cancer education & knowledge through people & facts · responses it evoked, show the power...

Education & knowledge through people & factsNumber 5, March-April 2005

➜ How Bruce Ponder is plugging research gaps ➜ Treating anaemia: damned ifyou do, damned if you don’t ➜ Has tamoxifen had its day? ➜ Patients groups andpharma: renegotiating terms of engagement ➜ The changing role of cancer nurses

Bruce Ponder

CancerWorld 5

MARCH

-APRIL2005

Contents

CANCER WORLD ■ MARCH-APRIL 2005 ■ 3

5 EditorialThe power of words

6 Cover StoryBruce Ponder: plugging the research gaps

15 Grand RoundTreating anaemia: damned if you do, damned if you don’t

23 Drug WatchBrainwaves in drug delivery

26 MasterpieceJean-Claude Horiot: the innocent inquisitor

34 Spotlight on...Women doctors offer alternative to costly mammographyPoorer countries take their place at the World Cancer Conference

41 Impact FactorHas tamoxifen had its day?

46 Patient VoiceLook – no strings!

56 Systems & ServicesCancer nurses – partners in care

61 Bookcase

EditorKathy Redmond

Assistant EditorAnna Wagstaff

Editorial AssistantMariarita Cassese

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 VouteUmberto Veronesi (chair)

Contributing WritersMarc Beishon, David BraydenRaphaël Brenner, Jose Julio DivinoJoanna Lyall, Peter McIntyreMary Rice, Anna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonChatrina Melcher

Project DesignerAndrea Mattone

Graphic and Layout DesignersPier Paolo Puxeddu+Francesca Vitale

Production ManagerGianfranco Bangone

Published byEditoriale Darwin srlPiazza Antonio Mancini, 4 - 00196 Rome

Printed byIGER Istituto GraficoEditoriale Romano s.r.l.Viale C.T. Odescalchi, 67 - 00147 Rome

Cover photographRichard Baker / IPG

Registrazione Tribunale di Roma Decreto n. 436 del 8.11.2004

Direttore responsabileEmanuele Bevilacqua

All enquiries about Cancer Worldshould be made to:ESO Editorial OfficeViale Beatrice D’Este 3720122 Milan, Italye-mail: [email protected]: +39 02 8546 4545

Copyright ©2005 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


Blogging – a novel form ofInternet communication – isstarting to enter the cancer

world. A ‘blogger’ is someone who poststheir thoughts and opinions to an onlinejournal (called a ‘web log’ or ‘blog’). Thebest bloggers are insiders – people whocan candidly describe a particular reality,warts and all. Ivan Noble was a wonderful blogger.Tragically, he died last month after a two-year struggle with a high-grade glioma. Hisonline diary, started soon after being diag-nosed, charted his fight against a particu-larly aggressive cancer – his frustrations,fears and despair as well as hopes, dreamsand joys. He wanted to use his ability as atechnology reporter to help demystify thedisease, but later he moved on to explore,with painful clarity, how to carry on livinga full life in the face of enormous uncer-tainty.E-mails flooded in from all over the worldwhenever he posted an entry. Many ofthem were published on the same page.Some people wanted to share their owncancer stories; others wanted to offer sup-port or tell Ivan about the strength theytook from his courage and tenacity. It wasa dialogue of solidarity in the face of adver-sity. In acknowledging the painful realityof living with a life-threatening disease,

➜ Kathy Redmond ■ EDITOR

Ivan prompted fellow cancer sufferers,their friends and families, to speak abouttheir experiences – the positive and theharrowing. He helped people make senseof an unfathomable situation.Ivan got a lot out of writing his diaries. Hewas determined to fight back against thepowerlessness of his grim situation andmake something good out of bad. He saidhe wanted to “prove that it was possible tosurvive and beat cancer andnot to be crushed by it.”Though he knew he wasdying, he wrote “I feel Imanaged it. I have not beendefeated.” His diarieshelped take Ivan out ofhimself and allowed him toretain a sense of continuitywith his ‘previous’ life. Hebelieved that the messagesof support and insight hereceived from readers helped him survivefor as long as he did. Ivan Noble’s Tumour Diary, and theresponses it evoked, show the power ofnarration in helping people cope with adevastating life crisis. The cancer commu-nity owes Ivan a debt of gratitude forsharing so frankly and eloquently allthe unpredictable ups and downs of hiscancer journey.

The powerof words

All correspondence should be sent to the Editor at [email protected]

Ivan’s diariescan be viewed at BBC News Online(www.bbc.co.uk). A collection of his diarypostings will be published later this year by Hodder

CoverStory

Bruce Ponder:pluggingthe research gaps

“Just do it” is a lesson Bruce Ponder learnt early in his research career, and it has stood

him in good stead. He is now director designate of one of Europe’s largest cancer research

centres, where he intends to plug many of the research gaps that the cancer community

has been complaining about for so long.

INconversation with Bruce Ponder,in his fairly unassuming office inthe Hutchison/MRC ResearchInstitute on the Addenbrooke’sHospital site in Cambridge, it

takes a while to appreciate just what he is presidingover. Using his background in genetics, molecularbiology and clinical oncology, his mission is to buildwhat will possibly one day be the largest scientificcancer research centre in Europe.

It will comprise not just a new £40 million(58.2 million euro) translational research institutestaffed by 300 researchers, but will bring togeth-er existing institutes such as the Hutchison/MRC– itself a very new facility that houses cancer cellresearch – and academic departments and clini-cal facilities in a ‘virtual’ cross-disciplinary effort.

That new translational facility, known at pres-ent as the Cambridge University/Hutchison/Cancer Research UK Institute, is a year away fromoccupation, and Ponder is its director designate, aswell as being Professor and Head of the Universityof Cambridge/Addenbrooke’s OncologyDepartment, and co-director of other institutes. It’s

➜ Marc Beishon

6 ■ CANCER WORLD ■ MARCH-APRIL 2005

a potentially confusing picture, but Ponder is ab-solutely clear about its aim.

“What I’m keen to do is ensure that, althoughthere will be this new institute that will be fund-ed and evaluated like any research facility of itstype, there is additional funding that supports theclinical side, and that the two are judged together.It is the interface between research and the clini-cal side that is really important.”

It is self-evident, perhaps, that creating thebest pathways for new, effective clinical practiceis always the priority. But as Ponder points out,despite the UK’s reputation for research excel-lence, funding agencies have tended to treatresearch institutes and clinical departments asseparate entities and “not looked at the interfacebetween them as closely as they should.”

In fact, until recently the UK has sufferedmany of the same structural and professionalproblems as other countries when it comes toresearch opportunities, best use of resources andcareer pathways. As recently as 2000, Pondergave evidence to a parliamentary committeeabout the state of cancer research, in which he

CoverStory


“It seemed to me that if you want to specialise

in cancer you need a strong scientific platform”

RIC

HA

RD

BA

KE

R /

IPG

CoverStory


pulled no punches, especially about the lack ofan adequate infrastructure for applied clinicalresearch. As a result, many of the brightestgraduates are going into basic medical research– and staying there.

Some of these criticisms have started to beaddressed. The formation of a National CancerResearch Institute has been a big step, whileBritain’s National Health Service (NHS) islooking at how its own research budget is spentto better effect, for example, by creating anational cancer research network to supportclinical trials and other research.

But there is still an awful lot to do, inPonder’s view, before the UK will see a stream-lined system where cancer doctors are trainingand working on the right subjects at the righttime and in the right places to maximise thatscientific-medical interface.

His own career path is a case in point, espe-cially in his early years, as he had to continually

move around to find the backing and resources towork on promising research while also progress-ing his medical training.

At school, he horrified his teachers byswitching from English and history to science,at a time “when it wasn’t respectable for an aca-demically minded boy to do biology – it wasconsidered a soft subject.” But the seeds hadbeen sown earlier, when a primary school-teacher had showed him how to look at pondlife under an old microscope, and he also ran aschool weather station for a year.

He went to Cambridge to read medicine –although he could equally have stuck to straightscience – but “it was clear that medicine was aninteresting and natural way to apply your knowl-edge.” Although he could have stayed on as anacademic, Ponder chose to begin a career as cli-nician, moving to St Thomas’ Hospital in London,and “thoroughly enjoyed six or so years of clinicalpractice and training,” doing the usual rotations in

RIC

HA

RD

BA

KE

R /

IPG

CoverStory


had,” says Ponder. “I went to get training in how todo science, not anything that was applied in a par-ticular way.” Certainly, the drive to carry outresearch seems to have sustained him ever since.

In any case, Ponder was already interested incancer, as it had the attraction of covering a widespectrum – from difficult palliative care issues allthe way to understanding fundamental biology. “Ithad everything for me – I realised I couldn’t do itall, but I knew I would end up somewhere on thisspectrum.” On a summer school in 1975 he metJohn Cairns and helped him write Cancer,Science and Society – a book for non-specialiststhat is still required reading on at least one courseof the same name at Johns Hopkins University.

“I wanted then to train in clinical cancermedicine, but there really was no place suitable– Barts [St Bartholomew’s, London] was thenthe leading UK centre, but specialised inleukaemia and lymphoma – and there wasn’tmuch epithelial oncology.” The Cancer

Determined to work on a sound scientific basis asan academic, and eschewing the chance tobecome an oncology consultant, Ponder wentback to the Cancer Research Campaign andobtained a career development grant that tookhim to the Institute of Cancer Research in Suttonand his own programme researching the organi-sation of epithelia in chimaeric mice. “I wanted tostudy epithelial cancer and its biology and itseemed to me that cancer wasn’t just a matter ofdisordered or excessive growth – more a problemof the breakdown of the rules that govern theorganisation of tissue.” The idea was to gaininsight into the clonal structure of an epitheliumand how it broke down in cancer.

“We didn’t have the tools then to take it fur-ther. What we needed were inducible markerslinked to a gene that you can also induce, thenyou could perturb particular gene expression incells that are marked and see how that affects thebehaviour of the clone. And that’s what

“That taught me a lesson. Don’t wait for someone

to tell you what to do – just go and do it”

various hospitals, and returning to St Thomas’ tofinish his general training in internal medicine.

“It was then I decided I really wanted to doresearch and go back into science – it seemedto me that if you wanted to specialise in some-thing like cancer you needed a strong scientificplatform, otherwise you wouldn’t be equippedfor the future.”

Casting around at St Thomas’ for a researchtopic and supervisor, he soon found that the teach-ing hospital didn’t have anyone really informedabout lab research. He was referred to theImperial Cancer Research Fund – “They’ll giveyou a tough project you won’t understand” – and toan array of top researchers. Director MichaelStoker duly set him up with a fellowship to do aPhD on the structure of chromatin in polyomavirus, which led to a paper in Cell. “I had a fantas-tic time – probably the happiest three years I’ve

Research Campaign awarded him the firstHamilton Fairley Fellowship to train abroad fora year at Harvard medical school, but althoughhe found the experience really useful and likedthe university, he stayed only for that year, as bythis point he was married with four young chil-dren. “The Americans weren’t sympathetic toanyone doing anything other than working – wehad very little money and my wife was rather iso-lated there.”

Back at Barts he worked as a senior registrarin oncology and, although he was soon to movemuch more into research and the genetics field,he considers that his experience on the clinicalside has put him in a far better position tobridge the clinical–research science gap thansomeone trained only as a scientist – and ofcourse today he also heads the university/hospi-tal clinical oncology department.

CoverStory


we are doing in the lab here 20 years later. It isonly now we have the technology to do it.”

While at the Institute of Cancer Research,Ponder also held a clinical appointment at thenext door Royal Marsden, a major UK cancer hos-pital, presenting himself as a free resource – butfound his background as a molecular biologistfailed to excite. “That taught me a lesson which Ikeep telling young people: Don’t wait for someoneto tell you what to do – just go and do it. The mis-take I made was thinking that anyone more senior

ing after the families. I’d read papers aboutHuntingdon’s and how researchers were settingout to find the genes by linkage – so I thought todo the same with cancer genes by collecting thy-roid families. It took me about five years to per-suade anyone I was serious, but we did it.”

He was told in no uncertain terms that whilehis work on bladder and also prostate cancer wasvery interesting, cancer genetics should be keptstrictly as a hobby. “They thought there was nofuture in it. My colleagues said, ‘This is a cancerhospital – we treat cancer patients here. Whatyou appear to be interested in is people whohaven’t got cancer but who might get it. Thatdoesn’t belong in a hospital – you should be insome epidemiology institute.’ The model for med-ical oncology then was restricted pretty much tochemotherapy – my approach just didn’t fit.”

Fortunately, Ponder was able to take oversome posts not filled in another department, andhe recruited a molecular biologist and also hisown wife as a research nurse to collect families,“and we linked the gene [for thyroid cancer] andso no one could really say boo then.”

It was crucial, says Ponder, to be based in thehospital and also to be trusted as a cancer doctor.GPs could be confident that if referrals revealeda raised risk (there was also a biochemical screen-ing test), then the best advice and, if necessary,treatment – which could be a thyroidectomy –could be given.

With both his gene linkage and work on micegoing well, Ponder needed to expand – and it wasCambridge that gave him the opportunity. “Ithought I was going to find the (thyroid) gene Ihad done the linkage for and understand how itworked,” he says. “I was also the Chair of theInternational Consortium for Breast CancerLinkage at the time, and I thought we wouldrepeat the process for that disease too.” The workwith mice would then help complete the pictureby manipulating the genes in tissues to find outwhat the effects were.

Ponder’s team found the RET gene implicat-ed in thyroid cancer in 1993. “But doing the biol-ogy for RET turned out not to be easy for me, asthe gene is a receptor tyrosine kinase – a memberof a large family – and there were real experts inthis around the world who could do in a week

The Ponder Lab,1989

had the time to worry about what I needed to do.” Casting around, he joined a group of urologists –identifying the bladder as a suitable organ to con-tribute to his research on epithelia and their clon-al organisation. “No one was doing much medicaloncology in that area then.”

“That’s where I learnt my second lesson: tocollect all the samples and work with a clinicalteam requires a lot more time and resource thanone person doing a lab project can possibly have– people constantly underestimate the resourcesneeded to do decent clinical research.”

Then came a ‘strike of fate’ that oftenchanges a career – in Ponder’s case, it was on aslow day in urology. Seeing that next door thethyroid clinic was very busy, he offered to helpout. He found piles of case notes on the clinictable and took two of the thickest ones there.“They were two different families with inheritedthyroid cancer – and while the cancer was beinglooked after, it was clear no one was really look-

CoverStory


to the international effort to find linkages, con-tributing families to Mike Stratton’s work on theBRCA2 breast cancer gene and making one ofthe first BRCA2 ‘knockout mice’. That biologicalwork is ongoing at the Hutchison/MRC instituteunder one of Ponder’s colleagues.

