C W 16 Education & knowledge through people & facts‘mini-doctors’, as Foubert puts it – there is a dan-ger of the bulk of bedside nursing remaining stuck in an assistant nursing

Education & knowledge through people & factsNumber 16, January-February 2007

Ü Jan Foubert: champion of cancer nursing Ü Would the right to a second opinionmake any difference to patient care? ÜHow will EMEA use its new powers of conditionalapproval?Ü Tackling the growing survival gap between eastern and western Europe

Jan Foubert

CancerWorld

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Contents

CANCER WORLD n JANUARY/FEBRUARY 2007 n 1

3 EditorialA question of public trust

4 Cover StoryJan Foubert: champion of cancer nursing

14 Grand RoundA second opinion, because there’s no second chance

22 Drug WatchFast and effective?

30 Best ReporterFrom plan to practice

34 MasterpieceTackling cancer the Tunisian way

42 Spotlight on…Not (just) another declarationClosing the survival gap

52 Impact FactorGene expression profiling for individualised breast cancer chemotherapy: success or not?Poor correlation between physician and patient assessment of quality of life in palliative careNewsround

62 FocusImmune no longer

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantCorinne Hall

Editorial BoardMariano Barbacid, Franco CavalliAlberto Costa (chair)Lev Demidov, Mario DicatoGordon McVie, Nicolas PavlidisHans-Jörg Senn, Antonella Surbone

Board of AdvisorsJan Betka, Jacques BernierVincent T. DeVita, Lex EggermontJan Foubert, Lynn Faulds WoodNeel Mittra, Santiago PavlovskyBob Pinedo, Mike RichardsMaurice Schneider, Tom VoûteUmberto Veronesi (chair)

Contributing WritersMarc Beishon, Paul Benkimoun, Jim Boumelha,Eduardo Bruera, John Ioannidis, Peter McIntyre,Anna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonChatrina Melcher

Project DesignerAndrea Mattone

Graphic and Layout DesignersLilith Mazzocchi

Production ManagerGianfranco Bangone

Published byEditoriale Darwin srlPiazza Antonio Mancini, 4 - 00196 Rome

Printed byMiligraf snc - Roma

Cover photographEligio Paoni / Contrasto

Registrazione Tribunale di RomaDecreto n. 436 del 8.11.2004

Direttore responsabileEmanuele Bevilacqua

All enquiries about Cancer Worldshould be made to:ESO Editorial OfficeVia del Bollo 420123 Milan, Italye-mail: [email protected]: +39 02 8546 4545All correspondence should be sentto the Editor at [email protected]

Copyright ©2007 European School of Oncology.All rights reserved

Cancer World is published six times per year by the European School of Oncologywith an average print run of 10,000 copies. It is distributed at major conferences,mailed to subscribers and to European opinion leaders, and is available on-line atwww.cancerworld.org

Editorial


Recent headlines in the UKpress have again put theissue of pharmaceuticalcompany sponsorship ofcancer initiatives under thespotlight, rekindling the

debate about its dangers and its merits.Whenever a non-profit advocacy, patient orprofessional group opens itself up to accu-sations that it is acting as a front for a com-mercial company, all groups and allcompanies find themselves under suspi-cion. But there are many reasons to resist aknee-jerk reaction on either side to pullback from any form of cooperation.

Pharmaceutical companies are in thecancer business to make money. And yet aslong as we need better drugs to addressexisting unmet need in cancer, their interestsoverlap with many non-profit groups. Com-mercial firms have a long tradition of sup-porting advocacy groups and campaigns,some of which have had a sustained impacton the quality of care that cancer patientsreceive. These campaigns can benefit fromthe industry’s resources and experience inresearch, marketing and communications aswell as financial support. But they can alsoopen themselves up to accusations of biasand hidden agendas, which can backfirebadly on the campaign.

Some voices in this debate argue that itis impossible to prove there is no hiddenagenda, and that any form of partnershipwith commercial interests fatally compro-mises the independence of non-profit

Ü Kathy Redmond n EDITOR

groups. But independence is of little usewithout the resources to run a democraticorganisation that can make an impact whereit matters.

In an ideal world, all the stakeholdersactive in the cancer arena should be able towork constructively towards shared goals,while acknowledging areas of conflictinginterests. The challenge is to define how thecorporate world can work with the non-profit world without undermining the repu-tation of all involved.

It may be impossible ever to allay the sus-picions of hardline sceptics, but public con-fidence in general may be satisfied withanswers to the following questions: whichcommercial concerns are contributing what,and what are they getting in return? Whodecides on the agenda and the way it is pur-sued, and to whom are they accountable?

Many non-profit cancer groups are nownegotiating a more arm’s length relationshipwith their industry sponsors, developingpolicies that clearly spell out the rules ofengagement. Many companies and industryassociations are going through similar exer-cises. Some voices have long been calling fora single, simple set of agreed standards toprotect those who follow best practice frombeing tainted by those who do not. Thereare many obstacles to achieving such a goal,but given what is at stake, it is importantthat all stakeholders take a fresh look at theway forward. Otherwise, a build up of neg-ative headlines could prompt politicians totake unilateral action.

A questionof public trust

CoverStory

4 n CANCER WORLD n JANUARY/FEBRUARY 2007

Jan Foubert: championof cancer nursingÜ Marc Beishon

Jan Foubert knows the value of a good cancer nurse – someone who understands the patient’s

needs, knows how to help them cope with the disease, symptoms and side-effects and has

skills to apply that knowledge. He believes it’s up to Europe’s nurses to redefine their role in

cancer care – but he’d also welcome a bit more support from the other oncology disciplines.

If there is one factor that can help a coreoncology specialty to develop aroundEurope it is consistent and long-term lead-ership, which European cancer nurseshave enjoyed in recent years in the form of

Jan Foubert. His credentials include a back-ground in paediatric oncology nursing, academicnursing positions at the Erasmus institute ofhigher education and the Free University in Brus-sels, and he is the immediate past president andlongstanding board member of EONS, the Euro-pean Oncology Nursing Society. Most recently,the US Oncology Nursing Society selected himfor their International Award for Contributions toCancer Care, which he will receive at the ONSAnnual Congress next April.

It is, however, a new role at EONS that willcement his relationship with the nursing cause inEurope. “I have accepted an executive director’spost, that will allow the society to build on all theprojects and development work I’ve been involvedwith as a board member,” he says. While the detailsof the new post are to be decided – he will also con-tinue with his teaching duties in part – his direction

is unequivocal. “I’ve just turned down two otherjobs so I can work with EONS – a director’s post atFECS (the Federation of European Cancer Soci-eties) and a principal’s position at the university.”

Those who have encountered Foubert on theconference circuit and as a board member ofEONS and FECS will not be surprised by hisdecision. While always open to discussion, he haslong been of the view that Europe’s oncology nurs-es – and there are around 30,000 in EONS – needa strong, independent voice, and they have enjoyedprecious little support from the medical oncologycommunity, despite the supposed rise of multidis-ciplinary working. Further, although oncology nurs-ing has developed as a specialty in a few countries,the overall picture is very fragmented in terms ofrecognition, educational opportunities and require-ments, and clinical knowledge and research.

In fact, Foubert feels there is an urgent need toaddress what he calls a ‘loss of identity’ among thenursing community generally. “A shocking defini-tion I’ve heard of a nurse is that they do things thatcan also be done by others,” he says. “What a lot ofnurses still do goes back to the days of Florence

CoverStory


“Nurses complain about respect and image –

but we have to create our own image and earn respect”

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Nightingale – basic care and being dependent ondoctors to tell them what to do.” While there are,of course, many specialised and advanced posts inoncology – such as pain management and tumour-specific roles, and some senior nurses acting as‘mini-doctors’, as Foubert puts it – there is a dan-ger of the bulk of bedside nursing remaining stuckin an assistant nursing role, suffering from a lack ofknowledge and empowerment. “Governments willsay, ‘Why should we pay so many registered nurs-es when one or two can coordinate the care?’”

The present-day situation is exacerbated, headds, by societal changes that have seen nursesless valued than they were. “The uniform andpresence once meant you were respected – nowsociety sees nursing as any other job. Nursesoften complain about respect and image – but wehave to create our own image and earn respect.”

It is the majority – the bedside oncology nurse– who Foubert has most in mind in his work tohelp raise the profile and professional attain-ment of nursing. Apart from his involvement inthe politics and strategic agenda setting forEONS, his teaching experience has no doubtinformed the development of the society’s mostimportant programmes so far. These includeeducational initiatives such as TITAN, whichdeals with thrombocytopoenia, anaemia and neu-tropoenia – conditions where nurses can play keytreatment roles – taught in a way that shows howsuch potentially forbidding topics can be shapedto be of practical value and not discarded asbeing too theoretical.

Foubert’s own pathway into a nursing career wasquite remarkable. Brought up in Germany, he hadinitial ideas about being a psychologist, until afriend of his mother, a night sister at a hospital,invited him to spend a shift with her – wheresomeone died. “He was put in bed in a bathroom,with no one with him. I thought, ‘This can’t beright.’” Then in a school holiday he found himselfvisiting a nursing home for older people withdementia, again through a family contact. “The

director was looking for holiday help – I went on atour with my mother and in one room there werefour women, one of whom was spreading faeces ona hot radiator. I stayed and did the evening shift. Mymother couldn’t understand it.”

This highly unlikely holiday job for a teenageboy – which was probably illegal – was neverthelesshighly stimulating, although Foubert says he had togrow up rather rapidly. He was determined then toqualify as a nurse, which he duly did at a nursingschool in Brussels, and then went to a new hospi-tal, Queen Fabiola Children’s University Hospital,also in Belgium, as a paediatric intensive carenurse. University training, as he often says to hisstudents today, hardly prepares you for the realitiesof such a job, but in this unit he was able to learnquickly about all manner of high-, medium- andlow-intensive care situations.

Foubert was also able to fit in a master’s degree,specialising in hospital science, which also had aneducational option, meaning he was then equippedto teach other nurses. “The hospital director askedme to build up hygiene practices in the hospital,and then one day called me in and offered me thehead nurse position in the paediatric oncologyward – I had to take it there and then.” He notes:“As a new nurse you have to be visible to the deci-sion makers so that they can see that you have com-petencies that can be of use for the organisation.Don’t follow the crowd.”

Foubert realised he knew next to nothing aboutoncology. “The doctors might as well have beentalking Chinese,” he says, adding that today’s nurs-es receive little oncology teaching on undergradu-ate courses, which hardly stimulates them to lookat specialised postgraduate cancer options. In amonth or so he had read up on cancer to the extentthat he felt he knew more than most on the unit,and brought his intensive care skills to bear –showing other nurses how to perform a resuscita-tion in one case and how to monitor and assess chil-dren in a critical situation on an oncology ward.

He also led the reorganisation of the unit. Nurses

Too often, trainee nurses bursting with ideas end

up in units where there is little scope to change things

CoverStory


needs of patients, which makes oncology nursingno different from general nursing. I was busy withnursing shortages, and generally the hospital, likemany others, was firefighting and found it hard togo forward with nursing development.”

With other cancer centres springing up in Bel-gium, all starting to do similar things, adds Foubert,it becomes difficult to maintain a unique referencepresence. His main focus there was as a nursechampion, visiting every unit each day, and payingparticular attention to the needs of head nurses,who he says can often be in very isolated positions.

Foubert went on to become a continuing edu-cation coordinator at Jules Bordet, while starting ateaching career as a lecturer in nursing and mid-wifery at Erasmus. He still has a strong link withJules Bordet, however, as he runs a fatigue clinicthere half a day each week – fatigue is a special

were working on only one of several areas, such asambulant care or closed bone marrow treatmentrooms, and they were asked to vary their work. Thisproved unpopular with some (who then left). Someevidence-based practice was brought in – such as theuse of specially prepared sterile food for bone mar-row patients. “It was from my master’s study that Ishowed the food we could get from commercialsources was much safer than food we prepared our-selves – all we needed was a decent kitchen with astore of safe food in a fridge, and a microwave.”

These two themes – challenging ingrained habitsand introducing evidence-based nursing – havebecome central to Foubert’s views about developingnursing practice. “If there is one profession that is dif-ficult to change, it is nursing,” he says. “Nurse train-ing is about a lot of theories and models – but whenyou go into practice you don’t often see them.” Toooften, he reckons, trainee nurses bursting with ideasend up in units where there is little scope to changethings, although there are some places where beingassertive and dynamic is welcome. “But the mostfrustrating thing a new nurse hears is, ‘We havealways done it this way.’”

Meanwhile, at the children’s hospital, Foubertand a doctor colleague who had been working in theUS brought in outside finance to equip the oncol-ogy department with TVs and toys, and decent bed-side clinical equipment. “I realised that to build aunit you need charitable donations, which weobtained from business people. It became an exem-plar unit, visited once by Princess Diana. Everyonewanted to see it.”

It was on a Europe Against Cancer course thatFoubert was noticed by the director of the JulesBordet Institute in Brussels, Belgium’s only dedi-cated cancer centre, and he moved there as anurse manager, taking a step away from the bedside.“At the time this was an ideal place – one of the fewhospitals doing rehabilitation, pain management,stoma therapy, breast cancer nursing and so on. Itwas a pioneer, particularly in rehabilitation underpsycho-oncologist Darius Razavi.”

However, Foubert says that it is all too easy tolose leadership status, which he feels happened atJules Bordet from his nursing perspective. “Youneed to keep on top of protocols, standard careplans, clinical pathways and quality – things youcan measure – and not just take care of the basic

FATIGUE – GOOD ADVICE IS KEY

Fatigue has become one of the more difficult side-effects for healthcare pro-fessionals to tackle, despite it being one of the most common complaints ofcancer patients. “Doctors and nurses tend not to be interested in it becauseits origin is not known – they prefer to treat symptoms such as pain, where theyknow they can do something,” says Foubert. At the recent World Congress ofPsycho-Oncology, he presented a case study of someone with fatigue and bor-derline anaemia. “The only questions from doctors were about the anaemia– it was a psychologist who asked me how you measure stress levels and wasinterested in the problem of fatigue in cancer survivors.

“Also, what I’ve learnt in my fatigue clinic is that most studies on fatiguehave been done on patients undergoing treatment, but it can continue in peo-ple who are cured or no longer treated – there is little available on this pop-ulation in the literature.”

Fatigue management should be integrated as a standard care plan, as withpain management – but it is not happening in most places, according to Foubert.He says nurses are well placed to develop management strategies by approach-ing the problem as a lifestyle issue, in a similar way to a dietician advising onweight loss. “If you want to lose weight I can coach and motivate you – but youare the only one who can lose weight. Fatigue is the same – you have to changeyour lifestyle and habits and think about how you deal with reduced energy.”This can touch on painful personal issues. “When I ask women with families,‘When was the last time you did something for yourself?,’ they often start cry-ing. When someone is diagnosed with cancer, the emphasis is on the waragainst it – the treatment – and not how you come to terms with it. We have tochange our minds about lifestyle issues being too difficult to tackle.”

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interest and one especially relevant to oncologynursing (see box).

At the same time, an involvement withEONS started to take off. Initially, he had littleknowledge of European oncology societies, orconferences such as ECCO (the European Can-cer Conference). That was all to change as hequickly made his presence felt, soon being invit-ed to become an EONS board member. “When I first became involved, EONS was look-ing at the status of oncology nurses, especially ineastern European countries. It’s still the case thatthere are major differences in status in Europebetween east and west and north and south –and what I saw was that EONS could only beimportant if we could reach the bedside nurse,those who do not normally have the opportuni-ty to go to conferences. That was my goal fromday one, and I’m happy to report that, by the timemy presidency of EONS came to an end, we hadincreased membership to 32 national oncologybodies from 28 countries.”

EONS has a core strategy under the acronymCARE – meaning Communications, influencingthe Agenda, Research and Education – and edu-cation has been the most important main activ-ity, and should remain so, according to Foubert.“It is the biggest need of European oncologynurses,” he says, noting a number of challenges,from increasingly specialised cancer treatments,to shorter hospital stays (which may mean com-munity nurses needing some cancer expertise),to changing role boundaries in hospitals, withsome countries allowing what were previouslymedical procedures to be carried out by nurses– those ‘mini-doctors’. He would also like EONSto be the platform to launch specialist nursinggroups, such as for breast cancer, palliative careand geriatric oncology.

According to Foubert, what has been lackingare educational packages that address real needs– rather than supposed requirements – and alsomaterials that are usable across the many different

cultural healthcare environments in Europe.“What used to happen was that the industry wouldbring out a pack, say on nausea and vomiting, fornurses, but there was no research on whetherthere was a need for it, and what the current stateof knowledge was. Also, much educational mate-rial has come from the UK. While some of this isvery valuable – such as materials on biological ther-apies – it is much too complicated for the bedsidenurse, and of course it is written or presented inEnglish, not a common language for many nurses.Bedside nurses don’t want an all-day lecture – theywant practical, interactive training that they canactually implement.”

What has also been missing, he adds, is eval-uation of the impact of education and the dis-semination or use of the new knowledge. “Weassume that people who have been educated willperform better. When I was an education man-ager, if a problem came up, managers said nurs-es need to be trained and the problem will besolved. That’s nonsense.”

Educational programmes at EONS, says Fou-bert, now emphasise needs assessment, piloting,evaluation and dissemination, and don’t justassume that the training alone is enough. Thefirst initiative was NOEP (Nutrition in Oncolo-gy Educational Program), launched in 2003,and a raft of other programmes with impressivesounding acronyms have since got underway,such as TITAN, BONE (BisphosphonatesOncology Nurses Education), Speak Up! (dia-logue with patients on nausea and vomiting)and Target (training in targeted therapies).

TITAN is being rolled out across Europe bynational oncology nursing bodies. So far, morethan 2,000 nurses have taken the course in 21European countries, and it is now spreadingworldwide, with Australia running its debutcourse last November.

