouble. 62 March / April 2016 Focus

Even when the right preparations have been made, the Amazingly, studies have found that people placed system can still swallow people up. One of my patients in hospice care often live longer than people with the was a man named Jack, a 78-year-old who had been same disease who are seeking active cures. I was struck ill for years and undergone about 15 major surgical to hear on the radio recently that the famous reporter procedures. He explained to me that he never, under Tom Wicker had “died peacefully at home, surrounded any circumstances, wanted to be placed on life support by his family.” Such stories are, thankfully, increasingly machines again. common. One Saturday, however, Jack suffered a massive Several years ago, my older cousin Torch (born stroke and got admitted to the emergency room at home by the light of a flashlight – or torch) had unconscious, without his wife. Doctors did everything a seizure that turned out to be the result of lung possible to resuscitate him and put him on life support cancer that had gone to his brain. I arranged for him in the ICU. This was Jack’s worst nightmare. When I to see various specialists, and we learned that with arrived at the hospital and took over Jack’s care, I spoke aggressive treatment of his condition, including three to five hospital visits a week for chemotherapy, he would live perhaps four months. Even with all his wishes Ultimately, Torch decided against any treatment and simply took pills for brain swelling. He moved in documented, Jack hadn’t died with me. We spent the next eight months doing a bunch of as he’d hoped. The system had things that he enjoyed, having fun together like we intervened hadn’t had in decades. We went to Disneyland, his first time. We’d hang out at home. Torch was a sports nut, and he was very happy to watch sports and eat to his wife and to hospital staff, bringing in my office my cooking. He even gained a bit of weight, eating his notes with his care preferences. Then I turned off the favorite foods rather than hospital foods. He had no life support machines and sat with him. He died two serious pain, and he remained high-spirited. hours later. One day, he didn’t wake up. He spent the next three Even with all his wishes documented, Jack hadn’t days in a coma-like sleep and then died. The cost of died as he’d hoped. The system had intervened. One his medical care for those eight months, for the one of the nurses, I later found out, even reported my drug he was taking, was about $20. unplugging of Jack to the authorities as a possible Torch was no doctor, but he knew he wanted a homicide. Nothing came of it, of course; Jack’s wishes life of quality, not just quantity. Don’t most of us? If had been spelled out explicitly, and he’d left the there is a state of the art of end-of-life care, it is this: paperwork to prove it. death with dignity. As for me, my physician has my But the prospect of a police investigation is terrifying choices. They were easy to make, as they are for most for any physician. I could far more easily have left Jack physicians. There will be no heroics, and I will go on life support against his stated wishes, prolonging his gentle into that good night. Like my mentor Charlie. life, and his suffering, a few more weeks. I would even Like my cousin Torch. Like my fellow doctors. have made a little more money, and Medicare would have ended up with an additional $500,000 bill. It’s no wonder many doctors err on the side of overtreatment. This blogpost was first published in 2011 on Zócalo But doctors still don’t over-treat themselves. They see the consequences of this constantly. Almost anyone Public Square (http://www.zocalopublicsquare.org/), can find a way to die in peace at home, and pain can be a not-for-profit Ideas Exchange affiliated to Arizona managed better than ever. State University. It is republished here with permission . Hospice care, which focuses on providing terminally Ken Murray is a retired family doctor and was Clinical ill patients with comfort and dignity rather than on Assistant Professor of Family Medicine at the University futile cures, provides most people with much better final days. of South Carolina. March / April 2016 63