As he points out, the early work on identify-ing often rare familial syndromes has fuelled themore recent work on cancer mechanisms. “Andin the current phase we have realised that thosestriking families are only a small part of the totalamount of inherited susceptibility. Fewer than 5%of breast cancers are attributable to single strong-ly predisposing genes. However, there is a distri-bution of risk across the population which isdetermined by combinations of weaker genes.We’ve now shown that probably half of all breastcancers occur in about 12% of people at highestrisk. In fact there is probably a 40-fold differencein risk between the top 20% and bottom 20%.”

Although only a model – though a robust one,

Ponder’s view is also that early work should be tar-geted at those at highest risk even if they comprisea minority of the disease. “If you establish theprinciples that your intervention is successful youcan then consider generalising it more widely.”

Any cancer centre head wants to carve outa distinctive profile. Ponder says that on the sci-ence side, the focus for the new institute will bemore on the environment of the cancer cell inthe tissue, than events in the single cell. “Mostother institutes focus on cell signalling path-ways, cell cycle transcription and that sort ofthing – very important but we are more inter-ested in the interaction between cancer cellsand surrounding normal cells.”

Meanwhile, on the clinical side, Ponder saysthe aim is not to be another experimental cancertherapeutics base – other UK centres are focus-ing on drug development and on phase III work,for example, and he’s happy with that. “We will doclinical trials but based on biological research –

“People constantly underestimate the resources

needed to do decent clinical research”

what it would take me two years to do. So Icouldn’t make much more of a contribution interms of what the gene did.

“But where we could make progress wasrelying on my clinical and genetic epidemiologyexpertise. Because we knew there were differ-ent clinical forms of the syndrome, we wereable to sample large patient collections anddemonstrate different mutations in the geneand different forms of the syndrome. That’scommonplace now but was fairly novel thenand gave useful insights.”

Ponder’s group was then able to help draw upnew guidelines for management of the familieswith thyroid cancer – and by the mid-1990s waspleased to report that outcomes had improvedover previous guidelines.

Work on breast and ovary cancer went for-ward in parallel, with Ponder’s team contributing

according to Ponder – the idea of a wide combi-nation of genes contributing to the distribution ofsusceptibility has been difficult for many. “I thinkI’m a fairly good lecturer, but I have to cover thisthree or four times,” he notes. “The idea of courseis well established in the literature on the genet-ics of flies, for example – it’s just that convention-al molecular biologists aren’t used to it. We haveidentified some of the variants but not many yet– it’s a massive task.”

As he continues: “We would like to under-stand how this genetic variation causes this pre-disposition. It’s likely to be mutations on thedirect pathway of the events that turn a normalcell into cancer cell, but the genetic variantsthat add to risk are more likely to influencethings that impinge on this pathway from out-side the cancer cell, and this may be a better setof targets for prevention.”

CoverStory


early stage trials of agents which impact on path-ways where we think we have particular scientif-ic expertise.” Genomics and molecular imagingexpertise will also be developed further.

“We think too there is mileage in finding outhow to use existing drugs better – by examiningmolecularly well-described cancers from the localpopulation to get insights into the determinantsof response and resistance.”

In the longer term, Ponder wants to hone thatfocus on the early stage of cancer development asthe most distinctive – and most difficult – contri-bution. “What I’m hoping is that the new institutewill provide the reagents and tools to complementthe genetic epidemiology and public health workwe have at the Strangeways Research Lab,”(another institute where he is co-director). Thisall means identifying higher risk groups, runningscreening programmes to identify early lesions –hopefully at some point from non-invasive imag-ing – and developing targets for intervention andmarkers of response.

It also means investment in a new cancercentre at Addenbrooke’s with the equipmentneeded for early intensive investigations.

Ponder is pleased to note that more funding inthe UK is earmarked for applied research – oneof the initial moves is the establishment of aNational Clinical Trials Network, withCambridge one of the first regional centres.With extra resources for nurses, the clinical tri-als entry has gone from 2% to 14% of newpatients in four or five years. Britain also has aNational Translational Cancer ResearchNetwork (NTRAC) – again Cambridge is one ofthe participants.

However, too many trials are determined byfunds from drug companies, says Ponder, who isconcerned that more intellectually useful work isnot being done. “For example on local trials we’vethought of ourselves, or MRC [Medical ResearchCouncil] trials, the hospitals simply don’t havethe money to do them.” This is one gap in his par-liamentary submission that he feels is not beingclosed yet, but he says there is “general recogni-tion that there is a problem.”

“I have, though, persuaded Cancer ResearchUK to invest also in the clinical department oninformation systems, sample collection, patholo-gy time and so on – above what we need for NHSservice – to provide an environment where clini-cal research can happen.”

Away from Cambridge, Ponder has mademany visits to other scientific research centres –including assessment visits in Europe – and feelsthat some lack the ‘buzz’ to provide a stream oftop-quality researchers. “I have a lot of recruit-ment to do here – including 10 professorialappointments – and in all the due diligence I doI just don’t find many candidates from Europe,”he says. “There are individually excellent peoplethere but I don’t get the sense that overall thecentres compare with the best in the US andprobably not with the best here.”

If top scientific researchers are hard to comeby – and more need to come from the UK as well– so too are top clinical academics, with expertisein the UK being spread too widely across too

“We’ve shown that probably half of all breast cancers

occur in about 12% of people at highest risk”

Visiting labs in the Universityof Shantou, People’sRepublic of China,as part of acollaborative projecton the genetics of nasopharyngealcarcinoma

CoverStory


many centres. “Many clinical academics havenot had much scientific training – we are stillinclined here to create new centres and profes-sorial chairs for people who are undoubtedlygood clinicians, but they do not really have theresearch background to sustain them.” That hasa knock-on effect with a lack of role models forthe next generation, he feels.

Ponder would rather see a smaller numberof cancer centres with some of these, oftenyoung, oncology professors dropping back tointermediate academic positions at a top quali-ty institute, and “really getting 10 years of solidresearch under their belt.”

He also feels oncology in the UK has beentoo focused on medical oncology and also radio-therapy (the latter being “academically quiteweak”). “So it was quite deliberate that the firstappointment I made here was a professor ofcancer surgery – the delivery of cancer care andresearch is a combination of oncology, surgery,pathology and imaging – and we need leader-ship in all of those disciplines.”

Again, there had been progress here, henotes, with Cancer Research UK taking on fel-lows in surgery and pathology as well as oncol-ogy. But there are currently relatively fewprofessors of cancer surgery in the UK, he feels,and pathologists are particularly hard to find.He’d also like to see his own university teachingmedical students more about cancer – there isonly a few days on the topic, he says, and a pre-sumption it will be covered in other organ-based sessions.

Until a recent submersion in all the admin-istrative work of launching the new institute,Ponder was regularly seeing patients in the hospital’s genetics department, sensitive alwaysto the relationships between family memberswho may be present, and what they want out of the visit. As he says: “A relative may have dragooned them into it, or their family doctor

may simply have thought it would interest me.” However, he feels it’s not his place to be

heavily involved in the ethical debate aboutgenetic testing and the like. He has contributedto the government’s Human GeneticsCommission at a high level, but says that advo-cacy work should come from the patient side –and indeed his wife Maggie is the chair of acharity called the Genetic Interest Group,which acts for families with genetic illnesses.

“There is a danger of the tail wagging thedog – people with sincerely held views but onthe whole obstructive of research,” commentsPonder. “I think there is a large silent majoritywho wish they would go away – but that’s mucheasier for patient representatives to say.”

Ponder has the usual string of top awardswith the stand-out being election to Britain’sfamous Royal Society. It’s not been enough totempt any of his children into medicine –although two are working as scientists. Homeinterests include walking, wine, golf (he’s beena single handicap player for many years) andgardening – they grow vegetables and flowersand keep ducks and other animals. “It’s all a bitof a shambles,” (one suspects a lack ofLinnaean order here).

That relaxation is understandable givenwhat’s on his plate at work – and he’s got anoth-er seven years in post to build the research basethat should be the rival of any centre, althoughof course an institute is there for the long term.

Despite the advances made in recent years,Ponder rattles off a long list of fundamentalthings we just don’t know about cancer – howlittle we understand about gene expression, cellto cell and protein interactions, and cancerstem cells, for example. And why do barely onein a hundred drugs hit their targets and why dothose that do work?

It’s axiomatic of the field perhaps that wher-ever you are it feels like you’ve only just begun.

Ponder feels it’s not his place to be heavily involved

in the ethical debate about genetic testing


GrandRound

Treating anaemia:damned if you do,damned if you don’t

Many cancer patients suffer unnecessary levels of fatigue due to a failure to

treat their anaemia. But just as the cost of erythropoiesis-stimulating proteins

looks set to fall, surprise research results are prompting questions over

whether these drugs might actually be stimulating tumour growth.

➜ Mary Rice

Until recently, epoetin, thehuman recombinant formof erythropoietin, was con-sidered by most oncolo-gists to be of considerable

benefit for patients suffering from can-cer-related anaemia. When used inthis way it improves red blood cell lev-els and hence reduces fatigue, one ofthe most common and debilitatingcomplaints of cancer patients. It allseemed fairly obvious: the literatureshowed that a low haemoglobin countis associated with poor outcomes insuch patients, and increasing thehaemoglobin can significantly improvequality of life. Improving the quality oflife generally has some bearing on sur-vival and disease progression in cancerpatients, and no-one had any seriousworries about this subject.

That was until the publication oftwo studies that appeared to showthat patients taking erythropoiesis-

stimulating proteins (ESPs) had worseoutcomes in terms of survival. Theresults were unexpected, not least forthe investigators, and prompted manyto wonder whether the establishedview of ESPs was correct.

In 2003, Michael Henke, fromthe University Hospital, Freiburg,Germany, and colleagues, publisheda study which showedresults that surprised boththe authors and fellowoncologists (Lancet 2003,362:1255–60). They ran amulticentre, randomised,placebo-controlled trial in351 patients with lowhaemoglobin levels whosuffered from head andneck cancer. All thepatients given epoetin ßhad considerable improve-ments in their haemoglobinlevels compared with those

who were on placebo. This was asexpected. But what came as a shockto Henke were the findings on dis-ease control and survival – in bothcases the outcomes were worse in theESP group. “Despite a reliable rise inhaemoglobin concentrations, we sawno benefit for locoregional progres-sion-free survival, locoregional

Michael Henke:findings werethe opposite of whatwe expected.We are waitinganxiously for ournext results

GrandRound

progression, or survival,” said theauthors. “On the contrary, patientsgiven placebo fared significantly bet-ter than those given epoetin ß. A con-tribution of study design to this unex-pected finding is unlikely.”

SURPRISE RESULTS“We knew that patients who hadhypoxia didn’t react as well to radio-therapy as those who didn’t,” saysHenke. “There is pre-clinical evi-dence that epoetin increases theradiosensitivity of tumours, and wethought it would therefore improvethe efficacy of radiation andchemotherapy. We therefore believedthat patients with anaemia undergo-ing radiotherapy would benefit fromhaving their haemoglobin levelsboosted with epoetin. So we wereexpecting just the opposite resultsfrom those we found, which reallysurprised and disappointed us.”

Imbalances with certain subgroupsin the trial might have contributed tothe negative effect of the drug onoutcomes, says the paper, but underly-ing biological phenomena are also apossibility. Further trials are needed,says Henke, to try and explain thebiological mechanism that mightunderpin the findings, and he is cur-rently looking further into the possibili-ty that tumour cells in some kinds ofcancers may express erythropoietinreceptors and that they use theerythropoietin system for growth andangiogenesis. If this is the case, he says,the finding could have considerableclinical benefit. “You could look forways of blocking epoetin expression inthe cells and thereby improve results,as well as giving doctors a new way ofpredicting outcomes more accurately.”

Henke’s study has, perhaps pre-dictably, come under considerablefire regarding its design, results, andinterpretation. He takes a sanguine


view. “When you do research andmake an unexpected observation youexpect to get criticism. However, Iwould say to critics that there is nogood clinical study that shows thatwhat we have found is wrong. Mostprevious ESP studies have focussedon quality of life in palliative treat-ment. We wanted to see if it wouldheal rather than ameliorate. Anotherdifference is that ESPs have previ-ously been studied mainly in patientswith disseminated disease, whowould probably have died anyway,whereas we were looking at peoplewith localised cancers in the hopethat we could make them well. As faras we are aware, ours is the onlyproperly designed study to look atthese issues. We are waiting anxious-ly for our next results.”

The study supports findings fromanother study of epoetin use (epoetinα) in breast cancer (Leyland-Jones,Lancet Oncology 2003 4:459–460). Inthis trial, the treatment group wasobserved to have an increased inci-dence of disease progression com-pared with the placebo group, and theoutcome was higher mortality in thetreatment group.

In the light of these studies, lastyear the US Food and DrugAdministration (FDA) convened apanel to scrutinise safety. A spokesmansaid: “FDA is currently working withsponsors of approved and investiga-tional erythropoietin products toensure that studies are conducted to

investigate possible impact of the drugon tumor growth promotion. Separatefrom the meeting last May, the productlabelling for the erythropoietin prod-ucts approved in the US (Epogen[epoetin α], Procrit [epoetin α], andAranesp [darbepoetin α]) have beenupdated to reflect this new informa-tion and revised labelling has been dis-tributed under the cover of DearHealth Care Professional letters to themedical community.” The EuropeanMedicines Agency (EMEA) currentlyhas no plans to undertake an investiga-tion of its own, and will await the out-come of further studies. So it appearsthat the jury is still out on this issue.

Amgen, which manufacturesAranesp, said it could not comment onother companies’ studies. However,Amgen’s European Medical Director,Dietmar Berger, said the company waskeeping a close eye on the situation:“Amgen has a robust pharmacovigi-lance programme that is evaluating theeffect of Aranesp on survival andtumour progression in multiple oncol-ogy populations with well-designedclinical and epidemiological studies.”

He also pointed out that the drugserved a real need: “Cancer patientscite anaemia as one of the mostdebilitating side-effects of chemo-therapy. When used in accord withthe approved prescribing guidelines,Aranesp effectively corrects anaemiaand reduces or eliminates the needfor blood transfusions in chemother-apy patients, without the burden offrequent injections and doctor’soffice visits.”

A REAL NEEDThere is no doubt that anaemia is aproblem for cancer patients. HeinzLudwig, from the Wilhelminenspital,Vienna, Austria, and colleagues fromall over Europe, collected data on can-cer-related anaemia from 748 cancer

Heinz Ludwig:ESP treatmentshould dependon severityof symptoms.In some subgroupsit should be usedwith caution


centres in 24 countries over a six-month period in 2001 (EJC 2004,40:2293–2306). This large studyshowed clearly that anaemia preva-lence and incidence among cancerpatients were high, and that anaemiahad a strong relationship to poorer out-comes. Treatment for anaemia maynot be optimal, say the authors: manyanaemic patients, including those withvery low haemoglobin levels who fallinto the category where they should betreated under existing guidelines, werenot treated at all. Of all patients whowere ever anaemic, 61.1% did notreceive treatment for their anaemia.

Most patients who were not treatedhad haemoglobin levels that were toolow, but not disastrously so – 47.2% ofthose not treated had levels between10.0 and 11.9 g/dl; but 12.9% who werenot treated had levels between 8 and9.9 g/dl; and 0.9% were below 8 g/dl.