Foubert – who travels to teach it himself –says cultural adaptability is a key marker ofsuccess. “I was in Slovenia at the Institute of

“A bedside nurse wants practical,

interactive training that they can actually implement”

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Team TITAN. At ECCO13 with colleaguesfrom the trainingcourse onthrombocytopoenia,anaemia andneutropoenia whichwas developed by EONS and is nowtaught all over the world

Oncology in Ljubljana recently – they havetranslated the materials, and even attended thetraining in English on a Saturday.” But there canbe obstacles to overcome. “In this case, a mediccalled the nurse director and said they could notgive this course as there is no medical doctorspeaking – how can nurses possibly explainanaemia management? It was cleared, though,by asking the medical director, who supportedthe nurse director. This sort of situation still aris-es in some countries.”

The educational approach that EONS is devel-oping is also designed to fit in with the BolognaAgreement, the European Union programme thataims to standardise higher education acrossEurope – examples are a core curriculum for can-

cer in older people and the EONS post-basic corecurriculum in oncology nursing.

Foubert is concerned by a global lack of atten-tion to ‘evidence-based nursing’ – he feels there isa pressing need to evaluate how research cantranslate into effective practice in often complexcare situations. Existing models, he says, “are notappropriate for the complex interventions inwhich the experience of the patient plays animportant role in effectiveness. The context ofcare in a complex nursing situation is almostnever the same, and that is where evidence-basednursing fails, as its principle is that the situationis always identical.” The solution, he adds, lies innurses receiving training in scientific research –and researchers in clinical research.

“The context of care in a complex situation is never

the same – that’s where evidence-based nursing fails”

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An example close to his heart – especially withhis experience with children – is the assumedneed in many units to wear protective clothingwhen with patients, say with neutropoenia, whoare at high risk of infection. As even newbornsin incubators – one of the best protected placesin a hospital – are colonised by many bacteriawithin 72 hours, evidence now points to aban-doning protective isolation, with subsequentbenefits for patient contact (such as being ableto hold a child). But for such initiatives tobecome the norm, says Foubert, training, meas-uring and monitoring, reflection on currentpractices and above all nursing leadership arerequired.

He cites thoughts from various academicsabout how advanced practice nurses can ‘unitethe worlds of scholarship and practice,’ and thatnursing, like all healthcare, needs ‘knowledgeworkers’ with skills such as leadership and del-egation, clinical judgement, teamwork and use ofnew technologies.

It all adds up to a substantial agenda – and for alliesin the effort, Foubert says partnerships with patientadvocacy organisations offer one of the best waysforward. “Nurses are often closer to patients thandoctors, and can be of great help when patientshave to make decisions,” he says, adding thatEONS is forming close links with leading advoca-cy organisations, such as Europa Donna and ECPC(European Cancer Patient Coalition). “Patientsand nurses together are much stronger than on theirown and have much more power than the medicsat the political level,” he says.

He is direct about problems he sees withdoctor–patient communication. “Although mostdoctors say patients are important, they are oftenafraid to involve them in decision making. WhenI was on the board of FECS and other advisoryboards I kept saying, ‘Shouldn’t we ask patients?’How else are we to know what they think andneed?” A particular bugbear for him is educa-tional material given out by nurses that has hadno input from patient groups.

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This is not to say that nurses can assume theyare close to patients – factors such as theshorter time patients spend having treatmentmake communications more difficult, whilecommunications itself is a skill that needstraining. Further, doctors have an advantage inthat communication about, for example, a cer-tain treatment is easier, as there is a specificgoal in mind. “Years ago I did research for apatient league in Belgium that found patientswere more satisfied with explanations they gotfrom doctors, who may have carried out hun-dreds of the same procedure. I think that nurs-es often talk to patients without a clearobjective in mind.”

As part of solving the nurse ‘identity crisis’,Foubert feels that making more of being anadvocate who makes time to know patientsbetter will help, and he is an advocate himselfof having nurse case managers to provide con-tinuity and a single point of contact for a patient– currently an ‘unusual role’.

On the wider stage, Foubert is organisingthe patient programme at the next ECCOmeeting in Barcelona, previously managed bydoctors. He sees this as an interim step tohanding over the job to a patient organisationsuch as ECPC. As he says, he knows how to‘work the system’, through working with FECSand EONS, and is hopeful that the patientadvocacy organisations will avoid the mistakehe feels that oncology doctors have made –speaking with too many voices. “It has been verydifficult for politicians to know who to listen to.I hope the patient organisations will avoid hav-ing too many lobby groups.”

These concerns played a role in his recentdecision to turn down the offer of a director’sjob at FECS. “I was honoured, and may wellhave accepted a post to run the conferenceside earlier in 2006 – but I don’t want to be partof lobbying, as the mission of FECS is still notclear to me.”

It was certainly a brave step to offer Foubert thatFECS post given his trenchant views on multi-disciplinary working and the tough time he hadas a board member, where he often spoke hismind. “When doctors talk about multidiscipli-nary teams they usually mean medics and notnurses. But nurses have to earn their place onthe team – and that has to do with image,respect and leadership.”

Foubert is a member of the ethics committeeat the Free University of Brussels, a post heenjoys greatly and where he feels among equals.As for his lecturing post, he admits he’s knownas a pretty strict teacher, not tolerating latenessor backchat, but says he applies himself more asa mentor and coach, taking a lot of time to helpstudents achieve goals. “Teaching is just explain-ing things – but coaching is, say, going on prac-tice with students and working together towardsobjectives.” Any new job for Foubert will have toaccommodate at least part-time teaching – it’s alove he won’t relinquish.

Foubert and his partner live in Antwerp, wherehe’s forced himself to get out to cultural activitiessuch as opera and ballet by buying season tickets.Long cycle rides are also on the agenda, and helikes entertaining – but not with prepackagedfoods. A favourite book is The Queen and I, by SueTownsend, which imagines Britain’s Royal Fam-ily forced to live as ordinary, poor citizens – but anythought of bringing down medics a peg or two ispurely coincidental.

“I have made a clear choice about my futureby taking on the daily business of EONS,” saysFoubert. “If I’m honest, I can’t say I’ve been theaverage nurse; I’m a man and I did notencounter any major opposition at work as anurse. Now I’m travelling everywhere, staying atthe best hotels. I recognise that it’s easy for meto say to nurses, ‘Stand up for your rights,’ but Ihope I’m respected enough for nurses to knowI really do mean to close the gap between theworst off and the best.”

“Patients and nurses together have much more power

than the medics at the political level”

GrandRound


A second opinion, becausethere’s no second chance

Ü Marc Beishon

Patients want the option of consulting a second doctor, and the evidence shows that, for a minority

of them, treatment decisions have altered significantly as a result. But could granting every patient

the legal right to a second opinion tie up precious resources as each one ‘shops around’ in search of

the opinion they want to hear?

“Iwish we had checked therewas nothing else we couldhave done” – it’s one of thecommon regrets of the rel-atives of people who have

died from cancer, and a reminder thatworries about treatment can extendbeyond the patient to possibly manyyears of soul searching by those leftbehind. Access to second opinionsabout diagnosis and treatment can pro-vide vital reassurance for patients andtheir families at a time when they feelmost vulnerable, and reassurance is acommon reason for asking for referralsto other specialists, or for people seek-ing information independently, partic-ularly on the Internet.

“I see three types of patients lookingfor second opinions on treatment,” saysFatima Cardoso, a medical oncologistat the Jules Bordet Institute in Brus-sels. “There are those who are happywith their doctor and just want to be

reassured they are having the best care.Some say they don’t want their oncol-ogist to know, just confirmation that heor she is correct. Then there is a groupwho are unhappy with the relationshipwith their doctor, and the third groupare people looking for new treatmentsand trials, normally referred on by theironcologist. We see all these types ofpatient and do a lot of second opinions– I wouldn’t say one reason is morecommon than another.”

The reasons why patients seek sec-ond opinions in cancer, and in medi-cine generally, raise many issues, someof which have not been wellresearched. Clearly, the opportunitiesfor patients to research medicine inthe Internet age is of primary interest.It is increasingly changing the face ofthe traditional doctor–patient rela-tionship, with healthcare becomingmore ‘consumer led’, although manypatients remain reluctant to ‘distrust’

their specialist, while there are still aminority of ‘paternalistic’ doctors whodo not encourage second opinions.

Then there is the question ofwhether a healthcare system or socie-ty should grant legal or just moral rightsto obtaining second opinions. In turn,there are questions about cost andstructure – should a second opinionsystem be formalised for some or allcomplex conditions, and would therebe a net cost, or would there be savingsthanks to better treatment? And couldthere be enough capacity to carry outmore formal second opinions?

A good place to start to answerthese questions is to look at what datathere are on where second opinionshave made a difference to cancer treat-ment. Much of the emphasis in studiesappears to be on the diagnosis of can-cer – and any patient researching theissue will immediately find alarmingwarnings about mistakes that are made.

GrandRound


Not surprisingly, these warnings appearmostly on US patient advocacy web-sites, and also on the websites of can-cer centres in the US that offer secondopinion services.

AN ENORMOUS IMPACTFor example, one of the most widelycited studies examined the impact of amandatory second opinion for surgicalpathology when cases were referred toa major cancer centre, John HopkinsHospital, in the US, during a period inthe mid-1990s. The study found thatsuch a programme could “result inmajor therapeutic and prognostic mod-ifications,” and although the number ofaffected cases was not large, theauthors considered that the rate of dis-crepant diagnoses “may have enormoushuman and financial impact,” (Cancer86:2426–35).

Another study, on pathology secondopinions for breast cancer, ‘confirmed’the benefit of a pathology second opin-ion, noting major changes that alteredsurgical therapy in 7.8% of 346 cases.Complete correlation between the ini-tial report and the second opinion wasfound in just 20% of cases. However,failure to confirm a malignant diagnosisoccurred in only one case, but theauthors note that benign diagnoses areseldom subject to a second opinion(Ann Surg Oncol 9:982–987).

This is a huge topic in its own right,but it seems to be the case thatpatients are not as likely to seek secondopinions on pathology and scan resultsas they are about prognosis and treat-ment. “Questions about the diagnosisare seldom raised by patients,” saysJürgen Schultze, a radiation oncologist

at Kiel University in Germany. “As Iam also trained as a radiologist, I dodeal with false-negative and false-positive results, but the questions arenormally raised by other doctors whoare not convinced that the findings ofthe original radiologist are right.”

It is very rare to see a misdiagnosisof malignant or benign tumours addsCardoso. “There is some controversy inthe classification of some types of can-cer – for example, you have a lot of dis-cordance in grading in breast cancerand some pathologists do grade differ-ently – and when you use techniquessuch as immunohistochemistry, youcan get different results. I think,though, that pathologists are moreadvanced than clinicians in asking forsecond opinions among themselves –they have been in the habit for manyyears of exchanging slides when theyare not sure about a diagnosis and willsend them to experts around the world.It’s much less frequent that a clinician

will send a patient for a second opinionbecause he is not certain.”

Clearly, though, there is a big dif-ference between routine checking ofpathology specimens and images forquality control purposes, and referral toa centre where different imaging andpathology tests may be done as part ofa new patient consultation. Anotherstudy on 148 women who went to theUniversity of Michigan Breast CareCenter for a second consultation fol-lowing a mammogram found that 7%had more cancer in the same breast, oran undiagnosed tumour in the otherbreast. But this was after a one-dayradiology, surgery and pathology con-sultation, with many patients receivingadditional imaging, resulting in addi-tional or different biopsies, additionalfollow-up imaging and changes to treat-ment in 30% of the women.

The superiority of the top multi-disciplinary cancer centres as places fordiagnosis and treatment is hardly a

Second opinions in breast cancer pathology led

to altered surgical therapy in 7.8% of 346 cases

MEETING PATIENTS’ NEEDS

A rare paper on the ‘motives, needs and expectations’ of cancer patients in the Netherlandsseeking a second surgical opinion (J Clin Oncol 21:1492–97) found that motives differgreatly. The authors identified five relevant variables: anxiety disposition, dissatisfaction withthe first specialist, preference for decision participation, need for more information, and hopeand expectation that the second opinion would be different from the first.

A majority of patients (62%) were identified as having ‘internal’ motives, relating more toreassurance and certainty, while the remainder had ‘external’ motives, relating to negativeexperiences or unfulfilled needs.

Given that some full second opinion consultations are unnecessary and put extra strainon health services, they suggest strategies that could avoid them. These could include phoneor e-mail consultation with an expert for the ‘internal group’, and improving communicationsskills – developing professionals as ‘educators and collaborators’ – to deal with theincreasing information and participation needs of the ‘external’ patients.

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surprise, although as referral centresthey also tend to see the more complexcases, which could make discrepantresults more likely. Major centres arealso more likely to have access to newertechniques, such as gene-expressionprofiling, which can provide addition-al information relevant to cancer prog-nosis and treatment.

A milestone reported recently isthe identification of a gene-expressionsignature for Burkitt lymphoma, whichcan distinguish it from Burkitt-like

lymphoma (reported in the New Eng-land Journal of Medicine, 8 June 2006).As Paolo Vigneri, a medical oncologistat the University of Catania in Italy,comments: “They sound alike and lookalike but are completely different.Diagnosis really requires an experi-enced pathologist, but even someexperts in this NEJM study misdiag-nosed it. The therapy for the two is verydifferent, but as an oncologist, if some-one tells you it’s Burkitt-like or not –that’s it. They are fairly rare, but theproblem is that rare diseases are alwaysless rare than you’d like and once you’veencountered one you never forget it.”

Rare cancers are of course morelikely to be referred for second opinions,but it is the now routine treatmentsthat may be being ignored that are prob-ably more disturbing for patients. Car-doso does see women who have had amastectomy when they could have hadneo-adjuvant chemotherapy and atumourectomy at a multidisciplinarycentre. She feels some isolated sur-geons may not be referring patients fora second consultation because they maynot believe in neo-adjuvant therapy orcould be afraid of losing their impact.Similarly, Schultze in Kiel sees patientswho have been told by their urologistthat the only treatment on offer is radi-cal prostatectomy for advanced disease,with 20% of men then having a localrecurrence – whereas he says his centrecan offer a combination of externalbeam radiotherapy and brachytherapy,with 97% local tumour control.

In Germany, concern about existingguidelines for testicular cancer notbeing adequately followed has led to anew second opinion project that couldalso be rolled out for other tumours(see box, p17). Other countries withfledgling second opinion systemsinclude Denmark, which has an expertpanel for patients and doctors; thehealth insurance is obliged to pay for the

treatment they recommend (see Mas-terpiece, CancerWorld September–October 2006), and Sweden, also witha recent oncology experts’ initiativecalled 2ndview (see www.2ndview.se).There also several e-mail based ques-tion resources, especially in the US,such as ‘Ask the cancer expert’ atwww.oncolink.com.

WHO GETS WHATNo country appears to have a national sys-tem for managing second opinions forall conditions. Some healthcare insurersin the US have had mandatory require-ments for second opinions on some pro-cedures such as mastectomy andprostatectomy to try and reduce the costof elective surgery and to prevent unnec-essary procedures. Most countries withhealth insurance systems have formal orinformal voluntary second opinion optionsthat are paid for in whole or in part. Insur-ers in the US now promote it as a patientright.

So European countries with healthinsurance systems, such as Germany,will pay for all or some of the cost ofsecond or even third and more opinions,although there does not appear to be alegal right anywhere. Indeed, the UK’sNational Health Service explicitly statesthere is no legal right to a second opin-ion, but “a healthcare professional willrarely refuse to refer you for one unlessthere is sufficient reason.”

In practice, access to second opin-ions appears to vary widely acrossEurope. The Euro Health ConsumerIndex, produced by Health ConsumerPowerhouse, has graded Europe’s healthsystems using a three-tier system, andincludes ‘right to second opinion fornon-trivial conditions’ as one of the cri-teria. At present, it adds Belgium, Esto-nia, Ireland and Latvia to the UK ascountries offering no right; other coun-tries such as Greece, Italy, Spain andSweden only score ‘yes, but difficult to

WHAT OUR READERS SAY

CancerWorld asked readers what they thinkabout second opinions. The respondentsinclude medical oncologists, radiation oncol-ogists, surgeons, radiologists, cancer nurs-es, pathologists, patient advocates,palliative care specialists and hospitaladministrators among others.n 81% answered ‘yes’ to the question:

should all cancer patients be givenaccess to second opinions? A quarter ofthose who said ‘no’ also ruled out anyspecial circumstances for a secondopinion.

n 66% have asked patients if they wouldlike a second opinion.

n 35% said cancer patients can easilyobtain a second opinion in their country;18% said bureaucratic procedures hin-der the process; 16% said their systemdoes not pay for a second opinion.

A comparison between Eastern and WesternEurope showed similar levels of support forthe right to a second opinion (80.8% vs87.5%), but a big difference in easy access,with 54% in the West saying patients alwayshave access in their country and 5% sayingthere is no such access. The equivalent fig-ures for Eastern Europe are 30% and 33%.The remainder indicated access is limited byregion, bureaucracy or cost.

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pointers on how to take steps to find analternative consultation.

Baird adds that in a system like theUK, where access to healthcare ismainly through a primary care ‘gate-keeper’ (the general practitioner orGP), referrals to other specialists cantake precious time and there is alwaysthe danger of vital notes and materialsgetting lost. “GPs may also only comeacross a few cases and know relativelyfew specialists,” she says. But as an ex-oncologist herself, she adds that thetwo biggest advances she’s seen in lungcancer in recent years are the growth ofmultidisciplinary teams and the role ofthe lung cancer nurse specialist – thelatter can act as a friendly second opin-ion source, she says. (And in the UK,

access due to bad information, bureau-cracy or doctor negativism’. France, Ger-many and the Netherlands are amongthe countries with the highest rank forsecond opinions (and these countriesalso take the top three slots for con-sumer-friendly healthcare systems acrossall criteria). France and Germany alsoallow direct patient access to specialists(see www.healthpowerhouse.com).

But even in the best countries,access to a second opinion is more orless ad hoc – referral choices are entire-ly up to the first specialist, or can besought by the patient via their ownresearch or in discussion with their pri-mary care doctor. In a survey of around150 cancer patients from across Europeconducted at a European CancerPatient Coalition masterclass in 2005,50% of respondents said that bureau-cracy was the main hindrance to gettinga second opinion in their country. Only13% said a second opinion was easy toobtain, 16% said it was available onlyfrom certain healthcare providers or incertain regions. Ten percent of patientssaid second opinions are never reim-bursed in their country.

It is no wonder that patient advo-cacy organisations are playing a vitalrole as information brokers in theprocess. As Jesme Baird, medical direc-tor at the UK’s Roy Castle Lung Can-cer Foundation, comments, “Patientsuse us like a second opinion – they calland say, ‘Here’s my stage of disease, andthis is what my doctor says; does thissound right?’ All we can say is that itmay be broadly right or wrong.” How-ever, the copious information nowavailable on advocacy and canceragency sites gives patients plenty of

personal breast cancer information isavailable by e-mail from nurses atwww.breastcancercare.org.uk). How-ever, even in a big centre Baird says alloptions may not be explored orexplained – in the UK, in particular,patients may not be told about a drugthat is not funded and not in the hos-pital formulary.

Vinod Joshi, a restorative dentalspecialist who runs the Mouth CancerFoundation, another patient group inthe UK, says meeting other patients,even in an online forum, can be animportant second opinion resource.“They can come to us without feelingthey are jeopardising the treatmentthey have been offered,” he says. Thefear that many have about ‘upsetting’

“Pathologists are more advanced than clinicians in asking

for second opinions among themselves”

SECOND OPINION PROJECT

A project in Germany is aiming to iron out the differences in outcomes for testicular cancerthat are still being seen despite long-established standard care guidelines. A network of 20second-opinion centres has been established by the German Testicular Cancer Study Groupin conjunction with a health insurer. The centres receive patient data and the treatment sug-gestion from the original doctor, and then recommend therapy according to evidence-basedguidelines. The project will follow up patients after two years; it will focus on recurrence-freesurvival data and will compare intended, recommended and actual therapy.

Mark Schrader, assistant medical director in the oncology unit at Berlin’s Charité hospi-tal, is coordinating the data management. “The problem with guidelines is that no one readsthem,” he says. “We have seen a lot of issues, particularly in some regions and small towns,with diagnostic work-up, therapy and surgery. Now patients and doctors have an easy wayto consult specialists at multidisciplinary centres. It is all done by software and e-mail.” Some200 referrals have already been made.

The project has not been without problems. “The health insurer is so far only paying for fiveof the centres, the others are doing it for free,” says Schrader. “But the main problem is theurologists – they are worried that other experts will get all their best patients and they will earnless money.” The head of the German Urological Association has been particularly critical, addsSchrader. “There has been an unbelievable amount of tension on this project,” he says.

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their doctor should not be underesti-mated; Baird makes the point thatunless actively encouraged, people canbe very reluctant to seek another opin-ion. Joshi notes that it is not easy in theUK to be referred to a multidisciplinarycentre outside of a patient’s homeregion, or for patients to discover thattreatment modalities may differ fairlysubtly, say in the radiation fractionsgiven. “These decisions can be affect-ed by finance,” he comments. He alsofeels strongly that oncologists shouldbe open about drug treatments thatare not funded in one area – such ascetuximab, which is available for headand neck cancer in Scotland but notyet in England. “It is better than notsaying anything about it at all.”

From the oncologist’s perspective,Vigneri notes that patients need to bearresponsibility too. “I have no problemwith people seeking alternative opin-ions, but some go to places that are notwell qualified and get answers theylike better.” The sheer volume of workthat referrals can generate is also an

obstacle. “Doctors need to prepare anextensive letter detailing the clinical sit-uation of the patient. This materialalso needs to be translated into Englishand coupled with copies of the neces-sary laboratory and radiological examscarried out to evaluate the patient.”

If they do go to a centre that is nothighly qualified and internationallyrecognised, “the end result might beconfusing, unreliable advice with con-sequent conflicts between the patient,their family, and the different oncolo-gists involved.” Vigneri has also comeacross patients who have had surgeryand, told they also need chemotherapy,delay treatment too long while they‘shop around’.

Another concern he has is whenpatients fail to seek a second opinionbefore enrolling on clinical trials, andthen drop out. “This can be a hugewaste of time for an oncologist.”

QUALITY OF LIFESchultze at Kiel feels that a key issuethat patients don’t ask about enough is

the consequences of treatment andquality of life. “These questions arenot raised much by patients,” he says.“For example, prostate cancer ispresently a problem, as we are in aphase where we have to make up ourmind if someone needs treatment atall, and if so, what treatment to give.And we need to encourage more sec-ond opinions on quality of life in pal-liative care for conditions such asinoperable lung tumours and head andneck cancers where you can apply veryharmful, aggressive treatments, but atwhat price?

“Doctors often decide on a courseof treatment easily, but we do not seethe burden we are bringing to thepatient – for us it is our surgery, for thepatient it is the rest of his life.”

It is a point strongly endorsed byJoshi. “Rehabilitation is an area that isnot sufficiently addressed,” he says, not-ing that, unlike some other cancer treat-ments, surgery for mouth cancer can besocially disfiguring and can create greatfunctional difficulties. Surgeons, he

The fear that many have about ‘upsetting’ their doctor

should not be underestimated

Searching for certainty.Websites like theseoffer varying levels of information,including extensivelists of FAQs, e-mailresponse servicesand even contacts for telephone or full face-to-faceconsultations

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says, may opt to perform a procedurethat is more comfortable for them thanthe patient, and there are major choic-es that can be made – such as restoringa hole in the mouth with a prosthesis, orsurgically, which can make other restora-tive work much harder.

“Part of getting a second opinionshould include speaking to a patientwho has had that treatment and becomforted that people do get through itdespite the disabilities. Suppose youhave surgery to your mouth, and thesurgeon says you should have a feedingtube to your stomach. Some people fearthis additional treatment – the secondopinion they need is from anotherpatient who may tell them that withoutit you can’t eat, you lose weight and it’sthe only thing that kept them alive.”

A second opinion could also extendto others specialists who are often notpart of the ‘loop’ in the early days oftreatment, such as gastroenterologists,who may be able to provide informationon the chances of radiation damage tothe bowel and subsequent lifestyleissues. Even if there is no alternativetreatment, there could then be conti-nuity of care for a patient group thatcurrently receives little attention.

Like many issues in cancer, muchopportunity lies in the multidisciplinaryteam. Paolo Vigneri says it is notuncommon where he works now inSicily to be visited by patients whohave had surgery and had no discussionwith a medical oncologist beforehand.Having recently also worked atBellinzona in Switzerland, which hasmultidisciplinary tumour boards, hehas seen the value of patients meetingboth parties prior to any procedure.

One of the strongest appeals for an auto-matic second opinion comes from theR.A. Bloch Cancer Foundation in theUS, founded by Robert Bloch, who sur-vived a terminal diagnosis of lung cancerand went on to live for another 26 years.One day, he was with a medical oncolo-gist who said that he had never in hiscareer treated a cancer patient without asecond opinion, because being onlyhuman, he could make a mistake – andthere is often no second chance. “Myconclusion is that any doctor treating acancer patient without a second opinionis not practising medicine, but trying toplay God,” says Bloch on the site.

Recognising the importance of mul-tidisciplinary decision making, Bloch’sfoundation has pushed for patients to bepresent when their cases are discussedby such teams – to take forward the

thoughts of ex-US Supreme Court judgeand breast cancer survivor Sandra DayO’Connor in a speech to the NationalCoalition for Cancer Survivorship backin 1994. “Let me tell you my dream... tohave a consultation with all the expertsavailable at the same time, who’vealready looked at these things, they’velooked at everything, and they are all inthe same room, and they are there tohelp you reach a decision.”

Dream may be, but the Bloch sitehas a list of about 100 institutions inthe US that say they will provide amultidisciplinary second opinion‘where doctors representing each dis-cipline which could treat the patient’scancer meet together at the same timewith the patient.’

Now that is a gold standard toaspire to.

“For us it is our surgery,

for the patient it is the rest of his life”

IN SHORT

n Women, especially breast cancer patients, are among the most likely to seek secondopinions, probably because of the many different treatment options for breast cancerand its high visibility in the media.

n Computers networks are obvious second opinion enablers. The European Union’s e-Healthaction plan predicts that by 2008 the majority of European health organisations shouldhave the technical capability to provide online teleconsultation services for second opin-ions and other needs.

n More than a quarter (29%) of US adults reported that they or a member of their familyreceived a second medical opinion from a doctor in the past five years, according to a2005 Harris Interactive survey. In 30% of these, the diagnosis differed from the original.Another Harris poll in 2006 found that 36% of US adults never get a second opinion andnearly one in ten (9%) ‘rarely or never understand’ their diagnosis.

n Australian researchers have found that ‘Googling’ symptoms on the Internet came up withthe right diagnosis in 15 out of 26 cases (reported in the New England Journal of Medi-cine). At Duke University in the US, medical physicists are using a Google-like approachto compare mammograms with the most highly ranked images returned from a database.

DrugWatch


Fast and effective?

Ü Anna Wagstaff

EMEA’s new system for fast-tracking drugs aims to offer quicker access to promising

new therapies without jeopardising essential research. Draft Guidance on the use of

the new conditional marketing approval procedure will shortly be published, and

patients, professionals and the public are being invited to have their say.

How will EMEA use its new powers of conditional marketing authorisation?

In July, the European Medi-cines Agency (EMEA) threw apossible lifeline to two groupsof patients who have reachedthe end of the road with con-ventional drug treatment.

EMEA gave conditional approval forthe use of sunitinib malate (Sutent) forpatients with advanced and/or metasta-tic renal cell carcinoma (mRCC)where interferon alfa and interleukin-2 therapies have failed. It also grantedconditional approval for its use inpatients with unresectable and/ormetastatic malignant gastrointestinalstromal tumour (GIST) where ima-tinib mesylate treatment has failed dueto resistance or intolerance.

For these patients, the earlyapproval of sunitinib gives some newhope. For everyone with an interest innew therapeutics – as patients, public,health providers or drug developers –this represents the first chance to seehow EMEA, which has responsibilityfor approving all new cancer medi-cines, intends to use its new powers togrant conditional marketing authori-sation (CMA).

The concept of CMA was adopted bythe EU in 2004 “in order to meet, inparticular, the legitimate expectationsof patients and to take account of theincreasingly rapid progress of scienceand therapies.” Pressure had beengrowing from European patients withcancer and other life-threatening dis-eases who could not understand whythey should wait months or years longerthan patients in the US for access todrugs that could save, prolong orimprove their lives.

There was also a perceived need toupdate the regulatory procedure to takeaccount of the way drug developmenthas been transformed by progress inmolecular imaging. The early stages oftraditional drug development (pre-clinical,phase I and phase II) tested whether thedrug was safe and effective enough to beworth trying in a large confirmatory(phase III) clinical trial. The regulatoryprocedure therefore focused on theoutcome of the phase III trials.

Now researchers are able to see moreabout what is happening at molecularlevel, and the early stages have becomea fount of information. Researchers can

explore how the drug works, what targetsit is hitting, which patients have the tar-get and what dose and schedule shouldbe most effective.

The new procedure, modelled inpart on the US ‘accelerated approval’procedure, gives EMEA two new pow-ers. The first is to approve drugs for aone-year period, renewable annually, assoon as sponsors show data strongenough to demonstrate a positivebenefit–risk balance. This has thepotential to reduce the period betweena drug going into development and themarketing application being handedto EMEA. (The time EMEA spendsassessing the drug, is dealt with by aseparate regulation on ‘acceleratedassessment’.) The second is the powerto lay down conditions with some legalstanding requiring the sponsors to carryout post-approval studies to clarify cer-tain aspects of the drug – duration ofeffect, which patients it works best in,what is the optimum dosage, and so on.

The CMA procedure is expected tobe widely used for new cancer drugs. Inparticular, it is likely to be used fordrugs that would previously have been

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It is equally vague about what EMEAcan ask for in post-approval studies.The regulation mentions only that theholder of a CMA shall be required tocomplete ongoing studies, or to con-duct new studies, with a view to con-firming that the risk–benefit balanceis positive and providing the compre-hensive clinical data referring to safe-ty and efficacy that would normallybe required for standard approval.

dealt with under ‘exceptional circum-stances’ approvals procedure, for whichthe criteria are more restrictive.

The implementation regulation(507/2006), which came into force inApril 2006, spells out the type of drugsthat may be eligible for CMA (see box).It also spells out the basis on whichconditional marketing approval can berenewed after the approval year is over.

However, the regulation is remark-

ably vague when it comes to criteria onwhich approval should be granted. Thefirst criterion listed under Article 4 sayssimply that “The risk–benefit balance asdefined in Article 1(28a) of Directive2001/83/EC is positive,” that is, anyrisk relating to the quality, safety or effi-cacy of the product as regards patients’health or public health. There is notthe merest hint of direction about howrisks or benefits should be measured.

THE CMA REGULATION

Eligible therapies (article 2)n Medicinal products aimed at treatment,

prevention or diagnosis of seriouslydebilitating or life-threatening diseases

n Medicinal products to be used inresponse to public health emergencies

n ‘Orphan’ medicinal products for rarediseases

Requirements (article 4)n Positive risk–benefit balancen Applicant ‘likely’ to be able to provide

comprehensive data post-approvaln Meets unmet needsn Early approval of benefit to public health

on balanceRenewal (article 6)n Annual renewaln Risk–benefit balance to be confirmed,

meeting CMA obligations

CMA versus Exceptional CircumstancesApproval under exceptional circumstancecan only be applied to drugs where it isdeemed impossible ever to collect com-prehensive data due to rarity or because itis contrary to medical ethics, or the stateof scientific knowledge does not allowsuch data to be collected. The CMA pro-cedure can be used to give early approvalto drugs that can show a positive bene-fit–risk before the comprehensive dataset is available, leaving the supplementaryclinical data to come later.

The Agency. Decisions on which new drugs will make it to the EU market and which won’t are madehere at EMEA’s headquarters in Canary Wharf, London

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Collection of further pharmacovigi-lance data can also be required.

Quite how this will translate intopractice, and the implications for can-cer patients, drug developers, andhealth providers, depend heavily onhow these broad-brush requirementsare interpreted.

Will there have to be data from arandomised trial? Will the new thera-py need to be compared against bestcare or a placebo? Could it be enoughjust to show the response in a single-arm trial? Will drug sponsors have toshow which target is being hit, andidentify the group of patients who aremost likely to respond? How manypatients will be required for data onefficacy or safety? Will the drug needto show clinical benefit on survivalor symptoms? If ‘surrogate endpoints’are used (see box), what level of cer-tainty will be required to show that thesurrogate is reasonably likely to pre-dict clinical benefit?

There are also questions about post-approval study requirements. Whatsort of studies will be asked for, andwhat will happen if a drug sponsordoes not fully comply? Will CMA bewithdrawn if the post-approval obliga-tions are not fulfilled?

Three main stakeholder groups will beaffected by the way EMEA addressesthese questions: patients who have runout of other options, drug developers,and the general public.

THE PATIENT – A LIFELINEWhat matters to patients is access toeffective drugs as quickly as possible,through ‘conditional’ approval or anyother route, such as participation inclinical trials or compassionate useprogrammes. Safety is not the primaryissue for many of them, who are facingthe prospect of death or a very impairedquality of life anyway. They wouldprobably set the risk–benefit hurdlefairly low. This translates into acceptingless demanding trial designs, and allow-ing benefit to be measured in terms, forinstance, of tumour shrinkage, whichtends to be quicker to measure, butmay not accurately reflect true or sus-tained benefit in terms of survival orquality of life.

Precise identification of the targetgroup will not be a major priority. If thedata indicate that the drug is effectivein one in ten patients with a given indi-cation, most patients would at leastlike the option of ‘giving it a go’, par-ticularly if side-effects appear encour-

aging. Patients are likely to be verysupportive of any studies that couldthrow further light on how and inwhom the drug in question works best– but not at the cost of delaying access.

THE INDUSTRY – QUICKERRETURNSThe second group of stakeholders arethe sponsors of experimental drugs,principally pharmaceutical companies.Kapil Dhingra, vice president of theoncology division at Roche, speaking atthe European Society for MedicalOncology (ESMO) last October, wel-comed the new approval, and said theapproval of sunitinib was “a good start”.He characterised the main advantagesfor the industry as early certainty abouta drug’s launch, and early return oninvestment.

The July 2005 issue of RegulatoryRapporteur said that early approval maybe particularly important for biotechcompanies, which play a key role indeveloping molecularly targeted ther-apies but don’t always have theresources to conduct long and expen-sive phase III trials.

Financially, then, this would be agood deal for the industry, good forshareholders, and good for the rest of usif lower costs stimulate innovativeresearch or result in lower prices andmore thorough research into new drugs.

From the developer’s point of view,the guiding principle on approval is‘the earlier the better’. In general, theywill be looking for the number ofpatients and the length of timerequired to prove efficacy and safety tobe set somewhere at the lower end ofthe scale, and they will want EMEA toadopt less rigorous measures of effica-cy. Rather than having to show sur-vival data, which can take a long timeto collect, the industry would preferCMA to be granted on data aboutresponse rate (tumour shrinkage), time

SURROGATE ENDPOINTS

Surrogate endpoints are measurable variables deemed likely to predict clinically meaning-ful endpoints such as longer survival or reduced symptoms. They can be quicker to evalu-ate than clinical endpoints, but their predictive powers are not very accurate. CMA is likelyto rely heavily on data from surrogate endpoints, with the option of requesting post-approval studies to see how this translates to clinical endpoints.