Most patients who beganchemotherapy during the study be-came anaemic. The longer they re-ceived chemotherapy, the greater theirrisk of developing anaemia: it was re-ported in 19.5% of patients in the firstchemotherapy cycle and 46.7% in thefifth cycle. Even in the anaemic groupwith the highest levels of haemoglobin

(10–11.9 g/dl) their anaemia had a sig-nificant impact on performance status.Using the physician-reported WHOscore, it was shown that performancestatus worsened as haemoglobindecreased, and the correlation was sig-nificant. Over half the patients withsevere anaemia (haemoglobin less than8 g/dl) had poor scores, and evenamong those with haemoglobin levelsof 10–11.9 g/dl, one quarter had poorscores. This association is consistentwith findings that show a correlationbetween increasing haemoglobin andquality of life, the study said.“From the biological point of view it’s

GrandRound

Combatting fatigue can make a huge difference

to a patient’s quality of life

IMA

GE

S O

F H

OP

E

GrandRound

clear that anaemia in cancer patientsshould be corrected,” says Ludwig,“and the trigger for ESP treatmentshould be the degree of symptoms.This will vary in different groups. Forexample, a 75-year-old man with heartdisease and mild anaemia would bene-fit from just a small increase in haemo-globin levels – he would have lessangina. But a young person can toler-ate a higher degree of anaemia, and Iwould personally start treatment later.It’s important that treatment is individ-ualised within existing guidelines.


EORTC Guidelines for use of erythropoietic proteinsin anaemic patients with cancer

Anaemia is a frequent finding in cancer patients andshould be carefully assessed. Additional causes ofanaemia such as iron deficiency, bleeding, nutritionaldefects or haemolysis should be corrected prior to ery-thropoietic protein therapy. The following recommenda-tions are related to adult cancer patients with solidtumours or haematological malignancies:■ In cancer patients receiving chemotherapy and/orradiotherapy, treatment with erythropoietic proteinsshould be initiated at a Hb level of 90–110 g/l based onanaemia-related symptoms.■ In patients with cancer-related anaemia not undergo-ing chemotherapy and/or radiotherapy, treatment witherythropoietic proteins should be initiated at a Hb levelof 90–110 g/l based on anaemia-related symptoms.■ Erythropoietic proteins may be considered in asymp-tomatic, anaemic patients with a Hb level of 90–110 g/lto prevent a further decline in Hb, according to individ-ual factors (e.g., type/intensity of chemotherapy, baselineHb).■ For anaemic patients who are transfusion-dependent,erythropoietic proteins should be initiated in addition tored blood cell transfusions.■We do not recommend the prophylactic use of erythro-poietic proteins to prevent anaemia in patients undergo-

ing chemotherapy and/or radiotherapy who have normal.Hb values at the start of treatment.■ Elderly patients experience the same benefits fromtreatment with erythropoietic proteins as youngerpatients.■ The target Hb concentration should be 120–130 g/l.■ The two major goals of erythropoietic protein therapyshould be to improve quality of life and prevent transfu-sions.■ The use of erythropoietic proteins with the aim ofimproving survival or response to treatment is not rec-ommended as there is no evidence to support this.Further studies are needed.■ Within reasonable limits of body weight, fixed doses oferythropoietic proteins should be used.■ We recommend the dosing of erythropoietic proteinsaccording to Fig. 1. However, the decision to dose-esca-late cannot be generally recommended and must beindividualised. Treatment should be continued as longas Hb levels remain ≤120–130 g/l and patients showsymptomatic improvement. For patients reaching thetarget Hb, individualised titration of lowest effectivemaintenance dose should be made repeatedly.■ Despite the common use of epoetin α QW (40,000IU), there is limited evidence to support this dosing

However, guidelines by their verynature are fairly general – if they arenot, they are just too complicated foranyone to follow, and they are boundto end up as a compromise.”

As to the effect of ESPs on sur-vival, Ludwig and colleagues did notsee a negative impact. However, theremay be sub-groups where they shouldbe used with caution, he says. “Inpatients with solid tumours and hightumour mass or people who wereincompletely resected, we should prob-ably be careful about recommending

ESPs, but in other groups we shouldexploit their benefits,” he says.

A Cochrane systematic review ofthe effect of ESPs used to prevent ortreat anaemia in cancer patients wasupdated in May 2004, after the publi-cation of the two studies causingconcern (Bohlius et al, The CochraneDatabase of Systematic Reviews 2004,3: CD003407.pub2). The authorsfound consistent evidence that ESPadministration reduces the risk forblood transfusions, and that for patientswith haemoglobin levels below 10 g/dl


GrandRound

schedule. The QW application of epoetin ß (30,000 IU)has been shown to be effective in patients with non-myeloid haematological malignancies. The QW admin-istration of darbepoetin α (2.25 µg/kg) can be recom-mended. There is currently limited evidence to supportthe use of darbepoetin α in Q2W, Q3W or Q4W dosingintervals.■The use of higher initial doses of erythropoietic proteinscan currently not be recommended as a standard approachwith epoetin α or epoetin ß, but limited evidence exists fordarbepoetin α. Further studies are needed.■ There are no predictive factors of response to erythro-poietic proteins that can be routinely used in clinicalpractice; a low serum erythropoietin level (in particular inhaematological malignancies) is the only verified predic-tive factor of some importance. Values must be interpret-ed relative to the degree of anaemia present.■ For patients undergoing autologous blood stem cell

transplants, the effects of erythropoietic proteins havenot yet been convincingly shown and they cannot there-fore be recommended.■ For patients undergoing allogeneic blood stem celltransplants, the clinical impact of erythropoietic proteinsis limited and they can only be recommended on anindividual basis.■ The fear of pure red cell aplasia should not lead toerythropoietic proteins being withheld in patients withcancer.■ When using erythropoietic proteins to treat anaemiain cancer patients, the combined analysis of all studydata indicates a slightly increased risk of thromboembol-ic events. However, this may be related to the target Hblevel achieved.

Reprinted from European Journal of Cancer vol. 40, C. Bokemeyer et al., EORTCguidelines for the use of erythropoietic proteins in anaemic patients with cancer, pp 2201–2206,© (2004), with permission from Elsevier

Fig. 1 - Suggesteddosing algorithm forerythropoieticproteins in patientswith cancer. Thetarget haemoglobin(Hb) levels arediscussed in the boxand are not above130 g/l

it improved haematological response.However, they conclude: “There isinconclusive evidence whether erythro-poietin improves tumour response andoverall survival. Research on side-effects is inconclusive.”

Jan Foubert, President of theEuropean Oncology Nursing Society,who runs a specialist fatigue clinic atthe Institut Bordet in Brussels,Belgium, says that ESPs are helpfulin boosting energy levels and control-ling fatigue in the patients he sees.“In studies of anaemia in cancer

patients, we see improvement in thehaemoglobin levels when they takeESPs.” He adds, however, that thereis a need for more research into thelink between fatigue and anaemiaespecially in elderly cancer survivors.Research is also needed into the linkbetween fatigue and depression, anx-iety and sleep disturbance, and intohow activity may help in managingfatigue.

Foubert worries that the results ofthe Henke and Leyland-Jones studiesmay hinder attempts to get the prob-

lem of anaemia in cancer patientstaken more seriously and dealt withmore consistently. “The significance ofanaemia and fatigue to the patient is

Jan Foubert:Anaemia-relatedfatigue is a heavyburden for cancerpatients.We shouldn’t jumpto conclusions

START

STOP STOP

STOP

Remain on increaseddose

Dose increase

Remain on dose

(4 weeks)

(4 weeks)(4-6 weeks)

Continue withdose adjust-ments if respon-se (adjust tosymptomsrather than Hb)

Decision point 2:no symptomaticimprovement or

no Hb rise

Decision point 1:no symptomaticimprovement or

no Hb rise

GrandRound

often overlooked in routine assess-ments, and optimal methods forassessing and treating these conditionsremain unclear,” he said. He is confi-dent that treating anaemic patientswith ESP helps their quality of life,and feels that there were probablyproblems in the design of the studiesthat showed worse outcomes. “Weshouldn’t jump to conclusions. Newguidelines are very careful about thetarget level, the duration and follow-upof treatment, and the endpoints.”

FALLING PRICESOne of the reasons why ESPs are notused more widely to treat anaemia incancer patients is cost. In Italy, forexample, the national health servicewill reimburse ESP treatment for onlya small and limited group of patients –anaemic patients with chronic renalfailure undergoing dialysis, and cancerpatients suffering chemotherapy-asso-ciated anaemia. Yet in 2001 ESPsranked fifth in terms of total out-of-hospital expenditure on drugs by theItalian national health service,accounting for 209 million euros, or1.7% of total drug expenditure.

The high prices make ESPs a majorearner for the industry; according to theIMS World Review, they rankedseventh in global sales figures for 2003,coming in at $10.1 billion, after choles-terol and triglyceride reducers, antiul-cerants, antidepressants, antirheumat-ic non-steroidals, antipsychotics andcalcium antagonists (plain).


However, this may now be set tochange, and Ludwig argues that pricecuts and the advent of biosimilar drugswill mean that epoetin will soonbecome a standard treatment forcancer-related anaemia. The problemis, given the question marks thrown upby the results of recent trials into theimpact of ESPs on tumour progressionand survival, which patients stand tobenefit and which to lose?

Giovanni Apolone of the IstitutoMario Negri, Milan, Italy, recentlywrote an editorial on the subject forthe European Journal of Cancer (vol40:1289–1291). He believes existingguidelines issued by regulatoryauthorities are sound. “Within theindications of the FDA, EMEA andother international and national regu-latory agencies, at present ESPsshould be considered a class of drugsthat has received a quite completeassessment in terms of risk-benefitanalysis. Several systematic reviewsand meta-analyses support theseindications. Basically, although somedifferences do exist between coun-tries, the use of ESPs in patients withcancer to treat or prevent anaemiasecondary to cancer or resulting fromits treatment is recommended fortreatment in patients with severeanaemia, as an alternative to bloodtransfusion. In less severe anaemia,the decision to give epoetin shouldbe determined by a careful examina-tion of the clinical circumstances,”he says.

To address this situation,EORTC have recently produced a setof guidelines for ESP use in cancerpatients (see pp 18, 19).

He adds, however, that the unex-pected correlations found betweenESPs and worse prognosis in the twostudies on head and neck cancer andbreast cancer show the need for fur-ther research. “We need to carry out

more studies in the light of suchunexpected results as Henke’s. Theseshould either be entirely new or re-evaluations of old studies in order tohave a better understanding of thereasons for these results. These couldbe due to the expression of biologicalfactors regulating or modulating theclinical expression of these drugs,and we need to know if they exist andwhat they are.

“There is some pre-clinical evi-dence that some cancers (breast,prostate, and ovarian) possess ery-thropoietin receptors and that thesecells may proliferate in response toepoetin use, but there are other can-cers, such as small cell lung cancer,where this phenomenon could not bedemonstrated. What is needed istranslational research to confirmresults from these pre-clinical studiesin randomised clinical trials in ahomogenous population, and with anaccurate and systematic collection ofinformation that allows for stratifica-tion of subjects in various categoriesaccording to receptor status (pres-ence and quantities).”

Until further trials are done, saysApolone, we cannot know whetherthe guidelines need to be amended,and he urges the industry to focus onthis task. “Pharmaceutical companiesmarketing variants of epoetinsworldwide, instead of arguing aboutthe internal and external validity ofavailable evidence from controlledclinical trials, should facilitate andsupport new pre-clinical studies todiscover the biological basis of theunexpected clinical results.” In themeantime, he says, the use of ESPsoutside the existing guidelines shouldbe considered only in the context ofvery well planned and carefullymonitored clinical studies thatimplement strict ethical safeguardsfor patients.

Giovanni Apolone:Existing guidelinesare sound.More researchis needed to explainthe unexpectedresults


DrugWatch

Getting drug therapies into thebrain to treat life-threateningillnesses is one of the most

challenging issues in drug delivery.Many drugs display excellent affinityfor their targets in cell cultures andisolated preparations, but remainundeveloped because they cannot getaccess to the brain. Companies work-ing on the central nervous system maybe able to translate potent moleculesinto significant patient advances ifthey only considered the delivery andtargeting issues more carefully.According to a 2004 study by theTufts Centre for the Study of DrugDevelopment, central nervous sys-tem (CNS) drugs are more costly andtake longer to develop than othertherapeutic classes, but the rewardsextend over a longer period. Thestudy found they take, on average,115 months to develop, at a cost ofUS$527 million; lifecycle sales peakat US$849 million, nine years afterlaunch. If delivery issues could beresolved at earlier stages of develop-ment, leads might emerge morequickly. A number of false dawns in the1990s suggested the blood-brain bar-rier (BBB) could be breached using

either a range of drugs to reversiblyloosen the BBB cells or by chemical-ly modifying drugs, making themmore likely to permeate it. Theseapproaches failed, however, becauseof a lack of sustained and adequatedelivery and also safety issues. Thishas led to scepticism about newdelivery approaches, even thoughpreclinical research suggests break-throughs may be possible.

GENE DELIVERY TO THE BRAINAt the annual meeting of theControlled Release Society (CRS) inHawaii in June 2004, Dr WilliamPardridge of the University ofCalifornia highlighted some of thepioneering work of his laboratory –on delivering gene medicine to thebrain by targeting receptors on theBBB. Typically, the BBB keeps water-soluble agents out of the brain andfavours access for small fat-solubledrugs such as diazepam. Water-soluble molecules such as levodopaand glucose can, however, cross thebarrier by being carried on capillarymembrane transporters, many ofwhich are still undiscovered. One problem is usually enough formost scientists, but Pardridge is try-

ing to solve both brain and genedelivery using a single molecular tar-geting tool 1. In justifying his meth-ods, he argues that the more conven-tional approach – using transcranialinjections of genes in viral carriers –gives rather weak results in confinedbrain regions, which is not much usefor diseases that spread throughoutthe brain such as Alzheimer’s andsome advanced cancers. In addition,there are concerns about the inflam-matory and autoimmune side-effectsassociated with the viral carrier itself. What Pardridge is trying to do isadminister tiny fatty particles loadedwith genes to the blood, which bringsthe particles to the brain capillariesof the BBB as it circulates around thebody (see box on page 24). The parti-cles are specifically targeted to capil-lary endothelial cell receptors towhich antibodies on the particlesurface can bind. Once across thebarrier, the gene is then free to dis-seminate within the brain and beexpressed in all or selected regions.This approach is non-invasive andwould not require surgery.These particular receptor targetswere chosen as a result of promisingrodent data. Somewhat unexpectedly,

➜ David Brayden*

Brainwavesin drug delivery

Delivering drugs through the blood-brain barrier has always confounded scientists, but new

developments in both non-invasive targeted brain delivery and brain-implanted drug

formulations may provide a way forward.


DrugWatch

the particles had traversed the barri-er and entered brain neurons. Datapresented at the meeting showedwidespread delivery of gene markersthroughout the brains of rodents andmonkeys using loaded particles target-ing the transferrin and insulin recep-tors respectively. In one pre-clinicalexample, intravenous injections ofparticles containing genes for a defi-cient enzyme improved motor func-tion in a rat model of Parkinsonism2. A second example demonstrated a100% increase in survival time inmice implanted with an experimentalhuman brain cancer following weeklyinjections of an agent to silence geneexpression of a cancer-associatedgrowth factor 3. Specific growth fac-tors encourage cell proliferation andtheir receptors tend to be expressedin many cancers in an unregulatedway. These data from Pardridge sug-gest his approach to silencing genescoding for cancer-implicated recep-tors may be appropriate to take intohumans. They showed a 90% reduc-tion in gene expression for the sus-pect receptor.

A PARCEL WITH TWO ADDRESSESPardridge’s particle system is a com-plex formulation and one of the first todemonstrate targeting from two anti-bodies on the same particle. It hasbeen described as a parcel with both aprimary delivery address (to the BBB)and a secondary forwarding address(to the brain cancer). The particletherefore acts as a Trojan horse, andthe cargo is released only when theparticle enters the cancer and is acti-vated by a tissue-specific trigger. Pardridge told the conference that thiswas one of the first drug delivery tech-nologies to prolong life in animals andthat it should soon be ready for clinicaltrials to deliver nerve growth factors(neurotrophins) for stroke. Outcomesin man are unknown, however, andcould fail for many reasons. One issueis whether humans have sufficientBBB receptors to transport enoughparticles. Another is whether there willbe sufficient drug or gene deliveryfrom each injection to treat chronicbrain disease. Despite theseunknowns, the technology has come along way. Many doubted whether such

a complex tri-partite system couldwork even in animal models. Dr Jorg Kreuter of the University ofFrankfurt, Germany, also providedconvincing pre-clinical data at theCRS conference that supports the the-sis that drug-loaded particles can bedelivered to the brain. His somewhatlarger particles were made from a glue-like polymer, and coated with a deter-gent (polysorbate 80). Kreuter believesthe detergent coating attracts lipid car-rier proteins in the blood, and thenbinds to cholesterol-related (low densi-ty lipoprotein) receptors on the BBB,leading to particle uptake by the brain. He also suggests the particles couldopen the tight junctions between thecells of the BBB capillaries, furtheraiding absorption to the brain. Theyalso block the BBB efflux transporterson the capillaries that normally act ina protective fashion to send toxinsback from the brain to the blood. Bythe same token, efflux transportersalso prevent the delivery of clinicallyuseful agents to the brain.Irrespective of the mechanism, how-ever, data showed that poorly-deliv-ered agents such as the anticancer,doxorubicin, could be made moreeffective against solid cancers in ratswhen these particles were used. Asecond example was the induction ofpain relief in rats using an opiate asthe cargo. There seems little doubtthat the capacity of particles to deliv-er drugs and genes to the brain hasbeen underestimated.

ANY ADVANCE ON WAFERS? An alternative approach to gettingdrugs to the brain has been to bypass

The particle acts as a Trojan horse, releasing

its cargo only when it enters the cancer

DELIVERING GENES VIA LIPOSOMES

The University of California’s laboratory work on delivering gene medicine to the brainuses particles long-established in drug delivery products, fatty globules (liposomes).The liposome construction comprises 85-nm-diameter multi-lamellar anionic units coat-ed with polyethylene glycol (PEG) polymer. It is, in other words, a negatively charged non-sticky onion-like system. PEG was used in order to avoid recognition and removal ofimmunoliposomes by macrophages; hence it improves particle stability and circulationtime. A small proportion of the PEG is then attached to monoclonal antibodies designedto target endothelial cell peptide receptors for either transferrin or insulin. Plasmid DNAcontaining the gene was entrapped in the liposomes and the exteriorised materialchemically removed.


the BBB altogether and implantlocalised controlled release formula-tions directly into areas of brainlesions. This is an invasive approachthat has had relative success in man.In 1996, Guilford Pharmaceuticals’Gliadel ‘Wafer’ was approved by theFDA as a treatment for recurrenthigh grade malignant brain glioma, acondition in which patients typicallysuccumb within 12 months. Seven oreight dime-sized wafers are implant-ed into the cavity left by the surgicalremoval of the recurrent glioma. Thewafers are made of a biodegradablepolyanhydride polymer and containthe anticancer, carmustine, which isreleased in the cavity as the polymerdissolves. In theory, the controlled release of theagent should kill any cancer cells notremoved by surgery. Controlledrelease of localised carmustine alsosuggests the drug’s side-effects may beless than when administered intra-venously. A major issue with thesetypes of formulations, however, is howto prevent dose dumping in the brain. In a recent clinical trial of Gliadel, themedian survival in selected patientswith severe types of glioma wasreported to have increased by 41%from 20 to 28 weeks. An eight-weekextension of life is regarded as signifi-cant for this kind of malignant braincancer, which has few treatmentoptions. Importantly, Gliadel hasrecently gained a wider indicationfrom the FDA and wafers can now beinserted at the time of the initial sur-

gery and diagnosis. In combinationwith surgery and subsequent radia-tion, this change in labelling hasexpanded the Gliadel market. In2003, annual sales were US$20 mil-lion at an average cost of US$10,000per patient, a 32% increase over 2002. Another paper presented at the confer-ence, by Dr Jon Weingart of JohnsHopkins University in the US,described recent studies to furtherdevelop wafer technology for other car-gos and to tailor the device to releasedrug cocktails in a programmed man-ner. Positive pre-clinical studies weredescribed in which two other anti-cancer agents (paclitaxel and camp-tothecan) were formulated intobiodegradable polymers and used totreat rodents with glioma implants.Other wafer formulations include anti-angiogenesis agents, cancer vaccinesand gene-silencing agents. There is also significant potential tocombine intracranial implantation ofchemo-therapeutics with the sys-temic delivery of a secondary agent toachieve additional benefit. Oneexample is the use of a wafer-ladenantibiotic (minocyclin) in combina-tion with intravenous carmustine totreat glioma in rats 4. This technologyextends the design kinetics of howcargos are released. By usingimplanted biodegradable scaffolds,anti-cancer agents that would nor-mally only be able to reach therequired sites in cytotoxic levels, canbe delivered directly to experimentalCNS models of solid tumours. The

university-based group are also work-ing with Guilford Pharmaceuticals toscreen new classes of more stableand potent anti-cancer agents fortheir suitability for local brain gliomatherapy in future clinical trials.While wafer implant technology ispromising and appropriate for life-threatening malignant localisedgliomas, the potential for non-invasiveparticle-based delivery systems cannotbe overlooked. These particles haveshown they can access receptorsexpressed on the blood-brain barrierand deliver cargo to animals.Intravenously-administered targetedparticles carrying genes and drugsthat can access lesions in the brainwould represent a significant break-through in the way a range of CNSdiseases is treated. These deliverysystems could be used to re-examinedrugs that have been discardedbecause of their poor pharmacokinet-ics and also to optimise the deliveryof new candidates. The question nowis whether these new particle sys-tems can work as well in human tri-als as they have done in animals.

DrugWatch

Drugs discarded due to poor pharmacokinetics

could be retried using the new delivery systems

References1. Nature Reviews (2002) 1:131-1392. Zhang et al. (2004)

Human Gene Therapy 15:339-3503. Zhang et al. (2004)

Clinical Cancer Research 10:3667-36774. J Neurooncology (2003) 64:203-209

*Dr David Brayden is chairman of the UK-Irelandchapter of the Controlled Release Society and a principal investigator at the Conway Institute of Biomedical and Biomolecular Research at UniversityCollege, Dublin, Ireland.

This article was first published in Scrip Magazine, October 2004 (138, 13-14). Reproduced by permission of PJB Publications Ltd.

Masterpiece

Jean-Claude Horiot:the innocent inquisitor

In 1972 Jean-Claude Horiot left a wonderful research job in the US to join a cancer centre

in Dijon that was too small to conduct clinical trials on its own. He teamed up with similar

centres, and in so doing laid the basis for cooperative research and helped end a culture in

which medics and hospitals answered to no-one for the quality of their work.

You led the development of internationalcooperative clinical research, whichgroups like the EORTC have used togreat effect in the past 25 years. Whatprompted you to undertake this mam-moth task?JEAN-CLAUDE HORIOT When I graduated as aradiation oncologist in the late 1960s, only ahandful of very large institutions, such as the can-cer institutes in Amsterdam or in Villejuif, werecarrying out clinical research. They were very elit-ist, and having done my medical training here inDijon, I knew I had no chance of going intoresearch in Europe. So I decided to build my career in the US. Aftergaining the US-equivalent qualifications, fromMD upwards, I joined the MD Anderson hospitalin Houston, and had a wonderful time doing clin-ical research, where basic, translational and clin-ical research were all carried out under one roof.But then an academic position opened up in myown city, Dijon, and I decided I would challengethe only candidate – who was from Paris. And tomy great surprise, I was nominated.

➜ Interview by Anna Wagstaff


In 1972 I found myself back in Dijon with anacademic position and the remit I had alwayswanted – to develop research. But I was in amedium-sized centre that was not nearly bigenough to carry out clinical research of anyweight – at least not on its own. I was convinced that cooperation between hospi-tals of this sort of size was the only way to get thenecessary critical mass to carry out meaningfulclinical research.This is when I came across the EuropeanOrganisation for Research and Treatment ofCancer [EORTC], which was exactly what Ineeded to accomplish what I wanted to do. The great encounter I made there was withanother man of my age, Emmanuel van derSchueren – ‘Manu’ – who went on to become oneof the great builders of European oncology, notonly creating the European Society forTherapeutic Radiology and Oncology [ESTRO],but also promoting cooperation between differentoncology disciplines, for instance through theestablishment of the Federation of EuropeanCancer Societies [FECS]. He was Belgian and

Masterpiece


had trained in Leuven, but had spent some yearsat Stanford University, California, MDAnderson’s great rival in radiation oncology.We became great friends, and much of what Icontributed to building European cooperativeresearch, was done hand in hand with him.

European cooperation is dreamed ofmore often than achieved. How did youset about realising your goal?JEAN-CLAUDE HORIOT The first step was to createa radiotherapy group within EORTC, which wedid in 1974. Until then, radiotherapy had only

existed as a subgroup of the radio-chemotherapygroup, which was mostly involved in Hodgkindisease.After this, we rather innocently invented the con-cept of ‘quality assurance’ in research trials. Wewanted to include centres in many differentcountries in a single protocol, so we had to find away to check that the data gathered in eachcentre was accurate and reproducible. We had tobe certain, for instance, that 1 rad (the unit ofradiation dose in those days) in Amsterdam wasthe same as 1 rad in Leuven, Dijon, Milan,Gothenburg and Lisbon. I visited all the partici-

They said we had helped them convince their

directors to invest in more staff or better equipment

Quality assurance has greatly reduced

late tissue radiation injuries and accidents

Research takes time and it is vital to make sure

that you are asking the right questions

Masterpiece


pating centres as part of a team of physicists andclinicians, and we measured the beam qualitiesand equipment parameters. We checked themethodologies as well as the quality of the equip-ment, because there was a lot of scope for varia-tion, resulting in inconsistencies.This was the first time a peer review system hadever been used to evaluate practice as opposed toacademic papers. Doctors believed what they didwas an art, and could never be checked by anyoneelse. We were warned that we would be seen asan inquisition and that no institution would giveaccess to a team of ‘self-promoted inspectors’.Fortunately, these predictions turned out not tobe true. One reason may be that we neverclaimed our measurements were right and otherswere wrong. We just wanted to ensure that thedata we were pooling from many centres wereconsistent.We banished the word ‘error’ from our language,using previously defined consensual parametersto define variations in measurements as minimal,minor or major. Centres with major deviationshad to stop patient entry until they regainedcompliance. Sometimes it was a problem ofhuman competence and sometimes their equip-ment was not good enough. Many centres toldus later that we had helped them convince theirhospital directors to invest in more staff or bet-ter equipment, as they were able to say: “Lookyou have refused us for years, and now we arenot good enough to participate in Europeancooperative trials.”It took just two years to eradicate major devia-tions and demonstrate that we could all speak

the same language. From the first publishedreports on quality assurance, the process wastotally legitimised and established. These prin-ciples, which were first developed for research,are now used routinely in radiotherapy unitsthroughout the world.

Did this process apply to radiotherapyalone?JEAN-CLAUDE HORIOT Once the methodologywas proven, everyone recognised the benefits ofexternal independent review, and wanted to par-ticipate. Shortly after we had proved the concept,Manu and I were asked to chair the first EORTCQuality Assurance Committee, with the task ofdeveloping similar procedures in other disci-plines, working with surgeons and medical oncol-ogists to analyse the sequences and parameters ina given procedure or treatment. The process wascompleted by the mid-1990s and quality assur-ance is now applied in all areas of oncologyresearch and clinical practice.You can see the beneficial effects. With betterradiotherapy resulting from quality assurance, theincidence and severity of late tissue radiationinjuries have considerably decreased, and acci-dents such as transverse myelitis have beenalmost eradicated.

Was the quality assurance system enoughto allow you to run trials on the scale youwere looking for?JEAN-CLAUDE HORIOT It was a learning process.Our intention had been to use the EORTC radio-therapy group to promote radiotherapy research,

slowed down for several years in cervix,prostatic and rectal cancers. Even though theorgan groups were not necessarily doingradiotherapy research themselves, they stilldidn’t want anyone else to initiate trials outsideof their group and their conditions. They weretrying to assert some kind of ‘ownership’ overthese types of cancer. By the mid-1980s, we’d proved that we could doour own trials and get internationally recognisedresults. It became clear that working with jointprotocols was in everybody’s interests, and this ishow we have been working for the last 15–20years, with remarkable outcomes in head andneck, breast, prostate, rectum and brain tumours.We have learnt so much about the importance ofcooperation. Today we have no problems evenwith trials involving multiple modes of treatment,such as various combinations of radiotherapy andchemotherapy, and possibly surgery and/or anorgan-oriented specialty as well. Another important lesson we learnt, by trial anderror, is the importance of high-quality dialoguebefore deciding on a protocol, because researchtakes time and it is vital to make sure that you areasking the right questions. We cannot have anindefinite number of really good ideas in a normallife, and we have to select very carefully the top-ics we want to address in research trials.