Traditionally, a limited group of surrogate markers have been accepted on a case-by-casebasis, including response rate (tumour shrinkage) and time to progression or progression-free survival. These may, in the future, be extended to include functional imaging, such asmeasures of apoptosis/antiproliferative effects, and also pharmocodynamic biomarkers suchas PSA as a marker for prostate cancer or CA 125 for ovarian cancer. However, statisticalvalidation of these sorts of surrogate biomarkers is proving very difficult.

DrugWatch


to progression (how long the drugkeeps the disease at bay), functionalimaging (imaging levels of cell death orcell proliferation) or biological markersof efficacy.

The industry also has a view onpost-approval studies. Once a new drugas been approved, pharmaceuticalcompanies will want to move on. Theyhave little interest in tying up resourcesin research that may offer little finan-cial benefit and may even diminish themarket as research identifies whichsubgroups of patients respond best.

There are also ethical and logisticalproblems to conducting such studies aftera drug has reached the market. Patientsoften join a trial of an experimental drugin the hope of being randomised toreceive the new treatment. Once thedrug is on the market, joining a ran-domised trial actually decreases theirchances of getting the drug which theycould otherwise have on prescription.

At the ESMO meeting, Dhingrastressed the need to have a very cleardefinition of the clinical objectives,scope and timelines for post-approvalstudies, and said that EMEA needed totake account of what was feasible.

THE PUBLIC – EFFECTIVETREATMENTAs a third stakeholder, what the generalpublic wants amounts to efficacy andefficiency. As potential patients, theywant a system that encourages drugdevelopers to find effective therapiestargeted precisely at the specific malig-nant phenotype driving the cancer.They want the treatments that can bedelivered in the most effective sched-ule, dose, combination, and method of

administration, and they don’t want totake therapies that might be of no ben-efit for their particular disease, butmight have nasty side-effects.

As tax, medical insurance or treat-ment payers, the public does not wantto foot the bill for prescribing anincreasing number of highly expensivedrugs to broad populations of patientsif only a minority are likely to benefit,and if clinicians do not have the infor-mation to use them to greatest effect.

A group of researchers at the MarioNegri Pharmacology Research Institute,in Milan, argue that EMEA and its UScounterpart, the FDA, have “a major rolein improving public health, as they fallbetween clinical trials and (public) healthcare” and that “drugs must be rapidlyreleased for patients who need them,but not at the expense of adequate knowl-edge about the benefit of the drugs.”

Their paper, published in the BritishJournal of Cancer (vol 93, pp504–509),analyses the basis on which EMEA hasapproved drugs for solid cancers over the10 years since centralised marketingwas introduced in 1995, and argues forraising the standard of proof, particular-ly for clinical benefit.

Looking only at applications fornew drugs or for extended indicationsfor therapies for solid tumours, theypoint out that response rate (usuallygiven as the percentage of patientswhose tumours shrunk by at least50%) was used as the primary basis forgranting 30 out of 48 approvals, butthat, in cases where data were avail-able, this translated very poorly intosurvival benefit. In 13 cases for whichsurvival data were also given, the ben-efit ranged from 0 to 3.7 months, with

mean and median benefit of 1.5 and1.2 months.

The authors also point out that 30%of approvals were given on the basis ofsingle-arm trials, despite the advice inEMEA’s own Note for Guidance ‘Eval-uation of anticancer medicinal prod-ucts in man’ (2002). This says thatrandomised comparative trials are nor-mally always required, with no com-parative trials being consideredacceptable only in the case of pre-treated patients when no establishedregimens exist.

In the US, more than 90% of post-approval study commitments remainedunfulfilled according to a 2005 FDAreport. The Mario Negri researchersconclude that the public interest isbest served by keeping the efficacyhurdle higher, rather than relying onpost-approval studies to come up withmore robust data.

They argue that EMEA should insiston seeing overall survival data in combi-nation with formal assessments of symp-tom control or quality of life. Theseassume greater significance given therather small median survival benefit of1.2 months offered by drugs for solidtumours approved over the past 10 years.

On the question of trial design,they make the case that there shouldbe a requirement for phase II ran-domised trials, with patients ran-domised to the new drug or to bestavailable care. They also argue thatphase III comparative trials should bethe norm for the approval of new anti-cancer drugs, with phase II studiesonly accepted in exceptional cases,when there is really outstanding,unprecedented or unexpected activity.

Response rate was the basis for 30 out of 48 approvals,

but this translated very poorly into survival benefit

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seeking approval for a targeted drugshould not expect to get approval for itsuse in an unselected population.

A key paper published in the NewEngland Journal of Medicine two yearsago (Roberts and Chabner, vol 351,pp501–505) argued that it may beunrealistic to expect pharmaceuticalcompanies to carry out these studies,as they can be very complex, time-consuming and are likely, at least in theshort term, to diminish the market fortheir drugs.

For the US, they proposed a mecha-nism for ‘selective approval’ wherebyearly approval could be granted, “only ifthe sponsor has initiated studies to iden-tify subgroups of patients who are likelyto have responses.” The regulators anddrug sponsors would reach agreementover how the studies could be conclud-ed, with an option of forming a partner-ship with a public body such as the USNational Cancer Institute or an aca-demic centre, with a certain percentageof profits from the early marketing of thedrug set aside to fund this research.

Sadly, Europe has no equivalent ofthe NCI. However, there are manyinternational cooperative groups, aswell as the European Organisation forResearch and Treatment of Cancer orthe French National Cancer Institute,INCa, which recently launched a post-approval trial (PHARE) to find outmore about the best way to use adju-vant trastuzumab (Herceptin).

THE VIEW FROM EMEAFaced with these potentially conflictingpressures from patients with unmetneed, from the industry and from thepublic interest, how is EMEA going to

To ensure that the regulatory processtakes into account the needs ofpatients for whom experimental drugsmay be their only hope, the researcherssuggest greater patient involvement inthe EMEA evaluation process to helpidentify which drugs really need fast-track designation. They also emphasisethe importance of effective informationto spell out to patients the risks of a par-tially proven therapy.

SELECTIVE APPROVALCurrent understanding about the com-plexity of cancer and of mechanisms ofaction and of resistance to drugs sug-gests that the disappointing clinical ben-efit shown by many drugs in the abovestudy may indicate not that the drugs areineffective, but that they are effective inonly a small part of the population theywere tested in. The worry is that thegreat promise of the era of individuallytargeted treatments may never berealised if therapies are marketed early,with insufficient information aboutselection of the target group, especiallyif nobody takes responsibility for thenecessary post-approval work.

The experience with gefitinib(Iressa) for non-small-cell cancer isoften cited to illustrate the problems.Rejected by EMEA because of lack ofsurvival impact in an unselected popu-lation, the drug has since been found tobe effective in a certain very specificsubgroup. Makers AstraZeneca claimit would have been almost impossible toidentify this target group had the drugnot been on the market, and thus wide-ly used, in the US and Japan. Manyvoices from the national regulatory agen-cies, however, believe that companies

implement the CMA regulation? Sofar, the approval of sunitinib is all thatanyone has to go on, because EMEA isstill in the process of drawing up draftNotes for Guidance. However,Francesco Pignatti, Scientific Admin-istrator at EMEA, agreed to share hispersonal views with CancerWorld.

Pignatti stresses that CMA requiresproof of a positive risk–benefit bal-ance. “Some people understand CMAas putting drugs on the market withoutknowing their efficacy, and that is notwhat is meant by conditional approval.I think that even for CMA it is crucialthat a drug is only ever put on the mar-ket when EMEA’s scientific committeehas judged that, based on the evidenceavailable, the benefit–risk balance ispositive The draft of the regulationstarted off saying the benefit–risk is‘presumed positive’. Now that wordhas gone from the final legislation.”

He accepts, however, that, despitebeing as objective as possible, assessingthe risk–benefit balance is not anexact science. “One needs to expressvalue judgements on multidimen-sional concepts – benefits, risks –each estimated with variable degreesof uncertainty. Without comprehen-sive clinical data, as for CMA, thereal challenge is to identify situationswhere it is still possible to conclude ona positive benefit–risk balance.”

Given the subjective nature of thejudgement, patients will need to havea strong voice in the regulatory processto ensure their voice is heard. Tradi-tionally, Europe has lagged far behindthe US in this respect, but EMEAhas been trying hard to catch up. AWorking Group with Patients and

EMEA is moving away from the ‘gatekeeper’

model towards more constructive communication

DrugWatch


Consumers Organisations now enablesthese groups to have a formal consul-tative role. Though for some patientsthis falls far short of the partnershipthey would like, the European CancerPatient Coalition and other patientgroups have welcomed the move.

Pignatti sees a cultural shift awayfrom the ‘gatekeeper’ model towards aconstructive communication amongstakeholders more appropriate totoday’s rapid progress of basic scienceand cancer therapies. “In this context,CMA makes a lot of sense – it weighsthe need for a comprehensive clinicaldevelopment with high unmet needand public health interest in gettingbeneficial drugs quickly to patients indesperate need.”

Pignatti envisages the use of surro-gate endpoints so long as they are con-sidered “reasonably likely” to predict aneffect on a clinical endpoint such assurvival, and so long as the effect on thesurrogate is great enough. “There aresome surrogates where the predictionis sufficiently high that if the effect isbig enough, and looking at all the sup-portive evidence, you know that it willbe very likely also to mean something interms of clinical benefit.”

MINIMUM DATA SETSAsked about what he would envisage tobe the minimum specifications interms of trial size and design requiredto grant approval, Pignatti said, “It isnot about the minimum. It is about giv-ing yourself the chance in a compre-hensive development of deciding atwhich point there could be sufficientevidence to go for approval.”

He is cautious about spelling thingsout in detail, because there are so manypossible variables: the rarity of the indi-cation, the level of toxicity, whetheralternative therapies are currently avail-able, whether the drug shows dramaticor less-pronounced activity and so on.

He recognises, however, that the win-dow of opportunity for performing arandomised study in a certain indicationmay only exist before approval, and heventures some general comments.

“To aim for early approval, oneshould randomise early in the clinicaldevelopment. Preference should begiven to study designs and endpointsthat can capture convincingly a clinicalbenefit as early as possible. In the stan-dard approach we would certainly say‘do a randomised trial, and if appropri-

ate plan for an interim analysis whenyou have a sufficient number ofpatients when it is meaningful to drawsome conclusions, in case the treat-ment effect is much larger than initiallyexpected.’

“I would not recommend a strategyfocussing on single-arm studies forapproval. However, if one happens toobserve a dramatic effect in a single-armstudy, it may be that randomised trialsare no longer needed. But this shouldbe the exception, and there may be

THE SUNITINIB PRECEDENT

Sunitinib is the only drug so far approved by CMA. Trial designThe demonstration of efficacy in patients with metastatic renal cell carcinoma (mRCC) whowere refractory to prior cytokine therapy with interleukin-2 or interferon αwas based on theproportion of patients achieving an objective response observed in two single-arm studies.The studies were conducted in a homogenous group of progressive patients with a predictableoutcome of the disease. ResultsThe estimated proportion of responders was 36.5% (95% CI 24.7%–49.6%) and 35.8% (95%CI 26.8%–45.7%).EMEA’s opinionEMEA’s Committee for the Evaluation of Human Medicinal Products (CHMP) considered theeffect in terms of tumour shrinkage to be unprecedented, even with the most active availableagents in a non-refractory population for which response rates in the order of 5 to 15% havebeen reported. They found that the efficacy results provided sufficient confidence to believethat treatment with sunitinib would translate into some effect in terms of progression-free sur-vival or overall survival in patients who have failed prior cytokine-based treatment, althoughthey were unable to assess the exact size of the effect on these clinical endpoints. Post-approval studiesAt the time of approval, the CHMP considered that data from an ongoing randomised trialof sunitinib as a first-line treatment in mRCC patients could help to confirm that treatmentwith the drug is associated with an effect on important clinical endpoints. Although theongoing trial involved an active control and patients in an earlier stage of treatment, basedon pharmacological and biological grounds, the demonstration of a favourable effect as afirst-line treatment would be considered relevant also for patients with mRCC who have failedprior cytokine-based treatment. This would confirm the existence of an effect in terms of rel-evant clinical endpoints even if the precise magnitude of this effect would not be known.Upgrading to full approvalThe randomised trial has now been completed and in October EMEA’s Committee for Med-icinal Products for Human Use recommended that sunitinib’s CMA should be upgraded tofull approval, with the approval being extended to cover first-line use in mRCC patients.

DrugWatch


different perceptions about what con-stitutes a ‘dramatic’ effect. Indeed inour experience, lack of an adequatelyrandomised controlled trial has beenan important reason for rejection.”

A look at EMEA’s track record,however, shows that 16 (44%) of the38 oncology new drug applicationsthat were granted marketing authori-sation in the last 10 years wereapproved on the basis of single-armtrials, and Pignatti acknowledges thatthis is an issue of concern in somequarters.

In the case of sunitinib, approvalwas based on the results of two single-arm trials. There were, however, earlysupportive data from an ongoing ran-domised trial in a different category ofpatients. Completion of that ran-domised trial was one of the condi-tions EMEA set for giving sunitinibconditional marketing approval.

A POWERFUL TOOLThe power to set these sorts of condi-tions is something new for EMEA.How that power will be used is one ofthe big question marks relating to thenew approval procedure.

Pignatti points to the second cri-terion under the Requirements sec-tion of the implementation regulation,that it must be “likely that the appli-cant will be in a position to provide thecomprehensive clinical data,” (post-approval), and he argues that gettingagreement with the drug sponsorsover what studies are feasible andappropriate will be key to overcomingcompliance problems.

He is clear that there will be strictlimits to what post-approval studies

are asked for. “You shouldn’t be impos-ing more requirements than neces-sary. So if for instance we have a drugthat works in refractory disease, andthen we are interested in knowingwhether it would also work early on,that should not really be a CMA typeof question. But if we have someuncertainty in the indication in whichit is currently approved, and we thinkwe could extrapolate information froman earlier indication to reduce thatuncertainty, then we can ask thatquestion.”

This is what was done in the caseof sunitinib (see box, p27).

Regulations are being drafted thatwill allow EMEA to impose fines fornon-compliance. Doubts have beenexpressed in some quarters overwhether financial penalties are anappropriate way to deal with issueslike clinical trials, and time will tellhow much use EMEA will make ofthese powers. Pignatti is clear, how-ever, that although approval is condi-tional on the required studies beingcarried out, no drug approved viaCMA (i.e. positive benefit–risk hadbeen established) would be with-drawn from the market purely becausethe conditions were not fulfilled.

The key, he believes, is to ensurethat patients and prescribers under-stand the implications if a therapythey are using has conditional ratherthan full marketing authorisation.

In the case of sunitinib, the infor-mation says: “This medicine has beengiven ‘conditional approval’. Thismeans that there is more evidence tocome about this medicine, in partic-ular in the treatment of kidney cancer.

Sutent [sunitinib] has shown to shrinkthe tumour. However, more informa-tion is awaited on the duration of thiseffect. The European MedicinesAgency (EMEA) will review newinformation on the medicine everyyear and this leaflet will be updated asnecessary.”

Pignatti believes that this kind ofclear information to physicians andpatients will be an incentive for com-panies to finish the required post-approval studies to upgrade tostandard approval.

Is it realistic to rely on clear com-munications to make the regulatorysystem work, or will EMEA’s voice bedrowned out by the heavy guns ofpharma advertising, at least amongthe non-specialists who are stillresponsible for prescribing cancerdrugs in many parts of Europe?Should CMA be used sparingly toavoid non-compliance, and if so,what of the patients who need quickaccess to new therapies? Once posi-tive risk–benefit has been proved tothe standard required for CMA, hasEMEA any business demanding anyfurther data? But if they don’t, thenwho has responsibility for carryingout the trials needed to find out howbest to use the drugs and in whom?

Clinicians, patients, health admin-istrators, policy makers and membersof the public who have an interest inthe new drug approval regulationsshould look out for the draft Notes forGuidance document scheduled to bepublished on the EMEA websitewww.emea.eu.int. It will be a consul-tation document, and EMEA wantsyour views.

No drug approved via CMA would be withdrawn purely

because the conditions were not fulfilled

BestReporter


From plan to practice

The French Cancer plan of 2003 raised expectations among the public and patients.This

article, which looks at how a key measure is being implemented in practice, was one of several

stories that earned Paul Benkimoun recognition in the 2006 ESO Best Reporter Awards.

Bad news will always be bad news, butthe way it is told makes a big difference.Throughout the year, some 37 pilotschemes running in 58 institutions havebeen trying out a novel way of breaking

the news of a cancer diagnosis that was developedin conjunction with patients. It aims to improve theconditions under which patients are notified oftheir condition and told about thetreatment they will be given. As thepilots started gradually, full results areyet to be obtained. And the pilotschemes are set to be extended to allthe sites treating cancer during thesecond half of the year.

In 1999, the White Book of theNational Anti-Cancer League car-ried testimonies from people whowere disgusted by the off-hand orbrutal manner with which they weretold of their illness. A symbol of thebattle of patients, the improvement of the conditionsunder which news of the diagnosis is notified, wasnumber 40 in a list of 70 measures of the CancerPlan, launched in March 2003 by [President]Jacques Chirac.

A budget of 3.2 million euros was allocated,amongst other things, to pay for the creation of newnursing jobs. Another 15 million euros were set asideto extend the scheme in 2005, a sum that will haveto be revised in 2006. The project was geared up toinclude 25,000 to 30,000 patients throughout theyear. Ten months into the trial, some 15,000 peoplehave taken part in the system, which is piloted by theNational Cancer Institute in tandem with the

National Anti-Cancer League and the Directorateof Hospitalisation and Care Management.