When you initiate a trial, it takes anything up totwo years to define it, write it, have the conceptvalidated by a peer review process, and then dealwith the onerous legal requirements. If it is alarge phase III trial, you may need to recruit up to5000 patients, and this can take another fiveyears. Then it may take an additional three yearsbefore you can analyse the results. Which meansthat once you have asked a question, you willrarely get the answer within eight or ten years. Youhave to ask the right question, or the answer may

but we soon realised improving technical aspectsof radiotherapy was too restrictive and we had topromote pivotal trials for all solid tumours bene-fiting from radiotherapy. Such research had to bedone in very close cooperation with surgeons,medical oncologists and organ specialists.In the beginning, some of the organ orientedresearch groups were reluctant to work with us,and tried to deny us the right to initiate trials in‘their’ area. For instance, in the mid-1970s andearly 1980s, EORTC cooperative research was

Masterpiece


Some private doctors may not have mentioned

radiotherapy, as they cannot do it at their own clinic

Manu (Emmanuel) van der Schueren, a founding fatherof ESTRO and FECS, who died of cancer at the age of 56.He shared Horiot’s experience of research in the US,and the two of them worked together to buildthe foundations of European collaborative research

Europe must hold its own in research or pay

commercial prices for every new tool and treatment

Masterpiece


be obsolete by the time you get it, and you willhave wasted a tremendous amount of time, ener-gy and money.For instance, we did a lot of research into optimalfractionation (the number and timing of radio-therapy sessions). Up until the mid-1970s, treat-ment was given once a day, five days a week, as ifsomeone believed that tumours don’t develop onweekends or at night. So we started from biologi-cal data, showing that the concept of fractiona-tion should be modified, depending on the speedof proliferation of the tumour and normal tissue,and on the type of tumour and tissues. Weshowed that treating the patient twice a day wasbetter than once a day, and that using multiplefractions per day made it possible to reduce theoverall treatment time significantly. It took 20years to reach these results. It was very interesting research, but it was also avery hard lesson, because although these resultswere very positive – for instance in head and neckcancers we could improve local control by 20% –it never came into standard practice. During the

second decade of our trials, similar improvementswere achieved by adding chemo- to radiotherapy,and this was a far more practical alternative as itis nearly impossible to treat patients with radio-therapy twice a day – you would need twice theequipment and personnel. So we had spent 20years demonstrating that the concept was right,but it was barely applicable.The concept could have been very important. Ifonly we had been able to recruit enough patientsto prove the point in five or six years, it wouldhave been very useful in curing a large number ofpatients and helping to justify the case forstrengthening radiotherapy departments.

Would you say that rivalry between sur-geons, medical oncologists and radio-therapists is now a thing of the past?JEAN-CLAUDE HORIOT In cancer institutes, weknew from the early 1970s that what is neededis not a choice between one type of interventionand another, but a multidisciplinary approach.People who work or were trained in cancerinstitutes cannot imagine working in any otherway.The trouble is that only a minority of patients aretreated in cancer hospitals. In France, 80% aretreated in general hospitals or private clinics,where the multidisciplinary approach has takenmuch longer to be established. However, this ischanging, and under the National Cancer Planfor 2003–2007, a multidisciplinary approach ismandatory. If a patient is treated outside this sys-tem, individual doctors or entire institutionscould lose the right to treat cancers.The National Cancer Plan also gives patients theright to be told about all treatment options.Many patients with prostate cancer, for instance,opt for treatment by radiotherapy rather than sur-gery. In the past, some private physicians may nothave mentioned this option, because they cannotcarry out the treatment at their own clinic. But

With Sweden’s Queen Silvia, then HonoraryPresident of the EORTC. Horiot led the EORTCfirst as Secretary General and later Presidentbetween 1994 and 2000

Masterpiece


the principle of informed consent has now beenextended to all cancer patients, so it is muchharder for clinicians to get away with this. Aspatients become better informed, all practition-ers know they need to demonstrate that theywork to the same high standards as the best can-cer institutes or university hospitals.

Are there wide variations in the qualityof radiotherapy available within andbetween the countries of Europe?JEAN-CLAUDE HORIOT First-class radiation oncol-ogy is practised in most European countries,although not every patient in those countries mayhave access to the best management. The majorproblem, depending on where you are, is unac-ceptable delays or limited access to innovativetechniques because of staff shortages, outdatedequipment, or both.With the latest techniques, it is not so muchthe machinery as the software and regularupgrading that is the real expense. Intensity-modulated radiotherapy, for instance, needs avery special multi-leaf collimator (that alignsthe particle beam), activated to modify not onlythe field size but the fluence (rate of particleflow) of radiation to each spot. It is a verysophisticated technique involving enormouslycomplex calculations and equipment monitor-ing, and you therefore need some extremelypowerful software, renewed every year or twoyears. These techniques also require a hugeamount of preparation time from radiationphysicists and oncologists, in order to tailor theradiation to each individual patient. So the bigdifference nowadays is not so much the varia-tion of knowledge as the amount of time onecan give to a patient who can benefit from thattechnique.The trouble with radiotherapy – and this appliesequally to surgery – is that there is no equiva-lent to the pharmaceutical industry, which can

discuss with bodies such as the EuropeanMedicines Agency [EMEA] and national healthsystems to reach agreement to use and fund anovel approach in a rational way. As a result,patient access to innovative radiotherapy canvary a great deal not just from one country toanother, but from one institution to another,and even sometimes from one patient to thenext within the same institution, which I feel isan ethical problem.

Do you see a time when the countries ofEurope will be able to pull together in acoordinated research effort as happensin the US?JEAN-CLAUDE HORIOT The US benefits from afederal approach. In Europe, under the principleof ‘subsidiarity’ research is defined as a nationalgoal, and the EC only contributes to what eachcountry cannot organise. This was the trouble with the Clinical TrialsDirective. We had hoped that European legisla-tion on research would help the conduct of inter-national clinical trials, by streamlining legalrequirements. As we now know, not only did theDirective endorse the need to spend hugeresources satisfying the legislation of each coun-try with a participating centre, but some moreEuropean rules were introduced in addition tothe national ones. The cost of clinical researchhas increased to a point where EORTC has to setstrict priorities. As a result, some projects origi-nating from EORTC groups have to be developedoutside the organisation unless they are top prior-ities or have adequate funding. The EORTC, which is by far the largestEuropean group conducting cancer research, getsno support from the EC; it is treated like anyother ‘expert group’ with the right to tender forprojects drawn up by the EC. The preparation ofan application requires an enormous amount ofeffort and money and the result is sometimes not

There is the ethical price of having the human

genome developed and patented purely in the US

Masterpiece


worth the game. We cannot define what we wantto do, we cannot choose our partners, and wehave to match the funding provided by the EC.In practice, the EORTC has to depend largelyon the pharmaceutical industry formost of its funding. Unlike con-tracts the industry may signdirectly with researchinstitutions or hospitals,the EORTC alwaysretains control overhow we collect,analyse and publishthe data, which ispriceless. However,the industry will onlyfund trials that fittheir marketing strat-egy, which means thatif we want, for instance,to research into the difference between treat-ment with radiotherapy andsurgery compared to radiotherapyalone, we have to find fund-ing from other sources,because it is of no interest tothe pharmaceutical industry. Many member states hardly invest in clinicalcancer research at all, and when they do, thefunds tend to go to national projects. This is alsotrue of most cancer charity money. Someresearch groups are worried about activatingEuropean trials in case they jeopardise theirchances of getting national funding. This iswhere the US does so much better than us, andit is very disappointing.

You paint a gloomy picture. Are there anyreasons for optimism about Europeancancer research?JEAN-CLAUDE HORIOT Europe has to hold its ownin research if it is to avoid having to pay commer-cial prices to access every new tool and treat-ment. More importantly, there is the ethical priceof allowing the techniques, agents and proce-dures derived from mapping the human genometo be developed and patented purely within thecommercial context of US research.

European research has a lot going for it, such asthe quality of the relationship between doctorsand patients, which is far more constructiveand less litigious than in the US, and is one of

the reasons I came back.The future really lies in transat-

lantic cooperation, which wasshown to amazing effect in

the Glivec [imatinib] tri-als in metastatic GISTtumours [gastro-intes-tinal stromal cell sar-comas], which wentfrom phase I tophase III in lessthan two years. Thecurrent ‘planetarytrial’ TRANSBIG

(Breast InternationalGroup, in which

EORTC plays a majorrole), comparing classical

prognostic indicators, such asstage, nodal status and hormonal

receptors with innovativebiological parameters, suchas genomic profile, is anexcellent reason to remain

optimistic: 5000 patients to be accrued in 3years by 39 leading institutions from 21 coun-tries, which stands to benefit a hundred thou-sand women per year worldwide.Looking to the future, everything we’ve learntabout the extraordinary complexity of the regu-lation of cancer growth makes it increasinglyunlikely that a single specific mechanism canresult in the discovery of a ‘magic pill’. Surgeryand radiotherapy will continue to be crucial inearly cancer, and the slow but very regularprogress we’re making in stopping cancergrowth for long periods in metastatic patientsmay revive indications for radiotherapy and/orsurgery on these ‘sleeping disease spots’. This isa very lively research field and Europe is playinga dynamic role. With a predicted shortage inthese two disciplines, my message to all youngoncologists is that there are tremendous oppor-tunities to add your talents to the Europeanresearch effort.

Cast in bronze. This medal commemorates Horiot’sESTRO Regaud honorary lecture, delivered in 1998

Women doctors offer alternativeto costly mammography

Breast examination by specially trained young women doctors is proving effective at picking

up tumours in the general population in a number of developing countries. If it can be

shown to affect mortality rates, this low-tech screening method could provide a solution for

poorer nations, and may even force a rethink in richer ones.

Early detection and quality treatmentare twin pillars in the strategy adoptedin the West to reduce mortality from arising incidence of breast cancer. Earlydetection in this context means mass

screening by mammography, backed by betterhealth education about breast self-examinationand breast cancer treatment.

But mammography is expensive, difficult todo and detects some cancers that were nevergoing to be a problem. Some argue that othermethods of early detection allied to treatmentwith tamoxifen and adjunctive therapy wouldsave as many lives without detecting so manybenign lumps and cancers that would never needtreatment. In richer countries with sophisticatedhealthcare systems doubts tend to be outweighedby the overall success of the strategy. It isassumed that the smaller the lump detected, thebetter the survival outcome. Consequently, thismodel has also been proposed as the way forwardfor other countries considering screening.

Developing countries have neither theresources nor the infrastructure to establish mass

➜ Peter McIntyre

screening by mammography, which requires alarge number of radiographers to take the filmsand highly trained radiologists to read them. Theyhave therefore been left with no viable strategy.

The international community consoled itselfwith the thought that breast cancer is a disease ofaffluence and of women who postpone childbear-ing and have fewer children. Increasingly thisview is being challenged and the need for earlydetection in developing countries is being assert-ed, especially as the lives of women change.

Indraneel Mittra, director general and headof oncology at the Bhopal Memorial Hospital andResearch Centre in India, is keen to find alterna-tive routes to screening. He says: “If you ask threedifferent radiologists to read the same mammo-gram you get three different answers. If youscreen 10,000 women for seven years you savefour lives. Even in the best countries mammogra-phy is hugely complex and to establish this indeveloping countries is impossible in my view.”

In 1997, while working at the TataMemorial Hospital in Mumbai (Bombay), heset up the first randomised trial of early

Spotlighton...


Spotlighton...


detection of breast cancer, comparing screeningthrough clinical breast examination with noscreening. The trial recruited women from 10socially disadvantaged areas of Mumbai, divid-ing each area randomly into a study group and acontrol group.

Women in the study group and the controlgroup both received health education aboutbreast awareness. In addition, health workerscarried out clinical breast examination on womenfrom the study group, referring those with suspi-cious findings for further specialist examination.In the first batch they enrolled 75,000 women,and another 75,000 in the second batch. In thefirst round of screening, breast cancer was threetimes higher in the screening group than in thecontrol group. In the second round the differencewas less, but still more than in the control group.

This trial, funded by the US National Cancer

Institute and the Tata Memorial Hospital, is nowinto its fourth round, but Mittra says it is still toosoon to determine the outcome. “The objective ofscreening is not simply detecting cancers early; itis to demonstrate that the screening has beenworthwhile. The end point you are seeking is areduction in mortality.”

Mittra believes this trial does demonstratethat screening by clinical examination can beefficiently set up and is acceptable to the popula-tion. “It has been a highly complex exercise. Youhave to screen many women to detect one cancerand you have to pay huge attention to detail.”

Egypt was the next country to pilot thismodel. Vittoria Buffa, wife of the then Italianambassador to Cairo, wanted to fund an ongoingproject from money raised every year at anEmbassy bazaar. The fundraising organisers(mainly women) suggested something that would

Young womendoctors explainthe breast screeningprocess to womenat a Cairo clinic

“Mammography is hugely complex and to establish

this in developing countries is impossible in my view”

promote the interests of Egyptian women. Buffatalked to people at the Italian Hospital in Cairo,who put her in touch with the Challenge Fund,set up ten years ago by the European School ofOncology (ESO) to support health professionalsin countries with limited resources.

An international team was formed to overseethe Cairo pilot study, including Salwa Boulos, aradiologist at the Italian Hospital,Mohsen Gadallah, a public health doc-tor from Ain Shams University Cairo,Alberto Costa of ESO, Indraneel Mittraand Anthony Miller, from the Universityof Toronto, who worked for 15 years onWorld Health Organization cancer con-trol programmes, as well as theCanadian National Breast ScreeningStudy. The pilot also won the backing ofEgypt’s first lady, Suzanne Mubarek.

As a radiologist, Boulos is wellaware that breast cancer is not talkedabout, not diagnosed and therefore nottreated in time. “Diagnosis of breastcancer is usually late and the prognosisis poor,” she said.

The first phase of the pilot began inMay 2000 with about 5,000 women aged 35-64living in an area around the Italian Hospital.Social workers conducted house to house visitsand the 4,116 women who agreed to join weretaken through a questionnaire and invited toattend a nearby health centre for examination byyoung female doctors who had received specialtraining. In all, 2,481 women were examined.Women were given health education messages onthe importance of breast care and shown how todo self-examination. Those who had an abnormalfinding at clinical examination were referred tothe hospital for examination by mammography orfor biopsy. They were reassured that whatevertreatment they needed would be free. In this first trawl, 291 women were referred to the

Italian Hospital and 20 women were diagnosedwith cancer – a rate of eight per 1,000 womenwho attended for breast examination. This veryhigh rate is not the incidence of cancer, since itincluded cancers that had developed over a num-ber of years, but it destroys the myth that breastcancer is only a disease of affluent Westernisedwomen. These women from a poor part of Cairo

would normally have been considered‘low risk’ for breast cancer. Their meanage of marriage was 20.5 years, themean age of first birth was 21.8 years,95% had been through one or morepregnancies and 45% had four or morechildren. A high number of women – 55 out of291 referred – did not attend the ItalianHospital despite an abnormal finding. Inthe second phase strenuous efforts weremade to contact these 55 women andencourage them to come forward. Somewould not open their doors to socialworkers. Only 20 were persuaded toattend hospital, and four of these werefound to have breast cancer, all withadvanced disease.

Gadallah believes that the women whodropped out did not understand the seriousnessof the disease or the potential benefits of treat-ment, or were too frightened. “They knew theyhad something. The doctor who examined themsaid there is something wrong with your breast,and you need to go to the Italian hospital to beexamined.”

Boulos believes there are also a few caseswhere family pressure was the deciding factor.“We had two cases where the women wereunder pressure. Both of them died. The firstwoman’s daughter brought her in quite early inthe disease. She had been living with her sonwho had refused to accept the concept of havinga sick person in the house. In another case, the

Spotlighton...


“Diagnosis of breast cancer is usually late

and the prognosis is poor”

Anthony Miller: skilledbreast examinationcan find as many poorprognosis cancersas mammography

Spotlighton...


In 2003, women in Group B areas werevisited by social workers who administered aquestionnaire to see whether they had noticedany breast problems. These women were thecontrol group since they were not invited forscreening, but any who disclosed a problem tothe social worker were invited to the hospitalfor a mammogram.

The pilot confirmed that young female doc-tors can detect breast cancers by screening.Miller believes that a study with sufficient power(number of women and length of screening)would show a mortality benefit. “What I think wewill find in the end is that the incidence in this

Indraneel Mittra: you have to screen many women to detect onecancer and you have to pay huge attention to detail

Salwa Boulos: family pressure sometimes prevents womenfrom seeking early treatment

woman presented at a very late stage. The hus-band refused completely to allow his wife to go.”

The only deaths known to have occurred inthe study have been of women who at firstrefused to go to the hospital. Nobody knows whatthe outcome has been for the 35 women whohave still not attended.

Phase 2 began in 2001. The original groupwas randomly divided by area into A and B.Women living in A areas were invited back for afurther clinical breast examination and werereminded about how to conduct self-examina-tion. Again those with suspicious findings werereferred to the hospital.

“Her son refused to accept the concept

of having a sick person in the house”

Spotlighton...


relatively young age group is 1.5 to 2 per thousandwomen, which is still high, but we have recog-nised that in North Africa there is quite a lot ofbreast cancer.”

The number of women who refused furtherexamination was a concern. However, there was agreater willingness to take part in Phase 2. Boulossaid: “The word spread about what we were doingand women had a greater confidence.” Gadallahintends to explore the reasons for women refusinginvestigation, to encourage women that hopefrom treatment should outweigh fear of the dis-ease. The pilot continues in a new area of Cairowith another 5,000 women.

The next step will be taken in the Yemen.Miller is preparing a protocol after discussing theproject with key staff at Kuwait UniversityHospital in Sana. “There are people there who areexpert in oncology and interested in breast can-cer, so there is a base for capacity building,” hesaid. Young female doctors will be trained inbreast examination and radiologists will receivemammography training. He hopes that in theYemen it will not be necessary to do a ‘Phase 1’and they can proceed from the start with a con-trol group and a study group.

Khadija Al Huraibi, a gynaecologist at theKuwait University Hospital, is anxious to startas soon as possible. “We met the social workersand the young doctors. The social workersalready have experience in going door to door.Our community is a little bit different fromEgypt. Women visit each other and are oftengrouped together in the day. We have thechance to meet 50 women together.”

Sudan also wants to test this method ofscreening. Ibrahim Elfadil, from the NationalInstitute of Oncology in Khartoum, said thatbreast cancer accounts for 75% of cancersreported in women and survival rates are poorbecause of late diagnosis.

There is only one specialist centre in the

“There is no justification in early diagnosis unless

we can offer treatment”

country. He said that the point of doing a pilotwould be to establish that an early detection pro-gramme was feasible and socially acceptable.

Cultural factors in each country must beaddressed for screening to work, to ensure thatwomen attend for examination and for follow-up care. Ethical questions also have to beaddressed. If clinical breast examination isknown to be effective, is it ethical to conduct atrial where half the population in the study doesnot receive it? However, effectiveness has notyet been demonstrated in a low-income country.Moreover, the control group receives educationabout breast care and self-examination so thatthese women are better placed to detect cancerearly than women in the general population.

It is essential that treatment is available andaccessible when cancers are discovered, whichmeans that it must be free or heavily subsidisedfor low-income women. Miller says: “There isno justification in going out to look for cancersand introducing early diagnosis unless we canoffer treatment.” The pilots include free treat-ment, but this would clearly become an issue ifscreening programmes were introduced on alarger scale.

None of these pilots has yet shown theimpact on mortality reduction, but it is possiblethat in a few years’ time a meta-analysis embrac-ing India, Egypt, the Yemen and Sudan couldgive the answer. If this is an effective method ofearly detection and it does save lives, it couldcause rich and poor countries alike to considerwhether mammography is the only route.

Miller is already sceptical of the cost-benefitsof mammography. “The costs of training and con-tinually doing the screening, and the cost in termsof women found to be abnormal by mammogra-phy but found not to have invasive breast cancer,are all very high. Mammography does not findpoor prognosis cancers that cannot be found bybreast examination if that examination is good.”

Spotlighton...


The World Conference for CancerOrganisations (WCCO) is an initiativeof the International Union AgainstCancer (UICC), the only internationalnon-governmental organisation dedicat-

ed exclusively to the global control of cancer. TheConference seeks to bring together all organisa-tions involved in the global fight against cancer,from small societies with limited funds andreliant on volunteers, to high-profile charityorganisations, which raise and dispense largesums of money and employ skilled medical, sci-entific, educational and administrative personnel.

The 4th WCCO was hosted by the IrishCancer Society at the end of last year. It wasremarkable particularly for the significant atten-dance from mid- and low-income countries,including Jordan, Libya, Tunisia, Malaysia,India, Ghana, Nigeria, Zimbabwe, Jamaica andCuba. Also new was a welcome focus on patientadvocacy initiatives, such as patient forums,which have provided effective platforms forpatients, caregivers and the growing number ofcancer survivors worldwide to voice their spe-cial needs and concerns to representatives fromthe medical community and government.

John Seffrin, UICC President and CEO of theAmerican Cancer Society, opened the conferencewith a rallying cry, calling on delegates to help putcancer on the global political agenda as a higherpriority than ever before. “Seven million peoplewill die of cancer this year alone. The untold storyis that most of those deaths will be needless. Weneed to share best practices and knowledge … towork together to develop effective national cancerstrategies that make the transition from what is towhat could be,” he said.

Isabel Mortara, Executive Director of theUICC, highlighted the potential for improve-ments among the lower-income countries,which bear the lion’s share of the world’s cancerburden yet suffer a chronic lack of resources incritical areas like screening, public health edu-cation and access to treatment and palliativecare. “With more effective sharing of knowledgeand a more coordinated approach to cancercontrol,” she argued, “developing countriescould make great strides forward, even withinthe context of severe resource constraints.”

The proven success of patient advocacy in anumber of countries was also seen as a modelfor progress: “Patient forums and other similar

Last November 800 people working to control cancer in 82 countries across the world gathered

in Dublin to share their experiences of what works and what doesn’t. This was the fourth World

Conference of Cancer Organisations, but for a number of developing nations it was a first.

➜ Jose Julio Divino

Poorer countries take their placeat the World Cancer Conference

groups are already helping change the wayhealth services are delivered in developed coun-tries like the US, UK, Australia and Canada.Our challenge now is to capitalise on thismomentum in mid- and low-income nations,where patients often face very tough social, eco-nomic and cultural issues,” said Mortara.

Ireland proved a timely choice of venue forthe event, as it is the first country in the worldto implement a total workplace ban on smoking.The ban, which came into effect on 29 March2004, covers not only shops, factories andoffices, but also restaurants, pubs, clubs andbars. In his welcome address to delegates, IrishPrime Minister Bertie Ahern applauded hiscountry’s “landmark effort to protect employees,children and others from the toxic effects oftobacco,” and urged delegates to take sometime out from the very full programme of ple-nary sessions, symposia and workshops to sam-ple the delights of smoke-free Irish pubs.

The conference programme was tailored tomeet the needs of a broad cross-section of thecancer community, including researchers, educa-tors, scientists, health professionals, advocates,programme coordinators, and information andcommunications officers from public healthorganisations, patient groups, and governmentalagencies. Among the very many topics covered indepth in a packed three-day agenda were: effortsto cut tobacco use, patient advocacy initiatives,national cancer control planning, early detection

and prevention strategies, psychosocial factors incancer care, survivorship issues, and effectivemarketing and fundraising strategies. SpecialSpanish- and French-speaking workshops werealso held.

The conference saluted extraordinary contri-butions to the global effort to control cancer at aGala Dinner held at Trinity College. Four peopleactive in different fields across the globe werepresented with UICC awards for their exception-al work. Ranjit Kaur, President of Malaysia’sReach to Recovery breast cancer support net-work, was recognised for her pioneering work inpatient advocacy. Leslie Sobin, chief of gastroin-testinal pathology at the Armed Forces Instituteof Pathology in Washington, DC, was awarded forhis work on the TNM classification of tumours.Awards were also presented to the FinnishCancer Society, for the effectiveness of its com-prehensive tobacco control policies and cervicalcancer screening programme, and MicheálMartin, former Irish Minister of Health andChildren, for his efforts to implement Europe’sfirst total workplace smoking ban.

Addressing the closing session of the event,Irish Cancer Society Chief Executive JohnMcCormack urged the global cancer communityto work together more closely and to use eventslike WCCO to forge and strengthen internation-al partnerships and networks that will help speedadvances in prevention, early diagnosis, treatmentand patient care.

Ranjit Kaur (right), Presidentof Malaysia’s Reach to Recovery BreastCancer Support Network,with the UICC’s Isabel Mortara.Kaur is holdingthe 2004 Outstanding UICC Volunteer Awardfor her pioneering work in patient advocacy

Spotlighton...



ImpactFactor

T rialists of the aromataseinhibitor anastrozole are call-ing for the drug to replace

tamoxifen as the preferred initialtreatment for postmenopausal womenwith localised hormone-receptor-positive breast cancer. A five-yearcourse of tamoxifen is the currentstandard treatment for this group ofpatients, which is prescribed to anestimated 500,000 women worldwide.The results of the ATAC trial(Arimidex, Tamoxifen, Alone or inCombination), published in theLancet (365:60–62), showed womentreated with anastrozole did betterthan those on tamoxifen in terms ofdisease-free survival, time to recur-rence, distant metastases, and con-tralateral breast cancer. The ATAC study is a double-blindrandomised trial, comparing fiveyears of anastrozole alone withtamoxifen alone, or in combination,as adjuvant therapy in 9366 post-menopausal women with localisedbreast cancer. The combination armwas closed early due to lack of effica-cy, so the five-year results compareanastrozole alone against tamoxifenalone. After a median follow-up of68 months, figures for disease-free

survival showed 575 events forwomen treated with anastrozole com-pared with 651 for women on tamox-ifen (hazard ratio 0.87, 95% CI0.78–0.97, p=0.01). Time to recur-rence was also better for the anastro-zole group (402 vs 498, 0.79,0.70–0.90, p=0.0005). If one looksonly at the figures for women with

hormone-receptor-positive breastcancer, the benefits are marginallygreater: 0.83, 0.73–0.94, p=0.005,for disease-free survival and 0.74,0.64–0.87, p=0.0002 for time torecurrence. The anastrozole groupalso did better in terms of reductionsin contralateral breast cancers (allpatients 35 vs 59, 42% reduction,95% CI 12–62, p=0.01; hormone-receptor-positive patients 53%,25–71, p=0.001).Anthony Howell, of the departmentof medical oncology at ChristieHospital, Manchester, who chairedthe trial steering group, believes thatthese results indicate that anastro-zole should replace tamoxifen as thestandard treatment in hormone-receptive breast cancer. “On the basisof the ATAC data, we feel it is appro-priate to begin adjuvant therapy withanastrozole as first-line treatmentafter surgery for breast cancer inpatients with hormone-receptor-posi-tive tumours,” he said. “The reason isthat if you start someone on tamox-ifen during the first 2.5 years thereare quite a lot of relapses which areprevented by anastrozole. When apatient gets a relapse, that usuallyends in further systemic disease and,

➜ Joanna Lyall

Has tamoxifenhad its day?

Anastrozole is being hailed by some as the new tamoxifen. But many researchers feel there

is a great deal more we need to know before we consider casting aside the hormonal

treatment that has served so many women so well.

Anthony Howell: anastrozole should replacetamoxifen as first-line treatment after surgeryin hormone-receptive breast cancer


ImpactFactor

“Fewer recurrences and metastases suggest

anastrozole may eventually show better survival”

I am afraid, death. Thus, preventinglapses at all costs is very important.”

OVERALL SURVIVALThe study has not, so far, shown anydifference in overall survival (hazardratio 0.97, 95% CI 0.85–1.12,p=0.7). However, the trial groupargues that this is to be expectedsince the trial population had rela-tively good prognoses: 61% ofpatients were lymph node negativeand 64% had tumours of 2 cm orsmaller. They point out that trials oftamoxifen versus placebo took atleast seven years to show a significantsurvival advantage, and argue that thereductions in recurrence and distantrecurrence associated with anastro-zole strongly suggest that a reductionin deaths from breast cancer willeventually be seen.“We are already seeing fewer metas-

tases and this trend is going to getstronger,” said Howell. But other researchers believe theresults of the study do not provide

sufficient evidence to warrant aban-doning tamoxifen as the first-linetreatment for this group of women.Their reservations concern the lackof evidence about the long-termeffects of anastrozole, and the factthat we have no way of predictingwhich women are likely to benefitfrom it. There are also concernsabout the cost and questions aboutlength of treatment. Henning Mouridsen, professor of on-cology at Rigshopitalet, Copenhagen,has recently reviewed the role of aro-matase inhibitors in the treatment ofpostmenopausal women with earlybreast cancer (EJC, in press). He con-siders that while aromatase inhibitorshave an important role in adjuvanttreatment, their long-term superiorityover tamoxifen remains uncertain. Hebelieves that the optimal treatmentapproach still needs to be defined,and argues that sequencing tamoxifenwith an aromatase inhibitor mayprove superior to non-sequencedtherapy with an aromatase inhibitor. Mouridsen’s view is that tamoxifenshould remain the treatment ofchoice for the first two years, with apossible switch to an aromataseinhibitor at that point. “The key sci-entific question yet to be answered inrandomised trials is whether anysuperiority is associated with theupfront or the sequential approach,”he said.He points out that at the internation-al conference on primary therapy ofearly breast cancer in St Gallen,Switzerland, in January, the consen-sus panel was in favour of maintain-

ing tamoxifen as the standardtreatment for postmenopausalwomen with early breast cancer. “Tamoxifen is still the treatment ofchoice for the first two years unlessthere are thromboembolic concerns,”he said. Andrea Decensi, director of thechemopreventive division of theEuropean Institute of Oncology,Milan, and director of the division ofmedical and preventive oncology atGalliera Hospital, Genoa, believesthe increased risk of endometrial can-cer associated with tamoxifen couldbe addressed by reducing the stan-dard dose. Preliminary results of a co-operative Italian Norwegian studyheaded by Decensi show that reduc-ing the amount of tamoxifen by threequarters is still effective in reducingthe incidence of breast cancer. He believes the best answer may lie incombining tamoxifen with anastrozole,and says that the problems with thecombination arm of the ATAC trialmight have been due to the dosage: “I

Andrea Decensi is testinga combination similar to the ATACcombined arm, but with a lowerdose of tamoxifen

Henning Mouridsen: tamoxifenis treatment of choice for firsttwo years, unless there arethromboembolic concerns


ImpactFactor

think 20 mg per day of tamoxifenmight have been too high in combina-tion with anastrozole.” He is currentlystudying the effects of a combinedArimidex and tamoxifen regimen usinga lower dose of tamoxifen.Martine Piccart, head of medicaloncology at the Jules BordetInstitute, Brussels, is coordinator ofthe TRANSBIG trial into genetic tar-geting of breast cancer treatment.She believes the problem lies less inthe choice of drug than the choice ofpatient. “We are entering an era ofindividualised treatment and at thesame time we are lacking strong pre-dictive tools for judging whichwomen will do best on which treat-ments,” she said. She is not convinced that five yearsof endocrine therapy is enough forwomen at high risk. “We have fivevery positive trials and my personalview is that most women who I seein my clinic should be consideredcandidates for an aromataseinhibitor. But that is not to say thatall women should be givenanastrozole from the beginning andfor five years. Things are morecomplex than that. The ATAC trial iscertainly the longest follow-up butthe benefits are still relatively smallin percentage terms.“We now have two trials showing thattwo years of tamoxifen and then anaromatase inhibitor is effective. I amvery tempted to go for tamoxifen andthen an aromatase inhibitor inwomen whose tumours express highlevels of estrogen and progesteronereceptors.”