“YOU DON’T KNOW ANYTHING” The trial relates to the notification of the diagno-sis, or its confirmation, but also to “the proposalfor a treatment plan” decided at a multidiscipli-nary meeting, and to “the provision of a team of

carers” including a psychologist anda social worker, as laid down in thespecifications.

Patients can find familiar con-tacts within the system, and in thecase of the reporting nurse, some-body who is more accessible than adoctor.

“The consultation with the nurseis a sort of ‘emotional catharsis’ for thepatient and a time when medicalterms will be translated into less aca-demic language than is used by a

doctor,” said Professor Henri Pujol, president of theNational Anti-Cancer League. “We feel physically,and also intellectually, diminished. We don’t knowanything when faced with the doctor, the one whoknows,” commented Henri Gontier, a memberof the patients’ committee at the Institut Paoli-Calmettes (IPC) in Marseilles.

“In the case of tumours whose location ishighly symbolic, such as the brain, you cannot justsay straight out: You have a brain tumour,” explainsDr Olivier Chinot, of the neuro-oncology unit atthe Timone University Hospital, in Marseilles, whois highly involved with paramedical staff in thesetrials. “Often patients do not ask the prognosis.”

This article was first published in Le Monde, 20 April 2005, and is reprinted with permission

BestReporter


Watchdog. Articles like this, which explore how farcommitments to cancer patients are actually being translatedinto better services for all, put pressure on health services to deliver, and let patients and their families know what they have the right to expect

“They or their family ask us,” elaborates SoazicDuval, a nurse in the same department. “Bearing inmind the loss of independence that results frombrain cancer, we have to take into account from thestart the friends and family of these patients, whoare often young,” adds Bruno Tivoli, the hospitalexecutive who implemented the new system at laTimone teaching hospital.

Patients are also more likely to speak to thenurse about matters deemed ‘delicate’, or too banalto raise with the doctor. It is at this point that manypatients discover that, in addition to causing themto lose hair from their head, chemotherapy oftencauses the loss of pubic hair. The matter of wigs isfrequently broached.

As a by-product of these pilot schemes on thenotification of cancer diagnoses, doctors have learnedthe value of information gathered by paramedicstaff. “We had not sufficiently questioned the ambu-lance drivers, who take patients home, about thesickness caused by chemotherapy,” acknowledges DrJacques Camerlo, trial coordinator at the IPC.

“A TURNING POINT”A notification system also calls for a rapproche-ment between hospital doctors and their colleagueson the outside. The general practitioner (GP) is, infact, involved in informing the patient of the diag-nosis. “A general practitioner from Marseilles toldme: ‘When I refer a patient to the Institut Paoli-Cal-mettes [specialist cancer centre], don’t you thinkthat I have held a patient notification consulta-tion?’,” says Dr Camerlo. “The GP needs to beinformed very quickly,” urges Dr Christine Bara,from the National Cancer Institute, who statesthat three-quarters of patients go to see their GPimmediately after the notification consultation.

The pilots of the project know that making thescheme universal will not be simple. Even in Mar-seilles, often cited as an exemplary case, things havenot always been simple. “Some doctors from la Tim-one University Hospital have had the honesty to saythat they did not want to take part. Some give theiragreement, but only send us one follow-up sheet permonth,” says Professor Pierre-Henri Juin, who hasbeen coordinating the experiment there for a year.

It is clear that there is a need “to proceed gen-tly and with flexibility”, as Christine Bara says. “It isa question of a qualitative approach. We must avoida purely administrative application of the system,”she adds. If you try to act on the frequent requestfrom patients that notification consultations shouldno longer be held on Friday, leaving them on theirown throughout the weekend, then you will prob-ably have to take into account the problem of avail-ability of doctors.

Flexibility is required, but also determination.“Patients have worked on this for four or five years.Therefore they are expecting changes. This will bea turning point in the relations between doctors andpatients,” predicts Professor Pujol. He agrees withDr Bara that further consideration needs to begiven to four areas: paramedical consultation, theinteraction between the local community and thehospital, the identification of psychological andsocial needs, and the personalised treatment plan.

Some practitioners look further ahead. “We willundoubtedly have to come up with an end-of-treat-ment system, as patients often collapse psycholog-ically when they are no longer cared for as closely asduring the treatment stage,” observes ProfessorDominique Maraninchi, director of the IPC andchairman of the science board of the National Anti-Cancer Institute.

BestReporter


Marie-Noëlle, 48 years of age, operated on in February:

“What are my chances?”She knew it as she pushed open the door to her GP’s office.In fact, she knew it when she felt a lump as she examinedher breasts one day in September 2004. Marie-Noëlle M.,48 years of age, was operated for breast cancer on Febru-ary 4th, at Martigues Hospital.

One month later, Marie-Noëlle pushes open the doorof the consulting room at the Institut Paoli-Calmettes inMarseilles, a regional anti-cancer centre, where JacquesCamerlo is waiting for her. This doctor coordinates the localpilot programme for the new cancer notification system.“We are going to go back over everything and reformulateeverything,” he announces.

Before starting to examine her, Jacques Camerlotalks to her about her illness: “Breast cancer is a commondisease which affects one in nine women. It can becured and removed if various stages and treatments arecomplied with.” Marie-Noëlle interrupts the stream ofexplanations and details: “No-one ever explained that tome,” or “that’s not much fun,” when the subject ofchemotherapy is broached.

She has clearly thought about her illness a great deal.Some questions are very specific: “Am I going to have a wig?”Other questions are more fundamental: “What are mychances of really getting better?”

Jacques Camerlo answers, without beating about thebush: “The treatment that you will have will make it possi-ble to get rid of the disease. We will have done everything inorder for you not to need to come back to see us. You will havemore than a 70% to 80% chance of it not coming back.”

Marie-Noëlle’s two sons, aged 27 and 25, are verywell-informed, as is her husband. “I want my children tocontinue with their lives as normal,” she says. “I don’t wantthem to be watching over me too much.”

A little later, she confides: “I am a worrier by nature,especially about others.” Jacques Camerlo tells her: “Takecare of yourself first. Your day-to-day, social and emotion-al life must continue normally. The side-effects of thetreatment are temporary and reversible.”

“ Call me”The doctor describes the different stages of the six-month treatment plan awaiting Marie-Noëlle –

chemotherapy sessions every three weeks, then dailyradiotherapy for four to six weeks. He gives her thenames of the doctors who will be involved. He then tellsher of the various possible side-effects of the treatment,and the symptoms that she should watch out for – par-ticularly any signs of a fever, as the treatment will severe-ly compromise Marie-Noëlle’s immune system. “I amgoing to need a computer to remember all that,” she quips.

Having summarised her forthcoming phases of treat-ment in a document entitled “Theoretical treatment plan”,which he gives her, and having dictated in her presence aletter to the doctor who referred her, Jacques Camerlo intro-duces Marie-Noëlle to Jean-François Cailhot.

Cailhot, a nurse, coordinates the care of women beingtreated for breast cancer at the Institut Paoli-Calmettes.“Whatever the problem, call me, I will put you in contactwith the people you need,” he says, giving her his card.

The nurse asks Marie-Noëlle what is the main problemthat she is concerned about. “Losing my hair”, she answersimmediately, adding: “I have already found out aboutwigs.” He tells her that her hair will start to fall out at thestart of the second week of treatment, and mentions thevarious models of wig, reminding her that a hairdresser isavailable at the Institute.

Next subject: side-effects. His advice relates to everydaylife: “You will be given drugs, but we cannot predict how youwill react. Try not to plan too many activities during the threedays following the chemotherapy session,” he stresses.

Mentioning the possibility of a fever, he recommends:“Somebody must be available to bring you here 24 hoursa day, 7 days a week. You must keep the phone numberof a taxi or an ambulance on you and a packed suitcase. Itdoesn’t happen often, but …”

He reminds Marie-Noëlle that a psychologist and asocial worker are at her disposal, and that she does not haveto pay for her transport to the Institute for the chemother-apy sessions. He concludes by giving her an informationleaflet on breast cancer.

Feeling a mixture of resignation and satisfaction, fol-lowing this initial contact with those who are going to steerher through her six months of treatment, Marie-Noëlle pre-pares to return home. She will soon be back.

Masterpiece


Tackling cancer the Tunisian way

Ü Jim Boumelha

Farhat Ben Ayed played a key role in building Tunisia’s cancer services, armed with little

more than a solid education, a sense of duty and a remarkable talent for motivating others.

Fighting cancer, he believes, is a question of citizenship and solidarity, and limited resources

cannot be allowed to stand in the way.

Rising life expectancy, swift urbanisationand major changes in dietary habits allpreface an inexorable rise in cancer.

Tunisia fits this description. With 10,000 newcases a year, this small country is on a risingcancer curve. With the limited resources of acountry in transition, it is about to cross itsRubicon.

Unlike many countries moulded by similarhistorical events (the French occupation ended50 years ago), Tunisia has no army to speak of,investing its human capital in education andhealth. Tunisia’s health budget tops 8% ofnational spending.

This is perhaps one reason why ProfessorFarhat Ben Ayed, the father of Tunisian oncolo-gy, is in an almost permanent state of reflectionon the meaning of the fight against cancer, inparticular with the cost “of what has alreadybeen done and what we have failed to accom-plish”. It is also a reason why equality of treat-ment has become almost an obsession. Hiscommitment to cancer patients is a commit-ment to people’s rights. “The fight against cancer

for me is not just a question of specialists, butmost crucially an issue of citizenship.”

In identifying risks and setting out strategiesto improve prevention and early detection, todevelop new therapies and to improve socialrehabilitation, Ben Ayed is careful not to followblindly the example of Europe. “We have differ-ent priorities. Our top priority is the fight toreduce tobacco consumption because lung can-cer is the number one killer in our country. It can-not be breast cancer detection, where we arehampered by the fact that it is most prevalentamong the under 35s, making it difficult toscreen. With our foreign friends we discuss con-tinuously what kind of projects we need toadvance, what can or can’t be achieved and,most importantly, what can we do to affect themaximum of people.”

With 25% of cancer patients coming for-ward at such a late stage that curative treatmentis no longer possible, it has been necessary todevelop psychosocial support for individualsand families living with cancer. In the Tunisiancontext, oncologists have also to grapple with the

Masterpiece


ent state of thinking, it does not justaffect the individual, but has animpact on the family as a whole.The whole family is weakened;their social status goes down, acutedepression follows.”

Patients are developing higherexpectations, both in terms ofwhich cancers can be cured andwhat happens to patients when acure is not possible. Palliative careand the concept of a hospital with-out pain have become the norm.Thanks to a monopoly on importa-tion of drugs, the state-owned Phar-macie Centrale makes most drugs,including all types of opiates, wide-ly available, putting Tunisia aheadof many other Arab countries in itsability to deliver pain relief.

Although Pharmacie Centraleimports most of the newer cancerdrugs, Ben Ayed stresses that muchof the progress, in particular in pae-diatric oncology, has been achievedby making better use of old drugs.The top priority must remain theoverall interest of all patients andnot just a privileged few, he says.Tunisia has not the means to gam-ble precious resources on a treat-ment that can only be used for 8%of patients.

The strong arm of the statemakes a difference for both drugs and infra-structure – most hospitals are now equippedwith scanners and there are six MRI machines inTunis alone – but there is an acute need to fur-ther develop the national cancer plan, so that itdoes not remain the sole property of the cancerspecialist. Ben Ayed argues that the involve-ment of citizens is a major missing component.

“Top priority must remain the overall interest

of all patients, not just a privileged few”

notion that cancer is a punishment. The firstand most crucial action has been to focus ondemystifying cancer which remains a taboosubject. Tunisian families live in such a fear ofthe disease that they cannot bring themselvesto call it by its name.

“We are struggling to convince families thatcancer is just like any other disease. In the pres-

Masterpiece


Unlike oil-rich countries in the Arab world,Tunisia has no petrodollar reserves. Pioneerslike Ben Ayed organise the fight against cancerwith few resources, armed with a solid educa-tion, a sense of duty and exceptional organisa-tional wizardry in the art of motivating others.Partly as a result, Tunisian oncology punches farabove its weight.

Ben Ayed learned two things from his child-hood – he assimilated from his home island ofDjerba the art of being a hard taskmaster and,from his parents, a sense of giving without expect-ing anything in return.

He set out to study philosophy but convertedto medicine once he saw his older brother inaction – Si Hassouna was to become the firstTunisian nephrologist. Ben Ayed enrolled at themedical school in Montpellier, France, and con-ducted his postgraduate diploma at Tunis and theGustave-Roussy Institute, in Villejuif, France.

Ben Ayed came home with a mission – to helpbuild the foundation of medical oncology inTunisia. He worked to strengthen the first andsecond pillars of this work, cooperation with theoutside world and the Tunisian Cancer Institute(now called Salah Azaiez). The third pillar, the

Farhat Ben Ayed talking to patients at the Eddar Hospice in Tunis

creation of an association to fight cancer, iswhere he has concentrated his efforts for the last20 years.

Over two millennia, Tunisia has been invadedby Vandals, Phoenicians, Greeks, Romans andArabs. In modern times, it became a province ofthe Ottoman Empire and later a French colony. Itis not surprising to find a tradition of cooperatingwith others profoundly ingrained in the coun-try’s psyche and within the scientific community.The French not only left a substantial legacy, butcontinued to play a major role in training Tunisianoncologists and helping the country develop itsinfrastructure.

Charles Nicolle, the first doctor to win theNobel Prize in Medicine while working on Africansoil (he discovered the transmission agent fortyphus), conducted his research from the PasteurInstitute in Tunis.

French oncologists gave the impetus in thelate 1960s to creating what was to become theSalah Azaiez Institute, the nerve centre ofTunisian oncology and the first cancer institutein the Arab world.

Ben Ayed shows great respect for the person-al commitment of French colleagues. “To be hon-est it was a generous cooperation. They gave somuch and never asked anything in return.”

His studies in France arose from a visit by aFrench team to Tunis during which he met JeanLouis Amiel, a leading oncologist at the Gus-tave-Roussy Institute, the beginning of a friend-ship that would last until Amiel died in 1985. “Wewent on to build an exceptional network offriends, people with an exceptional knowledge.This was the first step for us in building ourknowledge of clinical oncology and understandingthe founding principles of biological oncology.From there on, there was no going back. I washooked into medical oncology.

“Many outstanding personalities like ProfessorAmiel became icons. He often travelled to Tunisas a friend not just as a colleague. And even today,after his death, when confronted with a thornyproblem we often try to imagine: what wouldProfessor Amiel do in such a case?”

The mix of professional and friendship tiesmeant that it was not difficult to involve col-leagues from institutes and hospitals all over

Masterpiece


France – Marseilles, Rouen, Lyon, GustaveRoussy Institute, St Cloud. A simple phone callwas enough to convince them to make the trip.The multidisciplinarity of the Tunisian cancerinstitute was in large part thanks to this input.

Other countries became involved. The Italianshelping to set up screening for cervical cancer andshort courses for doctors and interns.

Later, the training of trainers was taken up bythe French national anti-cancer league with thehelp of the UICC. A French NGO, Douleur sansfrontières, set up training to show general practi-tioners how to treat pain. International collabo-ration is still important. A soon-to-be-publishedreport on the epidemiology of cancer of the larynxorganised by the International Agency forResearch on Cancer (IARC) brought togetherresearchers from Tunisia, Indonesia, Canada,China and France. Tunisia is also involved in anumber of international phase II and III researchprojects.

Tunisian oncologists also recognise the need tobuild horizontal links with colleagues from the restof the Arab world and the African continent. BenAyed has been building steps towards lastingcooperation between oncologists from theMaghreb (“the West”) – made up of Morocco,Algeria and Tunisia.

“The Maghreb is my top priority. We allreceived the same French training, which makesit easy for us to work together and communicate.So it’s not difficult to knit a web united aroundcommon options and joint work.

“Every year there are 70,000 new cases ofcancer – 30,000 in each of Morocco and Alge-ria and 10,000 in Tunisia. We are currently dis-cussing whether all these new cases arereceiving an adequate and correct treatment. Itwould be all too easy to find excuses because ofour inadequate resources. But this should notprevent us from researching, for example, thepsychosocial context – how to deal with the

quality of life in Tunisia and the rest of theMediterranean region.”

Ben Ayed is less optimistic about links withthe rest of the Arab world. He argues that theArab League has the necessary structures tolead the fight against cancer in the region, butsays that this is inhibited by rivalries betweencountries.

Tunisia would like to do more in the way oftraining for doctors from sub-Saharan Africa.Lack of international recognition for Tunisiandiplomas means that there is little incentive forAfrican doctors to do their training here. Howev-er, strong links have been built with French-speaking countries in West Africa.

None of this cooperation would have takenshape without the Salah Azaiez Institute as theengine driving the fight against cancer in Tunisia.Since its inception in 1969, the Institute hasbased its structures, development and day-to-day practices on the Gustave-Roussy Institute,including administration, care and training.

However, the Tunisian approach to cancertreatment and care has evolved from local real-ities. “Our starting point was to cure every case.We realised very quickly that we could not. Thisis one reason why developing palliative carebecame a prime dimension of our work. It isthrough training specialists in the treatment ofpain and in palliative care that we managed toopen the door for the training of paediatriconcologists. It has also led to the development ofpsychosocial support for individuals and familiesliving with cancer.”

The Institute has revolutionalised the teach-ing of cancer at the Tunisian medical faculty. Forexample, paediatric oncology was not recog-nised as a specialty at the faculty until it waspracticed at the Institute. Today, Tunisian chil-dren’s hospitals all handle childhood cancers.The Institute also encouraged the publication ofhigh-quality research reports by Tunisian teams

“It would be all too easy to find excuses because

of our inadequate resources”

Masterpiece


on child lymphomas, breast cancers and othertopics, raising their international profile.

The Institute has influenced other regions ofTunisia – Sfax and Sousse are also developing asmajor cancer treatment centres. Multidiscipli-nary treatment, palliative care, psychosocialthemes, and research have become central pil-lars in the fight against breast, colorectal andlung cancer.

Many doctors are still sent abroad to learn newapproaches to treatment and care. A few stayaway, lured by better wages and prestige. However,most return with a renewed allegiance to theirhome country and find immense satisfaction inwhat they are doing. “When 80% of children arecured of cancer, isn’t it great to see some of themgrowing up and becoming doctors or engineers,”notes Ben Ayed with a smile.

He believes that an effective fight againstcancer rests on a partnership between the public,the private and civic society. “Every person has arole to play. Cancer is a question of solidarity.Everybody should join the fight.”

After years of developing medical approach-es to cancer treatment, Ben Ayed was spurredto greater action by seeing patients in distress.In 1987, with friends and co-thinkers, he cre-ated the Tunisian Association for the Fightagainst Cancer (ATLCC), and in 2000, theAssociation for the Promotion of Pain and Pal-liative Care.

In the hands of Ben Ayed, the ATLCC hasgrown into a humanitarian and scientific associ-ation with a public service brief, that also pro-motes teaching and prevention.

Thirty percent of cancers in Tunisia arelinked to the environment and 40% to tobacco,especially cancers of the lungs, throat and blad-der. The campaign against tobacco has becomethe top priority for the association. This rangesfrom efforts to convince farmers to replace tobac-co cultivation with other crops, to lively teach-in

“I admire the Canadians and Irish for their willingness

to confront the tobacco lobby”

sessions in partnership with the train companySNCFT on one of their busiest commuter lines.Indeed, ‘smokeless’ trains have become arenowned feature of World Anti-tobacco Day,attracting positive coverage on Tunisian pressand television (although they revert to being‘smoking’ trains the next day).

Ben Ayed is committed to change in a countrywhere virtually half of men smoke. (A WorldHealth Survey in 2003, showed that 49.5% of menover the age of 18 smoke, while only 2.4% ofwomen over the age of 18 do so.) He said: “Iadmire the Canadians and Irish for their willing-ness to confront the tobacco lobby and take effec-tive action. In Tunisia we have adequatelegislation, but nobody takes any notice. In arecent study we found that 95% of people are wellaware of the risks. Our aim is not just to informbut to change behaviours.”

He believes in the value of engaging childrenat school about the risks during special nation-al and regional anti-tobacco days. When chil-dren go home they take with them theknowledge and arguments they have heard – apowerful means to debunk myths with parentsand family.

Education, training and information are thebedrock of the ATLCC prevention strategy.Special programmes, such as palpation tech-niques for breast examinations, are aimed at thegeneral practitioner (GP), who is seen as thefirst line of defence. Ben Ayed believes thatthe GP must also be an educator and a com-municator.

National training days, conferences andseminars are other useful ways to reach spe-cialists. A two-day international seminar wasorganised in Tunisia by Ben Ayed and FrancoCavalli from Bellinzona, Switzerland, with theEuropean School of Oncology in December2005.

The ATLCC is often at its most creative

Masterpiece


Ben Ayed with Henda Raïs, the first doctor in Tunisia to be trained as aspecialist for pain and palliative care in cancer

able to take care of our needs and better manageour expenditure.”

The association has also focused on devel-oping palliative care, becoming the local chapterof the International Association for the Study ofPain.

It has found time to address ethical issues,bringing together a philosopher, a jurist, a nurseand a sociologist to discuss clinical research andtrials. Ben Ayed brought in his own expertise asa member of the French and Francophone Soci-ety of Medical Ethics at University Paris V.

He concludes that value judgements are notthe same everywhere. “Ethics concerns person-al behaviour but it is also a reflection of society.However, we found in the end no differencebetween different religions in their stand onethical questions.”

Ben Ayed is renowned for saying little andsaying it quietly. He abhors loud plaudits. Hegrapples with philosophical concepts and aspectsof humanity beyond what can be recorded oncharts and medical records. Without raising hisvoice, he sums up his quest: “I want Tunisiansnot to be afraid of cancer anymore.”

when raising money. It raised funds to buy thefirst mammography machine for the CancerInstitute and teamed up with a chemical com-pany to buy another for Gabès hospital in thesouth.

The success of the association shamed theauthorities into action. Treatment centresopened in Sousse and in Sfax. The Governmentalso released land to the association to buildEddar hospice. It was built with hard work anddetermination – a dinar here and a lorry-load ofbricks there – with Ben Ayed as motivator, cam-paigner and executive. He asked students at theschool of architecture to lend a hand with thedesign. He begged students elsewhere to sellpostcards for a year to furnish it.

Since its launch in 1993, the hospice haslodged more than 1,000 cancer patients, most ofwhom needed somewhere to stay during treat-ment in Tunis. Thousands of other patients havereceived financial help. Ben Ayed says that thetremendous wave of solidarity around buildingthe hospice grew stronger after it opened.“Scores of volunteers are involved day in, day out,in a loose support network. Some prepare thefood, others just give moral support.”

Now Ben Ayed has set his sight on building,with the help of the Ligue française contre lecancer and the UICC, an information centre tobe used by the public and the media, as well asby students and health professionals.

Leading oncologists do not often vacatetheir labs to negotiate deals with outside organ-isations. One of the most imaginative was withthe national train company. Backed by the can-cer institute, the association agreed to screenthe rail company’s female staff for cervical can-cer, in exchange for SNCFT agreeing to trans-port cancer patients to and from treatmentcentres free of charge.

Another idea was to recycle printer car-tridges, which raised awareness about environ-mental issues and paid for a mammographymachine.

Ben Ayed says: “With limited resources, theonly option open was to innovate and developactivities commensurate with what is achievable.In Tunisia everything is a priority, but this shouldnot be an excuse for doing nothing. We should be

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Not ( just) another declarationÜ Peter McIntyre

The World Cancer Declaration, issued in July, aims to mobilise efforts behind a limited

number of aims that will make a big difference and can be quickly achieved.

The World Cancer Declarationadopted at the UICC Congress inWashington this summer aims tobe different from other closingstatements – longer on actionthan in words.

Most conferences end with a declaration orstatement, and most vanish into the ether.Nobody has yet been cured of cancer, or even ofthe common cold, by rhetoric. Without hard slogto turn the rhetoric into action, conventionsand declarations are soon forgotten.

On the other hand, declarations can play avaluable role in setting agendas, focusing atten-tion on the main issues, and bringing peopletogether to work in the same direction.

The cancer world has had its share of bigstatements in recent years. In 2000, the WorldSummit against Cancer in the New Millenniumadopted the Charter of Paris. This adopted arights agenda, and focused on early detection,translational research, clinical guidelines, evi-dence-based medicine, quality of life andpatient advocacy. Most people remember anoth-

er outcome of the summit better than the tenarticles and preamble of the Charter, since thiswas the meeting that established 4 Februaryeach year as ‘World Cancer Day’.

In May 2003, the World Health Assembly(WHA), the global ‘Parliament’ of the WorldHealth Organization, opened the WHO Frame-work Convention on Tobacco Control for sig-nature. The FCTC came into force in February2005 and has become one of the most widelyembraced treaties in the history of the UnitedNations. This was seen as a declaration of waron the harmful effects of tobacco, and hasstrengthened international campaigns againstthe tobacco industry. However, the 38 Articlesand more than 9,000 words are not especiallymemorable. And many governments haveproved readier to sign it than to take actionafterwards.

In May 2005, the WHA, “alarmed by the ris-ing trends of cancer risk-factors, the number ofnew cancer cases, and cancer morbidity andmortality worldwide, in particular in developingcountries,” passed a landmark resolution on

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calls to action are admirably brief. It was theresult of widespread consultation and has thesupport of high-profile global intergovernmen-tal agencies. However, the Declaration wasessentially produced by NGOs, so it has natu-ral allies to work with it in every country.

The Declaration has a short shelf-life, sinceprogress will be monitored and reported to eachWorld Congress, after which it will be redraft-ed. It must therefore show results by the nextUICC Congress in Geneva in August 2008.

Relative simplicity was not easy to achieve.Responsibility for the early drafts rested with thehosts for the Washington Congress, the Amer-ican Cancer Society (ACS). Ten months inadvance of the Congress, the ACS and UICCtrawled a list of 250 experts worldwide for ideasabout what it should contain. Unsurprisingly,the first draft ran to 20 pages.

This draft went back to the experts and globalbodies (WHO, IARC etc) for comment. The

cancer prevention and control that set the agen-da for comprehensive national cancer controlplans in each country. For the first time theWHO declared cancer to be a priority issue forall governments. This has given a tremendousboost to global efforts on cancer, but the com-prehensive nature of the resolution and theplodding UN language, means that it is hardlya call to arms.

The World Cancer Declaration adopted atthe UICC World Cancer Congress in Wash-ington July 2006 sets out to fill the gap. It doesnot set a new agenda, but attempts to identifystrategic and urgent steps that cancer organi-sations and campaigners can address in theshort term. This is unashamedly an advocacydeclaration, designed to give a much higherprofile to cancer and to put it on the politicaland public agenda.

At under 1,000 words, it is less than half thelength of the Charter of Paris, and the nine key

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Anti-cancer vaccination.Adding Hepatitis B to childimmunisation programmeslike this one at the HaiLinh Commune HealthCentre, in Vietnam,will have a significantimpact on the incidence of liver cancer – one of the most prevalent cancersin some areas of the world

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second draft was even longer. Then began theprocess of simplifying and clarifying – it took sixor seven drafts to achieve the short version. Atthe Congress itself, participants were giventhree days to comment on the draft, and sug-gestions were made at a ‘World Leader Summit’– although the Declaration hardly changed atthis late stage.

Franco Cavalli, President of the UICC, saysthat brevity and clarity were key aims, as it isimportant that the Declaration is backed withaction. “Of course, the World Cancer Declara-tion is based on the Charter of Paris, but theidea was to have something which could havemuch more immediate results, to pick topicsthat seem to be the most important and urgentand to summarise them very briefly. The Char-ter of Paris is a declamatory declaration without

immediate consequences; here we are trying tohave consequences.

“It is not enough to have governments signingdeclarations, you need interventions from civilsociety to push governments to realise whatthey have written. Here the driving forces wereNGOs. We are trying to follow the example ofthe AIDS NGOs, which have been able to putthe topic of AIDS on the political and mediaagenda, which, alas, has not yet been the casefor cancer.”

Cavalli admits that he was initially sceptical,but is increasingly enthusiastic about the Decla-ration’s power to mobilise. He was at the ChineseCongress on Cancer in October, organised bythe two major Chinese associations. They fur-ther reduced the World Cancer Declaration tosix points, set priorities for combating cancer in

The Declaration was essentially produced by NGOs,

so it has natural allies in every country

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The next generation. Can we stop the sort of smoking epidemic that ravaged Europe and America a generationago from being replicatedin developing countries?

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China, and adopted it as “the Tianjin Declara-tion”. At a meeting in Bangkok in early November– Empowering Cancer Prevention in the AsiaPacific – the Declaration was also a topic fordebate in many of the sessions.

“What I am hearing is much more positivethan what I expected. I have the impression thatthis is starting to create a little avalanche whichis increasing speed. The fact that such a decla-ration has been launched is a sign of themomentum which is being created currentlyabout the emerging problem of cancer in thedeveloping world. There was an editorial byPeter Boyle in the Lancet and I published an edi-torial in the last issue of Nature Clinical PracticeOncology. This is part of a movement which isjust starting to roll.”

The Declaration says that it “requires part-nerships between governments, private sector,non-governmental organisations, and interna-tional organisations”.

Cavalli cites the PACT global partnershipthat brings together governmental and non-govern-mental entities involved in cancer control, as agood example. “There are different types ofpartnership. I think that the private sector is tobe understood mainly in the sense that NGOsand private organisations should be also verymuch involved. As regards the private sector inthe narrower sense, meaning private hospitalsand structures, this is so different from countryto country, it is in my opinion very difficult tohave a general statement. If you set up a cancercontrol plan you have to include NGOs and theprivate sector, but the responsibility of courselies with the government. That is quite clear.”

The Declaration has been translated intoseveral languages and is now being distributedworldwide amongst UICC members. TheUICC is preparing an action plan based onthe Declaration, and is talking to WHO aboutmonitoring progress. “We want to monitor

where we will be in 2008 so we can judgeprogress,” says Cavalli. “We will see whetherthere will be 10 or 15 countries more with a can-cer control plan than in the past.”

The full text of the World Cancer Declara-tion can be downloaded at http://www.uicc.org/

WORLD CANCER DECLARATION – SUMMARY

The World Cancer Declaration predicts that by 2020 there will be16 million new cancer cases and 10 million cancer deaths eachyear, with 70% of the deaths in developing countries. It says thatcancer can be eliminated as a major threat, but only if cancer con-trol is made a priority for the decade.

PRIORITIES:n Investing in health: with compelling messages to win the argu-

ment for countries to invest in cancer prevention and controln Cancer control planning: increasing the number of countries that

have national cancer control plans with budgetsn Cancer surveillance: increasing the number of countries with ade-

quately funded cancer surveillance systems n Tobacco control: increasing the number of countries imple-

menting successful initiatives connected with the WHO Frame-work Convention on Tobacco Control

n Vaccines: developing an international plan for HPV vaccinationin low- and middle-income countries, and integrating Hepatitis Binto infant vaccination programmes

n Early detection/treatment: adopting evidence-based guidelinesfor early detection and treatment tailored to socioeconomic, cul-tural and resource settings

n Palliative care: increasing the number of countries that makepain relief and palliative care an essential service in cancer treat-ment and home-based care

n Mobilising individuals: empowering those affected by cancer toparticipate in cancer control efforts

n Supporting steps: implementing a process to monitor actions,report on progress and identify organisational roles

“I have the impression that this is starting to

create a little avalanche which is increasing in speed”

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Closing the survival gapÜ Anna Wagstaff

EU countries from Central and Eastern Europe are trying to close the gap with Western

Europe in cancer prevalence and survival rates. In Ljubljana, politicians, experts and

patients came together to debate cancer plans, political will, funding and ways to stop

skilled staff leaving home.

It had been a year since the signing of the War-saw Declaration on cancer services in Centraland Eastern Europe – long enough perhaps forpoliticians to have forgotten their undertakingsand moved on to other issues.

Instead, a critical mass of MPs, MEPs andhealth administrators gathered in the Sloveniancapital, Ljubljana, in November 2006 to renewtheir commitment to closing the gap between can-cer outcomes in the east and west of Europe, and todiscuss ways of making it happen.

This was a working conference, organised bythe European Cancer Patient Coalition, at whichpoliticians, cancer experts and patients groupsfrom all over Europe dedicated time to workingout how to ensure that the aims of the WarsawDeclaration are fulfilled.

Given equal services, people in Central andEastern European (CEE) countries should be atlower risk of dying of cancer, because these countrieshave the fewest diagnosed cases in the whole ofEurope. However, women in CEE countries are onlyslightly less likely to die of cancer than their sistersin Western and Northern Europe, while CEE menare much more likely to die than their counterparts.

In the period 1983–1994 the survival statisticsin some CEE countries improved, but more slow-ly than the average for the rest of Europe. In

some CEE countries, survival rates actually fell.So, the gap between east and west is growingrather than narrowing.

“Do our governments know about these fig-ures?” asked a representative from the Institute ofPatients Rights in Poland. “Where can we findcopies of these statistics?” asked another delegate(answer: www.eurocare.it). Irena Belohorská, med-ical oncologist and Slovakian MEP, had heard thestatistics for the first time at the October conferenceof the European Society for Medical Oncology.Two days before travelling to Ljubljana, she pre-sented them to her health minister. “He wasshocked,” she said.

The conference heard presentations about thetwo most comprehensive programmes implement-ed in Europe to date. The French and UK CancerPlans both tackle cancer from prevention and earlydetection to training, guidelines, organisation ofcare and rehabilitation. The French plan alsoaddresses social issues such as rights at work. Manydelegates cited these contributions as giving help-ful information to take home.

Ariana Znaor from the Croatian National Insti-tute of Public Health valued the precision of the UKexperience. “What I found useful was the setting ofvery specific targets,” she said. She was alsoimpressed by the patient-orientation of the

But there is evidence thatthings are beginning tochange. Evgenia Adarska,president of the cancerpatients group, APOZ, report-ed a political and media stormin Bulgaria, when a member ofthe parliamentary health com-mittee said: “It is immoral toask for more money for onco-logical treatment because can-cer patients are already dead.”The MP was disciplined – andBulgaria’s cancer patients nowstand to gain from the 30%increase in the health budgetthey had been fighting for.

In Hungary too, Kökénysays that people have startedtalking publicly about cancer– as part of a general climate

of greater openness. “Developing cancer care wasnot an area that local politicians and the governmentfelt should be a priority. It was swept under the car-pet. Now everyone has to face the statistics.”

RESOURCES AND STAFFHowever, there remains a problem with funding.Znaor, from Croatia, points out that CEE countriesmissed out on support from Europe Against Cancerbecause it ended before they joined. “Organisedscreening programmes are major undertakings thatdon’t give quick results, and cost a lot of money.”

Transformation from the old socialist systems hastaken its toll, while countries involved in the fightingthat accompanied the break-up of Yugoslavia are stilltrying to rebuild their infrastructure.

Fatmire Mulhaxha-Kollçaku chairs the Com-mittee on Health, Labour and Social Reform inthe Kosovan parliament. As part of Yugoslavia,Kosovo was progressively starved of resources, shesaid. The unresolved separation from Serbia leftKosovo without any oncology centre or even aradiotherapy facility. These are having to be con-structed from scratch, by an administration thatis struggling even to get its telephone systemfunctioning properly. Infectious diseases accountfor much of the Kosovo health budget, as many vil-lages still lack sources of clean water. Her entire

NEW CASES AND DEATHS PER 100,000 PER YEAR AROUND 2000

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French plan – “Cancer care in many places endsafter the patient is sent home from hospital.”