SIDE EFFECTSThe ATAC trial found that, comparedwith tamoxifen, treatment with anas-trozole was associated with significantreductions in the incidence ofendometrial cancer, thromboembolicevents, ischaemic cerebrovascularevents, vaginal bleeding, hot flushesand vaginal discharges. However, therewere more fractures and more arthral-gia among women on anastrozole thanamong the group on tamoxifen. Fracture rates per 1,000 womanyears were 22.6 for anastrozole and15.6 for tamoxifen. The risk ratios forall the prespecified adverse eventswere similar, says the trial group, toresults in two analyses conducted ear-

lier in the trial (Lancet 2002,359:2131–39; Cancer 2003,98:1802–10), suggesting that that thesafety profile of anastrozole remainsunchanged during the five-year treat-ment period. “No new safety concernsemerged,” they said. Howell points particularly to the dropin the incidence of endometrialcancer, from 0.8% of women ontamoxifen to 0.2% of women on anas-trozole. This, he argues, has a widersignificance on women’s quality of lifebecause of the spin-off effect on cut-ting down the number of hysterec-tomies – many of which may beunnecessary. “Gynaecologists arerightly worried that any form of prob-

“Tamoxifen may still be effective when used

at one-quarter of the standard dose”

Martine Piccart:we need waysto predict who willrespond bestto which drug,used alone,in sequenceor in combination


ImpactFactor

lem in the uterus may lead to endome-trial cancer on tamoxifen and I sus-pect this leads to the excess of hys-terectomies.” he said. The resultsshow 5.1% of women on tamoxifenhad hysterectomies compared to 1.3%of women on anastrozole.” The prob-lem of increased fractures, he argues,can be managed by bisphosphonates.The ATAC group also point out thatwithdrawals due to drug-related seri-ous adverse events were significantlyless common with anastrozole (4.7%vs 9.0%). “Since almost all patientshave completed their scheduled fiveyears of therapy, the safety and toler-ability of therapy can be deemedfinal,” the study concluded.

Decensi, who is involved in a separatestudy on tamoxifen and anastrozole, isconcerned about the lack of data on thepotential long-term toxicity of anastro-zole. “This is a good study and it’s clearthe new drug has potent advantages.But we have to be very prudent.Toxicity may become apparent afterseveral years,” he said. The fact thatfractures and arthralgia are higheramong women on anastrozole is also aconcern for clinical practice, he added.Decensi also points out that cost isan issue here, as anastrozole is muchmore expensive than tamoxifen. Hebelieves the new drug can only bejustified as a first-line treatment inwomen who are at cardiovascularrisk. Piccart concurs with Decensithat the side-effect benefits of anas-trozole over tamoxifen are relativelysmall in percentage terms.

CLASS EFFECT?The ATAC study, says Howell, is thelargest study ever done in early breastcancer, and its results have been treat-ed as reliable as far as anastrozole areconcerned. But how much does it tellus about the effects of aromataseinhibitors as a class of drugs? The trial group stipulate that theresults are only applicable to anastro-zole “since it is unknown how differ-ences between the aromataseinhibitors affect their clinical useful-ness.” However, Howell believes thatthere may be a class effect, thoughtreatment decisions must be made onthe basis of best evidence. “As a clinician you treat somebody

with the drug with which you havemost experience. At the moment wehave most evidence on anastrozole.But in five years it may be letrozole. “All the aromatase inhibitors areassociated with fewer deep veinthromboses and a good gynaecologi-cal profile. They are all associatedwith osteoporosis and increased jointaches in some women,” he said. Headded, however, that “exemestaneand letrozole are associated withincreased cardiac deaths which arenot seen on anastrozole.” Mouridsen also feels it is too early tosay whether there is a class effect foraromatase inhibitors. He argues that,while there clearly are differencesbetween their mode of action andpotency, we lack data that can relatethese differences to clinical activity.He believes that while the evidence

for aromatase inhibitors growsincreasingly strong, many questionsremain about the most effective useof tamoxifen and aromataseinhibitors in adjuvant treatment.“These questions relate primarily tothe optimal single agent or sequence,duration of treatment and selectionof individual patients,” he said. The ATAC trial seems to point to agrowing role for aromatase inhibitorsin the treatment of postmenopausalwomen with early breast cancer, inparticular in patients at cardiovascu-lar risk.The trialists argue that the higherrates of recurrence, especially inyears 1–3, and the increased

numbers of adverse events andtreatment withdrawals associatedwith tamoxifen, “lend support to theapproach of offering the mosteffective and tolerated therapy at theearliest opportunity.” Many otherseasoned researchers, however, urgecaution before ditching tamoxifen,which has served hundreds ofthousands of women so well over thelast three decades. More time is needed, they argue, toevaluate the impact on survival andthe long-term toxicity of anastrozole.And further research is needed toestablish whether anastrozole is real-ly more effective when prescribedalone rather than in combination orsequenced with tamoxifen, and toidentify which women are most like-ly to benefit and the optimum lengthof treatment duration.

“Fears of endometrial cancer on tamoxifen

may lead to many unnecessary hysterectomies”

PatientVoice


Look – no strings!Patient groups are seeking to redefine their relations with the industry

As patient groups begin to gain access to the corridors of power, the spotlight is falling on

their relations with the powerful pharmaceutical industry. In an effort to protect their

credibility from a murky sea of rumour and speculation, many patient groups are now trying

to negotiate a more transparent and arm’s length relationship with their industry sponsors.

AParliamentary Committee in the UKhas been hearing damning allega-tions about relations between phar-maceutical companies and patientorganisations, as part of an investiga-

tion into the influence of the industry. Patient groups have been accused of acting as

‘stooges’ for the pharmaceutical industry, Trojanhorses under whose cover the industry has beenable to infiltrate policy-making bodies. Criticismsrange from Biogen setting up Action for Access tocampaign for reimbursement of one of its multiplesclerosis drugs – it was later shut down by theregulators – to the time when the long-establishedAlzheimer’s Society sent out a statement from adrugs company under its own name. Questionshave been asked as to why, in the debate over thesafety of selective serotonin uptake inhibitors(SSRIs), one mental health group which has kepta distance from the industry was highly critical,while two others, who take industry sponsorship,were silent. The Association of the BritishPharmaceutical Industry came under fire forallegedly describing patient groups as ‘ground

➜ Anna Wagstaff

troops’ that they could use to weaken “political,ideological and professional defences” againstdirect to consumer advertising.

Similar debates are taking place in othercountries. The issue has come under the mediaspotlight in the Netherlands – the only countryin Europe to set aside 30 million euros a year forpatient groups. It is also a hot topic in Germany,where a number of cancer patient groups havebeen criticised for taking money from theindustry. European umbrella groups, which havemushroomed in order to have an input into theEU consultation processes, have also provedrich targets for rumour and speculation.

Taken together, a few examples of bad prac-tice, a greater number of allegations, and a murkyatmosphere of rumour, pose a severe threat to thecredibility of patient groups. Many are now tryingto erect firewalls against inappropriate influence byrenegotiating their relationship with the industry.

AN UNEQUAL RELATIONSHIPBy law, pharmaceutical companies are not per-mitted to communicate with patients directly.

PatientVoice


Building a relationship with a patient groupgives them an avenue for getting information topatients about their products and researchresults, and can be helpful in recruiting to clin-ical trials. It gives them a chance to getfeedback about how patients perceive theirproducts and to identify potential gaps in themarket. Support from patients can be very help-ful in getting a new drug approved or onto thereimbursement list. A good relationship withpatient groups also does wonders for the corpo-rate image, and can be particularly valuableduring a public relations crisis.

The relationship works both ways. Patientshave an interest in the effectiveness, safety,side-effects and cost of drugs, and want toknow about clinical trials they may be eligible

for. Patient groups want to influence researchand development and keep up to date withresearch results.

The industry and patient groups both bene-fit from a constructive relationship. Theproblem is that the relationship is unequal:pharmaceutical companies have money, scien-tific knowledge and expertise in marketing andpublic relations. Patient groups do not. Whenpatient groups accept money from the industry,questions are asked about inappropriate influ-ence. Is the group driven by the interests ofpatients or the agenda of sponsors?

Some patient groups refuse money on prin-ciple. They are, however, in a small minority.A survey of 45 groups who attended the firstconference of the European Cancer Patient

Europa Donnaput on this breastcancer exhibitionduring its campaignto get policy passedby the EuropeanParliament.Getting the rightfacts acrossto the right peopleat the right timecan’t be doneon the cheap

Patient groups have been accused of acting

as ‘stooges’ for the pharmaceutical industry

PatientVoice


Coalition in Milan last June elicited 22responses, covering nine countries: Belgium,Germany, Italy, Netherlands, Poland, Romania,Spain, Sweden and the UK. Results showedthat 19 of the 22 (86%) receive industryfunding on occasion. Two refuse money onprinciple. One is forbidden to accept industrysponsorship by its funding body, a nationalcancer charity.

Few of the 19 who accept industry sponsor-ship use this money to cover core running costs.The exceptions are in Poland and Romania,where there is little tradition of state or charita-ble funding for voluntary groups, and whatthere is, says Simona Ene of the RomanianAssociation of Cancer Patients, is not madeavailable to cancer patient groups because ofthe appallingly negative attitude towards cancerin that country.

Sponsorship from four or five differentcompanies is common. One group reportedsupport from 20 different companies; nonereported funding from a sole sponsor. Themoney tends to finance particular projects:public awareness campaigns, informationleaflets, newsletters, organising conferencesand travel costs.

The proportion of income derived fromindustry varied from marginal to well over 50%.It tended to be lower among groups with a focuson supporting and informing patients, and high-er among groups geared heavily to promotingpublic awareness and advocacy, and amongEuropean umbrella groups, where travel andtranslation costs can be heavy.

The majority of groups have some form ofpolicy on sponsorship, but it is rarely writtendown, almost never publicly available, and usu-ally amounts to a vague commitment not to takefunding from companies with a poor ethicalreputation or accept funding with strings.Sponsors are often acknowledged on the back

of publications or on a group’s website, but veryfew patient groups have a policy on declaringsources of funding.

A recent survey of its affiliates by EuropaDonna Italy revealed that just under one-thirdof the 67 groups that responded receivedsponsorship from the pharmaceutical industry,but only two had a policy document on trans-parency.

Few groups are aware of laws or regulationsgoverning sponsorship. Deutsche Leukaemie-und Lymphom-Hilfe say they were obliged tosign a statement of good intent in order toaccept sponsorship from the pharmaceuticalindustry without jeopardising grants fromGermany’s health insurance companies.

The overall picture shows that, in general,pharmaceutical companies choose what activi-ties they wish to sponsor, but details of the sizeof the sponsorship, what it is used for, andwhat they can expect in return are rarely dis-closed in full.

RENEGOTIATING TERMSLack of clarity and transparency does not meanthat inappropriate relationships are being delib-erately concealed. In fact, cancer patient groupstend to be strongly driven by patients’ priorities,as one might expect of groups run largely by peo-ple who know what it means to have cancer.

But bad practice does exist, and a numberof cancer patient groups are now taking steps toensure they don’t get tarred with the samebrush. Central to this has been a move to definerelations with industry sponsors in quasi-legaldetail. The European Cancer Patient Coalitiondefines four types of funding – ‘sustaining part-nerships’ (unrestricted grants of at least 20,000euros as one among a group of sponsors), proj-ect funding, sponsorship, and smaller unre-stricted grants. It spells out what input sponsorsget into a project, the nature of acknowledge-

A number of patient groups are now taking steps

to ensure they don’t get tarred with the same brush

PatientVoice


ments and what sponsors can expect in return.As well as guiding principles, it sets guidelinesfor commercial companies governing the usecompanies can make of ECPC’s name and logoand the avenue of communication between thecompanies and ECPC, down to the terms onwhich ECPC will deal with companies’ publicrelations agencies.

The ECPC policy borrowed ideas from sim-ilar documents drawn up by other patientgroups such as the European Organisation forPatients with Rare Diseases (EURORDIS).Other patient groups, including Europa Donna(the European Breast Cancer Coalition) andthe Global Lung Cancer Coalition, have usedthe ECPC guidelines to beef up their own poli-cies. New European groups will be able to drawon these policies. In this way a new and moretransparent relationship with the industry isbeing forged.

The concept of a ‘sustaining partnership’ or‘founding partner’ is becoming increasingly popu-lar as a way of receiving funding that can bespent entirely as the patient group sees fit. Thetraditional model of sponsorship for particularprojects opens patient groups to allegations thattheir activities are skewed towards issues of com-mercial interest. Conferences, newsletters, infor-mation leaflets and websites are of interest to theindustry because they all help spread awarenessabout the latest treatments. Campaigns to cutwaiting lists for radiotherapy or to ensure thatcancer surgeons treat a minimum number ofpatients per year are of less interest, and there-fore less likely to receive funding. Using the sus-taining partnership model enables patient groupsto follow their own agenda.

Efforts are also being made to avoid beingtied too closely to a single sponsor – somethingfor which the Global Lung Cancer Coalitionwas criticised in the Australian press. TheCoalition had been set up from a meeting

organised by AstraZeneca, who also initiallyprovided the secretariat. Jesme Baird, a found-ing member, said “We all knew it didn’t looktransparent from the outside to have just onecompany supporting us, and we felt thecoalition should be more independent.” Thesecretariat has now been taken over by the UKRoy Castle Lung Foundation, and more compa-nies have come on board to finance activitiesthrough a sustaining partnership agreement.Baird argues, however, that the Coalition hasbeen a huge boost for lung cancer patientgroups, who struggle with a unique set of diffi-cult problems. She insists that withoutAstraZeneca taking the initiative, it could neverhave got off the ground.