Mihály Kökény, chair of the Health Commit-tee in the Hungarian parliament, was similarlyinspired. “Many of our currently good and validnational cancer plans and programmes shouldbe much more citizen- and patient-centred. Weneed to support patient groups, and involve them.Cancer is an important issue but it cannot just beleft to the medical people.”

A PLACE ON THE AGENDAIn many CEE countries, cancer remains taboo,denied a profile in public life and the media, with nochance of becoming a political priority. Both MikeRichards, architect of the UK Cancer Plan, andBrigitte Guillemette from the French NationalCancer Institute, stressed that advances had onlybeen possible with top-level, sustained politicalsupport. The Ljubljana gathering was itself in partthe result of political backing from former Sloven-ian President, Alojz Peterle, the founding spirit andvice-chair of MEPs Against Cancer.

Countries struggle to break free of a negativemind-set. Simone Ene, who works with the Associ-ation of Cancer Patients in Romania, says that peo-ple and politicians “are blind to the issue of cancer.They treat cancer as a fatal disease not a chronic one.”

Unacceptable. Men in Central and Eastern Europe have a lower incidence of cancer than men in otherparts of Europe, but mortality rates are significantly higher Source: Globocan 2002, IARC

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However, the Ljubljana con-ference explored some of theways in which the EU canhelp to move things forward.The 10 EU countries thatjoined in 2004 can choose sixpriority areas for structuralfunds, which could be puttowards revamping and reor-ganising health services,screening programmes or stafftraining, and could free upmoney for increased salariesto keep doctors and nurses inthe country. Hildrun Sund-seth, conference organiserand head of the Brusselsoffice of the European Can-cer Patient Coalition,appealed to MEPs, MPs andpatient groups alike to arguethe case for investing in can-cer. Cancer plans, she said,

were also on the agenda for the next meeting ofMEPs Against Cancer.

An acute awareness of the benefits of national,quality-assured screening programmes, includingone for colorectal cancer, was evident across all thecountries.

Joaquim Gouveia, Portugal’s first NationalCoordinator for Oncology Diseases, emphasisedthe importance of creating a “common languageof indicators and effectiveness studies”, andsaid that benchmarking could be crucial to bring-ing cancer control in all countries up to thelevel of the best.

Kökény supports the need for standardiseddata, even down to individual hospital level onwaiting times, caseloads, complication rates andso on. He mentions three areas where he wouldlike the EU to take a lead. On smoking – Hungaryhas by far the highest incidence of male lungcancer in Europe – Kökény would like to see abinding directive. On drug prices, he wants an EUdiscussion about how to make new cancer drugsmore accessible. On research, he believes Europeshould be far more ambitious, and cites the oppor-tunities presented by ideological opposition togenetic research in the USA.

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budget for chronic diseases, including cancer,heart disease and diabetes is 3 million euros, fora population of 2 million people.

Even peaceful change has brought problems. InSlovakia, transformation brought decentralisation ofthe health service. Belohorská says that one resultis that poorer regions get a poorer quality service,while a shortage of nurses has led to the closure ofmany beds. “The plan is not the problem. There isnot the money.”

Belohorská sees staff shortages as the singlegreatest threat to cancer care and cancer screening,as specialists and nurses exercise their EU labourmobility rights to work in better paid parts ofEurope. Patients, she points out, are not so mobileand are left high and dry. Ene from Romania agrees.“You have to give [doctors and staff] a reason to stay– increase their salary and improve their workingconditions. You can’t just give them the opportuni-ty to run off and leave the patients to die.”

CAN THE EU ADD VALUE?Belohorská asserts that a failure to allow the EU agreater role in health policy in the member statesamounts to “punishing the people” and says that“without healthcare it is not the Europe of the people.”

A growing gap. Survival rates are improving faster in Northern and Western countries than in EasternEurope, which means the survival differences are increasing Source: Coleman et al, 2003

EUROPE, MEN DIAGNOSED 1983-94

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CANCER SURVIVAL TRENDS TO 1999

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Jan Potocnik, EU Commissioner for Research,welcomed a discussion on the merits of research,and assured the conference that cancer has beensteadily moving up the agenda for allocation offunds from EU framework programmes.

Two years ago, the EU Clinical Trials Directivecaused widespread dismay as it failed to takeaccount of the need to conduct independent, aca-demic clinical research. Potocnik made it clearthat he does recognise the vital role of such work. Hesaid that the forthcoming Research FrameworkProgramme would link research, prevention, diag-nosis and treatment, emphasise translationalresearch, back the identification of best clinicalpractices and optimise the use of cancer registriesfor cancer research.

He acknowledged concerns over the failure toagree a Europe-wide validation system for contin-uing medical education (CME) to keep physiciansup to date in a rapidly changing field.

TOP PRIORITYThe Ljubljana meeting was another important mile-stone in the long process of getting cancer onto thepublic and political agenda. The journey has includ-ed the emergence of patient advocates, national can-cer plans, the Europe Against Cancer programme(1985–2000), the development of a European net-work of cancer registries, the establishment of theEuropean Cancer Patient Coalition (2004), thefirst meeting of EU health ministers on cancer(Paris, 2005), and the launch of MEPs AgainstCancer (2005). Ljubljana brought many elementsthat reflect this progress together in the same room.

Slovenia’s secretary of state for health, DorjanMarusic, said that there was clearly a strong will “tocontinue on this track, to share ideas, to find solu-tions – not just at the level of experts and citizens butalso at a political level.” During a political roundtablediscussion, MEPs, MPs, experts and patients decid-ed to meet again in 2007 to continue the dialogue.

For Marusic, this is part of the build-up to theSlovenian EU Presidency in 2008, which they

intend to use to give the fight against cancer a toppriority. This will offer an unprecedented chance forpatients, experts and politicians to push the issue upthe agendas in their own countries.

It could also give a boost to patient power acrossEurope. Alojz Peterle, a prime mover behind theconference, has himself been diagnosed withprostate cancer and is standing for the SlovenianPresidency. Were he to win, the EU would, in2008, have a cancer patient advocate at its head forthe first time.

THE WARSAW DECLARATION

The Warsaw Declaration was launched at the second summit of can-cer patient and advocacy groups in Central and Eastern Europe inNovember 2005, and called for urgent action to close the gapbetween CEE countries and the rest of Europe in cancer prevalenceand survival rates.

1. Develop national cancer plans, setting priorities and allocatingresources, for improving cancer control and research in all CEEcountries and assure patients’ groups monitoring over theimplementation of these plans.

2. Invest in cancer prevention by promoting awareness, informationand education campaigns about the risk factors of cancer,building on the European Code against Cancer.

3. Invest in national screening programmes as recommended bythe European Union; and implement high-quality EU standardsto support early diagnosis.

4. Make high-quality up-to-date treatment, rehabilitation and careattainable for all cancer patients throughout Europe.

5. Encourage and ensure patient participation in all decisions onhealth policy and health care affecting cancer.

6. Advance cancer control as a priority for action where necessaryto qualify for grants from the EU Structural Funds.

7. Oppose discrimination because of age, race, gender, domicileand economic status in respect of the latest cancer treatment.

8. Encourage and adopt national Charters of Patients’ Rights accord-ing to European guidelines.The full text plus a list of signatories can be found at www.cancerworld.org/ecpc

This was an important milestone in the process of getting

cancer onto the public and political agenda

ImpactFactor


Gene expression profiling for individualised breast cancerchemotherapy: success or not?

Ü John Ioannidis

Results of a recent study indicate that gene expression profiling seems to improve prediction of

chemotherapy effect in breast cancer, but methodological caveats remain worrisome.

Astudy by Paik et al. (see oppo-site) has shown that a well-characterised recurrence score

(RS) using information on the expres-sion of 21 genes can successfully sep-arate women who benefit from breastcancer chemotherapy from those whodo not. Their study has severalstrengths: the RS has been developedwith careful attention to both labora-tory and statistical procedures and hasbeen standardised to become com-mercially available, RS has alreadybeen found to predict recurrence andsurvival in a validation dataset (NSABPB-14),1 and a meticulous training phasewas carried out using three independ-ent databases to maximise generalisa-tion. Moreover, the treatment–RSinteraction is demonstrated in 651node-negative, oestrogen-receptor-pos-itive women, a sample size much larg-er than used for most previous researchon gene expression profiles.2

The interaction term betweentreatment and RS identified by Paik et

al. has borderline statistical signifi-cance (P=0.038). Interestingly, eventhough the study population is derivedfrom a randomised trial (NSABP B-20), the distribution of RS levels dif-fers significantly between thetamoxifen and the tamoxifen pluschemotherapy arms (P=0.036). Thisresult illustrates that biases andchance alone may yield similar P val-ues to those found for the interactionterm; however, an interaction is notnecessarily required for a predictivescore to be useful in therapeutic deci-sions. In the low-risk group, absoluterisk is so low that chemotherapy is notrecommended in any case.

The question is whether RS pro-vides treatment guidance in addition tothat available using routine information(e.g. age, tumour grade and receptorlevels). RS correlates with and might bemore informative than these classicpredictors; however, even age, whileclearly seen to have an interaction withthe treatment effect in the full NSABP

B-20 database, did not reach nominalsignificance in the 651 patientsanalysed in this study, owing to limitedpower. We need very large studies todiscern the exact incremental benefitof RS interactions over classic predic-tors. Such predictors, which are rou-tinely available, should be included inprognostic models.

The greatest concern regarding Paiket al.’s study is that tamoxifen-treatedpatients from the NSABP B-20 studywere used in the original developmentof the RS, and data from these patientswere important in the selection of the21-gene signature1. RS is thus expect-ed to (and does) differentiate the riskwithin the tamoxifen arm, since it hasbeen trained purposely on these data.Conversely, RS does not appropriatelydifferentiate recurrence risk in theNSABP B-20 chemotherapy arm. Thiscontrast of good predictive perform-ance in the tamoxifen arm and poorperformance in the chemotherapy armis what causes the significant treat-

John Ioannidis is Chair of the Department of Hygiene and Epidemiology at the University of Ioannina School of Medicine, Ioannina, Greece, with a joint appointment at TuftsUniversity School of Medicine, Boston, Massachusetts, USA. This article was first published in Nature Clinical Practice Oncology 2006 vol. 3 no. 10, and is reproduced with permission.www.nature.com/clinicalpractice, doi:10.1038/ncponc0631, ©2006 Nature Publishing Group

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ment–RS interaction effect. Given thatthe tamoxifen arm was a trainingdataset, the correct interpretation ofthe data is not necessarily that RS is asuperb predictor of treatmentresponse. An alternative interpretationis that RS, while previously validated inthe independent NSABP B-14dataset,2 now fails to be validated in theindependent data of the chemotherapyarm of NSABP B-20.

As gene expression profiling movesfrom exploratory research into clinicalpractice, rigorous testing with fullyindependent validations should con-

tinue.3 Useful molecular signaturesneed to be trained and tested on sev-eral thousands of patients.4 The vali-dation work to date is retrospectiveand thus provides only preliminaryevidence. The TAILORx trial, a largeprospective trial of 8,000 patients,will try to validate this 21-gene signa-ture in the clinical setting. Similarly,the MINDACT trial will try toprospectively validate a different 70-gene prognostic signature. As we moveinto large-scale evidence, makingsense of gene expression profilingremains a fascinating challenge.

SynopsisS Paik, G Tang, S Shak, et al. (2006) Gene expression and benefit of chemotherapy in women with node-negative,estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734Background.A 21-gene recurrence score (RS) assay has been developed and validated to quantify the probability of distant recur-rence in women with node-negative, oestrogen-receptor-positive breast cancer.Objective. To determine whether the RS can also predict the magnitude of chemotherapy benefit.Design and intervention. Tumour tissue samples were obtained from the National Surgical Adjuvant Breast and Bowel Project(NSABP) B-20 trial, which investigated the value of adding chemotherapy (methotrexate and fluorouracil with or without cyclophos-phamide) to 5 years of tamoxifen therapy in 2,363 patients with node-negative, oestrogen-receptor-positive breast cancer.Patients were enrolled between 17 October 1988 and 5 March 1993. Gene expression was measured using the Oncotype DX assay(Genomic Health Inc., Redwood City, CA). Each RS was determined by measuring the expression of 16 cancer-related genes and5 reference genes, and was calculated on a scale of 0–100. Prespecified cutoff points for low-risk, intermediate-risk and high-riskdisease were RS<18, RS in the range 18–30, and RS ≥ 31, respectively.Outcome measures. The primary endpoint was freedom from distant recurrence. Cox proportional hazards models were usedto study the interaction between chemotherapy treatment and RS as a continuous variable. Analysis was also performed using thepredefined RS risk categories.Results. Gene expression results were successfully obtained for 227 patients treated with tamoxifen alone and 424 patients treat-ed with tamoxifen plus chemotherapy. Patients did not benefit equally from chemotherapy; those with a high risk of recurrencehad a greater magnitude of benefit from chemotherapy than those with an intermediate or low risk of recurrence. Adding chemother-apy to tamoxifen improved the 10-year Kaplan–Meier estimate for freedom from distant recurrence from 60% to 88% in the high-risk group. The high-risk category benefited from chemotherapy, with a large reduction in distant recurrence at 10 years (relativerisk [RR] 0.26, 95% CI 0.13–0.53; decrease in absolute risk 27.6%). This benefit was less clear for patients in the intermediate-risk group (RR 0.61, 95% CI 0.24–1.59; increase in absolute risk 1.8%), but a clinically important benefit from chemotherapy couldnot be excluded. No reduction in distant recurrence at 10 years was demonstrated for patients in the low-risk category (RR 1.31,95% CI 0.46–3.78; increase in absolute risk 1.1%). In a multivariate analysis, the interaction between chemotherapy treatmentand RS was significant (P=0.038); however, no clear cutoff point for RS could be defined.Conclusion. The RS can predict the magnitude of benefit from chemotherapy for patients with node-negative, oestrogen-recep-tor-positive breast cancer, as well as the likelihood of recurrence of breast cancer, and could be used to select patients who wouldrespond well to chemotherapy.Acknowledgement: The synopsis was written by Petra Roberts, Associate Editor, Nature Clinical Practice.

References

1. S Paik et al. (2004) A multigene assay to

predict recurrence of tamoxifen-treated, node-

negative breast cancer. N Engl J Med

351:2817–2826

2. EE Ntzani, JP Ioannidis (2003) Predictive

ability of DNA microarrays for cancer outcomes

and correlates: an empirical assessment. Lancet

362:1439–1444

3. JP Ioannidis (2005) Microarrays and molecular

research: noise discovery? Lancet 365:454–455

4. L Ein-Dor et al. (2006) Thousands of samples

are needed to generate a robust gene list for

predicting outcome in cancer. Proc Natl Acad Sci

USA 103:5923–5928

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Poor correlation between physicianand patient assessment of quality of life in palliative care

Ü Eduardo Bruera

Wide variations found between quality of life assessments made by patients and by physicians

indicate that patient symptom expression is a complex multidimensional construct.

In a recent study (see opposite),Petersen et al. observed a poor level ofagreement between patient and

physician assessments of patients’health-related quality of life (HRQOL) on firstcontact, with no significant improve-ment during follow-up encounters. Myresearch group made a similar observa-tion in 49 patients admitted to an acutepalliative care unit,1 with a tendency forphysicians to underrate most symptoms,particularly sedation, shortness of breath,and pain. Other authors have observedboth underrating and overrating byhealth-care professionals.2 These findingsemphasise the need for routine patient-based symptom assessment in the clini-cal setting. Unfortunately, except for painevaluation, such assessments are infre-quent in clinical practice, even withinpalliative care centres. Even for painevaluations, the accuracy of these assess-ments when conducted within regularclinical care has been questioned.3

Why does this discrepancy occur? Itis possible that physicians do not appro-

priately assess the intensity of somesymptoms, because of limited time, orinsufficient focus on emotional distresswhen debilitating physical symptomsare present. Another possible interpre-tation is that palliative care physiciansmake consistent errors in symptomassessment. An approach that considersthe patient’s numerical report regardingtheir symptoms as the ‘gold standard’would reach this conclusion. Thepatient’s self-rating of symptom inten-sity needs to be interpreted as a multi-dimensional construct, however.4-5 It isnot possible to measure the actual pro-duction of nociceptive input from apainful bone metastasis, the productionof afferent dyspnoea by ‘J’ receptors inthe lung or respiratory muscles, or theafferent nausea stimulus emerging fromthe gastric wall to produce numericalrepresentations of the primary patho-physiological mechanisms. The per-ception of these stimuli within thesomatosensory cortex also cannot bemeasured. A number of inhibitory and

facilitating pathways are capable ofaltering the intensity of symptom per-ception. Finally, the numerical ratingreflects the individual’s expression ofsymptom perception, which may besignificantly affected by their beliefabout the nature of the symptoms, theirunderstanding of the assessment tool,and cultural and social factors.

The impact of this numerical ratingon the treatment of the patient’s symp-toms has to be taken in context. Forexample, a pain intensity score of 8/10 ina patient whose pain had been consis-tently scored at 2 or 3, and who has expe-rienced considerable tumour growth, islikely to overwhelmingly reflect increasednociceptive input and require specificanalgesic therapy. On the other hand, apain intensity score of 8/10 in a patientwho has been consistently expressingsimilar intensity for several months andwho has a history of heavy chemicaldependence is much less likely to reflectnociceptive input and will, therefore,require less analgesia and more psy-

Eduardo Bruera heads the Department of Palliative Care and Rehabilitation Medicine at The University of Texas, MD Anderson Cancer Center, Houston, Texas USA.This article was first published in Nature Clinical Practice Oncology 2006 vol. 3 no. 11, and is reproduced with permission.www.nature.com/clinicalpractice, doi:10.1038/ncponc0635, ©2006 Nature Publishing Group

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chosocial interventions. Symptoms suchas fatigue, nausea, or dyspnoea are sub-ject to similar levels of variability.

Patients and palliative care physicianscould be interpreted as contributing com-plementary rather than opposing infor-mation from different perspectives. Usinggeneralisability theory, it might be possi-ble to reach a better understanding of themultidimensional construct included ineach of the different symptoms reportedby patients.5 Future research should focuson the influence of mood, delirium,chemical coping, and so on.6 In addition,qualitative studies should be conducted to

better characterise how palliative carephysicians make decisions when notice-able differences are observed betweentheir interpretation of a symptom andthat symptom as reported by the patient.

References

1. CL Nekolaichuk et al. (1999) A comparison of

patient and proxy symptom assessments in

advanced cancer patients. Palliat Med 13:311–323

2. KDA Sneeuw et al. (2002) The role of health

care providers and significant others in

evaluating the quality of life of patients with

chronic disease. J Clin Epidemiol

55:1130–1143

SynopsisMA Petersen, H Larsen, L Pedersen, et al. (2006) Assessing health-related quality of life in palliative care: comparing patientand physician assessments. Eur J Cancer 42:1159–1166Background. Assessment of the efficacy of palliative care measures is subject to a number of biases, linked to difficulty inpatient recruitment and the severe attrition that must be expected because of deterioration in patient condition or early death.Although patients’ assessment of their own quality of life must be considered the ‘gold standard’, the use of ‘proxy’ assessments(e.g. from nurses, clinicians or family) could improve the range and applicability of studies in palliative care. It is importantfor accuracy, however, that these proxy assessments concur with patients’ own ratings.Objective. To determine the reliability of physician assessments of patients’ health-related quality of life (HRQOL) in palliativecare compared with patient assessments.Design. This was a longitudinal study in adult palliative care patients with breast, colorectal, gynaecological, head and neck, lungor other cancers, seen at a single centre and being managed as inpatients, outpatients, or with home care.Intervention. Between June 1998 and August 2003, patients and physicians completed questionnaires including items from theEuropean Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30, at their firstcontact, and then weekly for 13 weeks or for as long as the patients wished or were able to continue.Outcome measure. The outcome measure for this study was the degree of agreement between patients’ and physicians’ assess-ment of HRQOL at first contact and for the following 13 weeks of care. Results. At the first assessment, 115 patients met the inclusion criteria. A high number of patients were not able to complete 13full weeks of the study (only around 25% of patients were still alive 13 weeks after referral); therefore, the authors focused primarilyon the initial questionnaire and used data from the further time points (weeks 1–13) to verify their findings. Agreement betweenpatients and physicians was poor overall. Patient and physician assessments were significantly different for all HRQOL domainsassessed (P<0.01 for all). Generally, physicians judged that patients had fewer symptoms and better functioning than did their patients,the exceptions being physical and social functioning. The smallest absolute differences (indicating better reliability) between physi-cian and patient assessments were seen for physical functioning, nausea/vomiting and constipation, and the largest absolute dif-ferences were seen for insomnia and two psychosocial scales: emotional and social functioning. The overall agreement betweenpatient and clinician for the period of time following admission was no better than at the admission consultation. Conclusion. The authors conclude that, despite their experience, physicians working in palliative care have very different per-ceptions of patients’ HRQOL than do their patients themselves. The use of physician assessments in palliative care studies maybias findings and should not be considered a viable alternative to patient self-assessment.Acknowledgements: The synopsis was written by Carol Lovegrove, freelance medical writer.

3. E Bruera et al. (2005) Pain intensity

assessment by bedside nurses and palliative

care consultants: a retrospective study. Support

Care Cancer 13:228–231

4. E Bruera, HN Kim (2003) Cancer pain.

JAMA 290:2476–2479

5. CL Nekolaichuk et al. (1999) Assessing the

reliability of patient, nurse, and family caregiver

symptom ratings in hospitalized advanced

cancer patients. J Clin Oncol 17:3621–3630

6. PG Lawlor (2003) Multidimensional

assessment: pain and palliative care.

In: E Bruera and RK Portenoy (eds) Cancer

Pain. Cambridge University Press, Cambridge,

UK, pp67–88

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N E W S R O U N DSelec t ed p re s s repo r t s comp i l ed by the ESO Cance r Med i a Cen t re

No advantage to givingadvanced lung cancerpatients more than threecourses of chemotherapyÜ British Journal of Cancer

Astudy has found that giving patients withadvanced non-small-cell lung cancer

(NSCLC) more than three courses ofchemotherapy does not improve quality of lifeor survival. It is important that patients are notovertreated with drugs that offer no survivalbenefits and are associated with burdensomeside-effects.

Despite improvements in cancer treat-ment, patients with NSCLC, the most commonform of lung cancer, often have a poor prog-nosis. The latest research looked at the optimalduration of palliative chemotherapy forpatients with NSCLC.

Two hundred and ninety-seven patientswith advanced NSCLC (stage IIIB or IV) wererandomised to receive either three or sixcourses of the latest platinum-basedchemotherapy (carboplatin and vinorelbine).Eighty-eight percent of the patients com-pleted an EORTC Quality of Life Question-naire. The researchers also analysed overallsurvival data.

The study found that there were no sig-nificant differences between the groups inquality of life, pain or fatigue up to 26 weeks.Two-year survival rates were 9% in the armthat received three chemotherapy treatmentscompared to 5% in the arm that received sixrounds of chemotherapy, but the differencedid not reach statistical significance. The study

concluded overall that palliative chemother-apy with carboplatin and vinorelbine beyondthree courses gave no survival or consistentquality of life benefits in advanced NSCLC.n Palliative chemotherapy beyond three courses

conveys no survival or consistent quality-of-life

benefits in advanced non-small-cell lung cancer.

C von Plessen, B Bergman, O Andresen, et al. for

the Norwegian Lung Cancer Study Group. Br J

Cancer 23 October 2006, 95:966–973

More colorectal cancerpatients should receiverecommended surgeryÜ JNCI

Arecently published study has shown thatonly one-third of US American patients

who underwent surgery for locally advancedadherent colorectal cancer received a multivis-ceral resection, a procedure proven to reducelocal recurrence and improve survival com-pared to standard resection.

An assessment of 8,380 patients from theUS Surveillance, Epidemiology and End Results(SEER) registry revealed that only 33.3% ofpatients who had surgery for locally advancedadherent colorectal cancer underwent multi-visceral resection. The remaining patients onlyhad their tumour removed.

Compared with standard resection, multi-visceral resection was associated with improvedoverall survival for patients with colon and rec-tal cancer, with no associated increase in earlymortality. Patients who underwent multivis-ceral resection had significantly greater five-

year survival rates (35.1% vs 27.7%).Several factors increased the likelihood of

receiving multivisceral resection, includingyounger age at diagnosis and being female.There was also a significant variation in thelikelihood of receiving the procedure based onthe geographical region in which patientswere treated.n Population-based assessment of the surgical

management of locally advanced colorectal cancer.

A Govindarajan, NG Coburn, A Kiss, et al. J Natl

Cancer Inst 18 October 2006, 98:1474–1481

Postponing surgery reduceslong-term side-effects for childrenwith kidney cancerÜ European Journal of Cancer

Children given chemotherapy before sur-gery to treat the most common form of

childhood kidney cancer, called Wilms’ tumour,require less treatment and experience fewerlong-term side-effects than if they undergoimmediate surgery.

The Children’s Cancer and Leukaemia Group(CCLG) undertook a ten-year trial involving 205patients with newly diagnosed Wilms’ tumours.The patients were randomly assigned to receiveeither immediate surgery or six weeks pre-oper-ative chemotherapy and then surgery. Dependingon the size of their tumours and how much theyhad grown, all children on the trial were givenchemotherapy, radiotherapy or both after theirsurgery to destroy any remaining cancer cells.

Overall survival between the two groups

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was the same, but the researchers found thatgiving six weeks pre-operative chemotherapyenabled easier removal of tumours. Also 20%fewer children needed radiotherapy or treat-ment with doxorubicin after their surgery, min-imising their risk of long-term side-effects.

The author of the study, ChristopherMitchell from the Oxford Radcliffe Hospital,said, “Deciding what is the best way to treatWilms’ tumours has been under debate formany years and this study was the first time thatthe two treatment methods were compared ina randomised clinical trial…. We were able tobenefit a group of patients who could benefitfrom a reduction in treatment without com-promising their survival chances. For some chil-dren with advanced tumours, delaying theirsurgery reduced the size of their tumoursenough to prevent them needing intensivetreatment after surgery. This improvement inquality of life for patients is significant and wehope children diagnosed with Wilms’ tumoursin the future will benefit from our findings.” n Immediate nephrectomy versus pre-operative in

the management of non-metastatic Wilms’ tumour;

results of a randomised trial (UKW3) by the UK

Children’s Cancer Study Group. C Mitchell,

K Pritchard-Jones, R Shannon, et al. Eur J Cancer

October 2006, 42:2554–2562

Breast cancer care isimproving across EuropeÜ International Journal of Cancer

Anew study has found that breast cancersurvival rates in some European countries

have improved since 1970. The study, conducted by a group at the

Istituto Nazionale per lo Studio e la Cura deiTumori, Milan, analysed and estimated breastcancer trends in 10 European countries from1970 to 2005. Interpreting breast cancer survivaldata can be difficult, as activity such asimproved screening and earlier diagnosis caninflate both incidence and survival. The studytherefore analysed survival trends in relation tomortality and incidence in order to give an

accurate overview of breast cancer trends. The study showed that, in most countries

included in the analysis, survival from breast can-cer had improved and this could be attributed tobetter care. Those countries included Sweden,the UK, France, Italy and Spain.

The study also found that differences inincidence rates seen across Europe in the 1970scontinued into the 21st century, with the low-est incidence in Spain and Italy and the highestincidence in the Netherlands, Denmark, Fin-land, Sweden, and France. In Finland, theNetherlands and Denmark, there was anincrease in breast cancer mortality and inci-dence, indicating an increased breast cancer risk,probably related to life-style factors.

In Estonia, the research indicated that therewas inadequate care for breast cancer patients,as there was poor survival in the context ofincreasing incidence and mortality.

The figures overall look promising and pointto improved treatment helping patients livelonger in the wealthier European countries.However the poor results from Estonia suggestthat the survival and treatment differences inEuropean countries continue to exist.n Time trends of breast cancer survival in Europe

in relation to incidence and mortality. M Sant,

S Francisci, R Capocaccia, et al. Int J Cancer 15

November 2006, 119:2417–2422

Maintenance therapy with thalidomide shown to have a role in multiplemyelomaÜ Blood

There is no known cure for multiple myelo-ma, a cancer of the plasma cells. Current

treatments involving high-dose chemothera-py have increased the response rate but moreeffective approaches are needed to maintainthe duration of response.

Results from a randomised trial of main-tenance therapy with thalidomide andpamidronate carried out by a team of Euro-

pean researchers were recently published. Thestudy showed thalidomide is an effective meansof maintaining duration of response in patientswith multiple myeloma.

The study involved 597 patients divided intothree groups. The first group was treated with thedrug pamidronate alone, the second group withpamidronate and thalidomide and the thirdgroup received no maintenance therapy.

The researchers showed that, four yearsafter diagnosis, the group treated withpamidronate and thalidomide had an overallchance of survival of 87%. Patients in thepamidronate-alone arm had a 74% probabilityof survival compared with those not receivingtherapy, at 77%. The three-year probability ofthe patients remaining relapse-free was 36%without maintenance therapy and 37% withpamidronate alone. The addition of thalido-mide significantly improved these odds, to 52%.

Pamidronate has been used by doctors toprotect against bone damage; however, thestudy found that the drug did not decreasethe number of bone events, as anticipated,and there was no significant difference inthe number of these events between the threetreatment groups.

However, thalidomide remains a powerfuldrug and difficult for some patients to tolerate.The drug was originally dosed at 400 mg per day,but after 15 months, the median dose wasdecreased by half because of drug-related tox-icity. Thalidomide was discontinued in 39% ofthe patients taking the drug due to side-effectssuch as numbness, tingling or pain in the handsand feet, fatigue and constipation. In contrast,only 4% of patients discontinued pamidronate.

Patients most likely to benefit from theaddition of thalidomide to maintenance ther-apy were those whose responses to the originalchemotherapy were not as successful, and thosewho did not have a chromosome 13 deletion –an abnormality found in about 15–20% ofpatients with multiple myeloma and one that isassociated with a poorer prognosis.n Maintenance therapy with thalidomide

improves survival in multiple myeloma patients.

M Attal, J-L Harousseau, S Leyvraz, et al. Blood

15 November 2006, 108:3289–3294

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Common antibiotic is auseful treatment for rarelymphoma of the eyeÜ JNCI

The common antibiotic doxycycline effective-ly treats a type of lymphoma associated with

chlamydia infection, according to a recent study.Ocular adnexal lymphoma of the MALT-type(OAL) is an uncommon type of non-Hodgkin’slymphoma that affects tissues surrounding theeye. It is not normally fatal, but its symptoms canaffect a patient’s quality of life. Some research hassuggested an association between OAL andChlamydia psittaci (CP) infection.

A group led by Andrés Ferreri from the SanRaffaele Scientific Institute in Milan, Italy, exam-ined whether doxycycline was an effectivetreatment for OAL. They gave 27 OAL patients athree-week course of doxycycline therapy,regardless of whether they were positive ornegative for CP. They assessed lymphomaresponse at 1, 3 and 6 months.

The authors found that doxycycline treat-ment caused lymphoma to regress in both CP-positive and CP-negative patients. Failure-freesurvival at two years in the patients treatedwith doxycycline was 66%, and 20 of the 27patients (74%) were progression free. Theresponses observed in patients who testednegative to CP may suggest a need for devel-opment of more sensitive methods for detec-tion, and investigation of the potential role ofother doxycycline-sensitive bacteria.

According to the authors, doxycycline maybe a useful therapy even in patients whereother treatments have failed, and it is a validalternative to chemotherapy and radiationwithout causing the same toxic side-effects.

In an accompanying editorial, EmanuelZucca and Francesco Bertoni, of the Oncolo-gy Institute of Southern Switzerland, advised“While doxycycline appears to be an easy-to-implement therapeutic approach, westrongly encourage all physicians to enrolpatients in clinical prospective trials to helpanswer these questions.”

n Bacteria-eradicating therapy with doxycycline

in ocular adnexal malt lymphoma: a multicenter

prospective trial. AJM Ferreri, M Ponzoni,

M Guidoboni, et al. J Natl Cancer Inst 4 October

2006, 98:1375–1382

Chemotherapy cuts thechance of rectal tumoursreturning by half but doesnot affect overall survivalÜ New England Journal of Medicine

Giving a patient chemotherapy before orafter an operation to remove their rectal

cancer cuts the chance of the tumour return-ing in the rectum by half. Unfortunately, itdoesn’t increase the patient’s overall survival– according to a recently published study.

A total of 1011 patients were enrolled inthe study to see whether giving rectal cancerpatients radiotherapy before or after theiroperation affected their survival. Theresearchers also evaluated the benefits ofadding chemotherapy to radiotherapy beforeor after the operation.

The radiotherapy was given to patientsover a period of five weeks. The chemothera-py consisted of fluorouracil plus leucovorindaily for five days. There was no significantdifference in overall survival between thegroups that received chemotherapy preoper-atively (P=0.84) and those that received itpostoperatively (P=0.12). The combined five-year overall survival rate for all four groupswas 65.2%. The five-year cumulative inci-dence rates for local recurrences were 8.7%,9.6%, and 7.6% in the groups that receivedchemotherapy preoperatively, postoperative-ly, or both, respectively, and 17.1% in thegroup that did not receive chemotherapy(P=0.002). The rate of adherence to preoper-ative chemotherapy was 82.0%, and to post-operative chemotherapy was 42.9%.

Chemotherapy, regardless of whether itwas given before or after surgery, did benefitthe patient because it reduced the chance of

the tumour coming back by half. However,fluorouracil-based chemotherapy adminis-tered either pre- or postoperatively had noimpact on survival. n Chemotherapy with preoperative radiotherapy

in rectal cancer. J-F Bosset, L Collette, G Calais,

et al. for EORTC Radiotherapy Group Trial 22921.

New Engl J Med 14 September 2006,

355:1114–1123

New cancer drugs approvedfor EuropeÜ European Medicines Agency

The European Commission has granted mar-keting authorisation approval for a number

of novel cancer medicines. Novartis was award-ed approval for Exjade (deferasirox), indicatedfor the treatment of chronic iron overload dueto frequent blood transfusions in patients withbeta thalassaemia major, aged six years or over.The agent can also be used in the treatment ofchronic iron overload in patients with otheranaemias where defoxamine therapy is contra-indicated. Topo Target’s Savene (dexrazoxane)is now approved for use in the treatment ofanthracycline extravasation. Merck Sharp andDohme was given approval to market the vac-cine Gardasil/Silgard to prevent high-gradecervical dysplasia, cervical carcinoma, high-grade vulvar dysplastic lesions, and externalgenital warts causally related to human papil-lomavirus types 6, 11, 16 and 18.

EMEA’s Committee for Medicinal Productsfor Human Use gave a positive opinion to Bris-tol-Myers Squibb’s Sprycel (dasatinib) for thetreatment of chronic myeloid and acute lym-phoblastic leukaemias in patients with resist-ance or intolerance to prior therapy. TheCommittee also recommended extending Tax-otere’s (docetaxel’s) indication for use in com-bination with cisplatin and 5-fluorouracil for theinduction treatment of inoperable locallyadvanced squamous cell carcinoma of the headand neck. n European Medicines Agency

(www.emea.eu.int)

Documents

C W 16 Education & knowledge through people & facts‘mini-doctors’, as Foubert puts it – there is a dan-ger of the bulk of bedside nursing remaining stuck in an assistant nursing