International umbrella groups in theprocess of formation, such as MyelomaEuronet, are learning from that experience.Even if they are set up with the support of oneparticular pharmaceutical company, there doesappear to be a recognition that it is important tobring in other industry partners at a very earlystage.

IT TAKES TWO...Renegotiating a relationship does, of course,require the agreement of the other side. Thismay be less difficult than expected, as theindustry is aware of the need to polish its image.Relations with an increasingly confident andcritically minded set of patient groups will alsosuffer if pharmaceutical companies are per-ceived to be acting in a cynical and manipula-tive manner.

Six years ago, the European Federation ofPharmaceutical Industries (EFPIA) drew up aMemorandum of Understanding with Europe-wide patient groups. In 2003, the SwedishFederation drew up its own ethical guidelines,which rule out, for example, core funding. TheBritish Federation is currently reviewing its

Some companies are beginning to move away

from a purely commercial relationship

Mamazone criticises companies it receives money

from, for instance, about the price of drugs

PatientVoice


Code of Practice. The current version makes noexplicit reference to relations with patientgroups, but the Federation expects the revisedversion at the end of this year to cover this.

This change of approach seems to bereflected among big companies, at least at theEuropean level.

Catherine Steele, International Head ofPublic Policy at Roche, says the company ismoving away from a purely commercial rela-tionship with patient groups to a more carefullystructured and transparent ongoing relation-ship. Steele confirms an industry-wide change

away from funding individual projects towards agreater use of unrestricted grants. Companiesare increasingly playing a sustaining role, shesays, because many of the international organi-sations would otherwise not survive.

AstraZeneca recently hammered out a for-mal policy on its approach to patient groups.Head of public affairs in oncology, Lynn Grant,says that this aims to achieve “long-term andmutually beneficial relationships … based ontransparency and trust.”

Smaller patient organisations may, however,be less able to negotiate unrestricted grants. Forexample, Romanian pharmaceutical companiesrecently rejected an approach from theRomanian Cancer Society for a 10,000 europartnership agreement.

IS IT ENOUGH?Some argue that any cooperation betweenpatient groups and the industry necessarilyshifts the patient group towards the industryagenda. Anita Hardon of the University ofAmsterdam says that the influence is inevitableand often subconscious. Writing in a Dutchnewspaper, she says that patient groups tend tofocus on medical rather than non-medical treat-ments, and tend to take the same line as drugcompanies.

Jenny Hirst of the UK Insulin-DependentDiabetes Trust, giving evidence to the UK par-liamentary enquiry, put it this way: “You cannotcriticise the pharmaceutical industry and spe-cific drug companies and take their money atthe same time.”

Ulla Ohlms, of the German breast canceradvocacy group Mamazone, rejects what shecalls ‘fundamentalist’ arguments, and says thatMamazone does criticise companies it receivesmoney from, for instance, about the excessiveprice of drugs. Jesme Baird, of the UK RoyCastle Lung Cancer Foundation, says that if

Do you know your risk? Mamazone used shock tactics to getGermany talking about breast cancer

PatientVoice


you are professional and remember that you arethere for patients, you have no compunctionabout criticising a company when appropriate.Both point out that patients have pressing rea-sons for wanting access to certain drugs, andshould not be denied the right to speak out justbecause a sponsoring company could benefit.

Consumer watchdog Andrew Herxheimer,writing in the British Medical Journal (31 May2003), argues that the key is to be transparent,take money from a variety of sponsors, and keepthe industry contribution down to no more than20% of total income.

Few argue against transparency or multiplesources, although there can be practical diffi-culties with declaring all small donations, while‘rare disease’ organisations can find it difficultto attract multiple sponsors.

There is less consensus, however, over the20% limit.

For the bigger national and Europeanpatient advocacy groups, which make thepatient voice felt in the policy arena, the 20%formula doesn’t seem to work in the absence ofother funding. These groups equip cancerpatients with the information and skills theyneed to argue in a variety of arenas, for moreand more appropriate research and better pre-vention, screening, treatment and palliativecare. To do this, they need to be up to date withresearch, knowledgeable about healthcare sys-tems and policy, familiar with political process-es and able to communicate effectively withtheir members, policy makers, healthcare pro-fessionals and the public. None of that comescheap, while working at a European levelentails travel and translation costs.

Some, such as the Swedish breast cancergroup BRO and the NFK (Dutch Federationof Cancer Patient Associations) receive sub-stantial unrestricted national funding from thestate or national charities. But they are theexceptions.

German health insurance funds are meant toset aside half a euro per member to fund patientgroups. However, Ohlms of Mamazone believesthat the grants are out of step with the needs oftoday’s cancer patient groups; Mamazone hasnever been able to access such support or evento verify whether health insurance funds reallydistribute what they should. UK groups canapply for potentially generous grants for specif-ic activities from the Department of Health.But like commercial companies, governmentsonly fund projects that match their own priori-ties.

The European Commission’s consultationprocesses require the existence of Europeanumbrella groups, but the EC gives them nofinancial support. Most umbrella groups aretherefore dependent on the industry.

It appears that the European MedicinesAgency (EMEA), which is currently developingits own policy document on relations withpatient groups, recognises this reality. EMEA isexpected to reject setting an upper limit to theproportion of income from pharmaceuticalfunding, focusing instead on issues of trans-parency, disclosure of direct and indirect fund-ing, and on ensuring no single company has adominant position.

There has been talk in the UK about estab-lishing an independent body to ‘kite mark’patient organisations on the basis of trans-parency, sources of funding, membership size,internal democracy and so on. However, theNational Institute for Clinical Excellence(NICE), which draws up guidelines for treat-ment and takes decisions over which drugsshould be reimbursed, has not seen such abureaucracy to be necessary.

Marcia Kelson, Director of the NICEPatient Involvement Unit, says the industrycannot unduly influence NICE throughpatient representatives, “because whateversubmission they make we will use to go and

The EC needs the existence of umbrella groups

to consult with, but gives them no financial support

Some patient groups resent people who are free

from cancer staking out the moral high-ground

PatientVoice


look at the evidence to see whether it supportswhat they said.” She says that NICE is perfect-ly capable of differentiating between a method-ologically sound randomised survey undertakenby an established patient group and a letter-writing campaign put together by an organisa-tion established to lobby for a particular drug ortreatment.

HONEST DEBATEThis issue is not new, but the stakes have beenraised as decision-making structures at anational and European level open themselves togreater patient involvement, and patient groupsbecome more assertive and effective. Betweenthe highly pragmatic attitude of NICE and thearguments of the ‘fundamentalists’ are manyshades of opinion and ideas on how to move for-ward, and new policies and contract-basedfunding models are being developed even as theissue is debated by politicians and discussed inthe media. However, industry influence is notthe only issue here.

Some patient groups resent what they seeas people who are free from cancer staking outthe moral high-ground with little regard for theadverse impact they may have on patients. Nordo the accusations over ‘tainted money’ seem tovalue the thousands of hours of voluntarylabour provided by the members of thesegroups, which in most cases are worth manytimes the value of industry sponsorship. Manygroups rely on volunteers to providecounselling, support and information to otherpatients, staff a phoneline, run a websiteor newsletter, write and produce informa-

tion leaflets, travel to conferences and sit oncommittees.

Nor are critics of these groups always moti-vated entirely by ethics. Ohlms talks of the timeGermany’s health minister Ulla Schmidtattacked Mamazone for “sticking together withindustry” after the advocacy group had voicedcriticisms of the Government’s forthcoming dis-ease management programme. Ohlms feels thiscomment was a cheap alternative to respondingto the issues.

If this debate is to be honest and construc-tive, then those who contribute need to berespectful of the people with cancer and whatthey have at stake. For every alleged ‘stooge’organisation there are a hundred groups keptgoing by patients of tremendous bravery, self-lessness and dedication.

They have brought hope and comfort tohundreds of thousands of patients, and havebeen a driving force towards patient-centredresearch and care.

All groups need funding, from EuropaDonna, which successfully lobbied for aEuropean Parliament policy on quality breastcancer care, to cash-strapped patient groups inRomania who are trying to secure chemothera-py pumps, drugs and safe blood products with-in a system that considers cancer an automaticdeath sentence.

Simply attacking an important source offunding in the name of ethics and independencewill not help them. Supporting them in theirattempts to secure their independence throughnegotiating new terms with industry and findingalternative sources of unrestricted funding will.

For every ‘stooge’ organisation there are a hundred

groups led by patients of tremendous dedication

Cancer nursespartners in care

Cancer nursing is changing across Europe. Nurses are studying to higher levels, taking

greater responsibility and making more autonomous clinical decisions. One important result

is that they are better able to help cancer patients make sense of what is happening and

learn to become partners in their own care.

Cancer nursing developed as a special-ty in the 1970s. At the RoyalMarsden Hospital in London – oneof three specialist cancer hospitals inthe UK – Robert Tiffany encouraged

other cancer nurses to study up to Masters leveland extend their role in prevention, early detec-tion, care, and even in an intensive care setting.He was inspirational in starting the InternationalSociety of Nurses in Cancer Care (ISNCC) andin 1984 was a founding member of the EuropeanOncology Nurses Society (EONS).

The Royal Marsden is still a Europeanleader in cancer nursing. In 2000, ShelleyDolan became nurse consultant in cancer criti-cal care here, the first nurse in the UK to bemade a consultant. Her consultancy involvesher in work across the UK and internationally.Dolan chairs the Royal College of NursingCancer Care Forum, is on the board of theISNCC and is an active member of EONS.

She says that almost all cancer patientswant more control of their lives. “If you are tobe master of your own destiny and you have a

➜ Peter McIntyre

chronic illness, most people would like to bewell informed and a partner in decision-making.To control pain and manage their condition athome, it is important that they understand whatis going on.”

INTENSIVE CAREThe critical care unit at the Royal Marsden is anintensive care unit for cancer patients, who arelikely to be on a ventilator and need cardiac mon-itoring or kidney support after complex majorsurgery. Patients are also admitted for treatmentof a life-threatening renal failure, respiratory fail-ure, cardiac arrest or major bleed, as a result oftheir cancer or treatment. The mean stay is threeto four days, but 20% stay longer – up to 44 days.

Despite the relatively short length of stay, itis important, says Dolan, for nurses to get toknow their patients. “This is an acute blip in achronic illness and they could have many moreblips, so it is really important that they have thebest experience possible, or they are going to bescared if they have to face surgery again in threeyears’ time. When I employ a critical care nurse,

Systems&Services


Systems&Services


Shelley Dolan,nurse consultantin critical careat London’s RoyalMarsden Hospital.She was the firstnurse in the UKto be made aconsultant

I am looking for technical expertise, knowledgeand experience, but I am also looking for some-one who can give a lot of love to the patients.They have a very hard diagnosis to deal with andthe family has a very hard diagnosis to deal with.Suddenly you are in this environment wherethere are bells and buttons and machines allaround you; it is very scary for you and your fam-ily. It is very important to me that we do every-thing you would expect a supportive care nurseto do. Even when the patient is sedated and ona breathing machine we talk to them as thoughthey can hear every word that we are saying.”

Contact continues after discharge, througha critical care ‘cool off ’ service to help peoplewith cancer cope with their psychological andemotional reaction. “As soon as they are dis-charged from the unit to the ward, one of mycritical care outreach nurses makes sure thatthey are recovering and goes through any wor-ries that they have.

“They come back to my clinic at threemonths, six months and a year. I do a physicalexamination but also let them tell their story of

their critical illness, to make sense of what can bea very disorientating time, where night and dayget confused. People may think they have been ina film. It can be very florid. They sometimesdevelop what we call ‘critical care psychosis’where they think that everyone is trying to killthem and that the doctors are Russian spies. Wehelp them to make sense of it, as though theirbrain needs a bit of help to put these images andflashbacks into the right place.”

This story telling is now part of a researchproject at the Royal Marsden, and Dolan saysthat many patients express immense reliefwhen they find they are not the only ones tohave been deeply affected.

Cancer nurses administer chemotherapy,manage symptoms, and must understand theprogression of the disease and possible side-effects of treatment. Dolan sees one of the keyroles of her nurses as providing a point of refer-ence and education for their colleagues.“Haematological conditions, such as leukaemia,lymphoma and myeloma, are quite complex dis-eases, and most intensive care nurses only see a

Systems&Services


stand patients’ concerns and to explain clearlywhat is happening and about choice.

Dolan says that this means learning to listen, aspeople may express their real thoughts in casualthrow-away remarks. “When people give us cues weneed to hear them. When you are giving an injec-tion if someone says ‘I’m not sure if I am going toget through this’ it is much easier to say: ‘Of courseyou are. Don’t worry’ and rush off to do somethingelse. But that would not be listening to the person;and would not meet the standards we want. It ismuch harder to expose yourself to their pain, theirsadness and their fear.”

Dolan rejects the idea that you have to choosebetween technical competence and a good bed-side manner. “You do not want a science textbookon the ward who cannot relate to the humanity ofthe person who has cancer. On the other hand youdo not want someone who is warm and fuzzy butdoes not understand the drugs and how they work.Healthcare is complex and you are deliveringdrugs that are very toxic. To expect nurses to look

after people without a good education to the levelof a degree is a big mistake. Some of the best bed-side nurses are very highly qualified.” And shepoints out: “All doctors have medical degrees,including the caring GPs and palliative care physi-cians who have a really good bedside manner.

“I hope we get to a stage where we allrealise that total care of the patient is the aimand it is actually much more rewarding to worklike that,” says Dolan.

In the UK, nurses are able to prescribe ifthey have done an extended pharmacologycourse, but this has not yet arrived in the com-plex world of oncology. Dolan believes it willcome sooner rather than later. “Our critical careoutreach service is very much nurse led. Nursescarry out a physical examination of the patient,assess them and need to prescribe care. What

small number of those patients a year. Thesenurses will not necessarily understand aboutthe complex chemotherapy, bone transplantand why patients are so sick.”

The specialist knowledge of nurses isincreasingly recognised across Europe as animportant factor in patient outcomes.Experience has shown that knowledge andtraining of nursing staff is essential for optimalcancer care. The Wisecare+ project in a num-ber of centres, including the Royal Marsden,showed the benefits of using new technology tohelp patients keep in touch with nursing expert-ise even after they leave hospital.

PAIN REDUCTIONOne of the key roles of nurses is to minimise painfor patients. People with cancer often fear painas much as any other aspect of the disease and in90% of cases this can be effectively controlled.

At the Royal Marsden patients are askedbefore an operation where on a scale of 1–10 they

would want their pain control following treat-ment. Dolan says that most cancer patients arestoical and realistic and, rather than asking for a 0,ask for pain to be kept to no more than a 3 or a 4.

“If you have had major surgery you will not dowell afterwards unless you have good pain control.You have got to be able to breathe well so you cancome off the ventilator, you have got to be able tocough and you have got to be able to walk, to avoidthings like thrombosis. Patients in pain won’tcough and won’t do their physio properly andwon’t be able to walk about and will get all thecomplications that can arise. Pain is not just dam-age to a nerve. It is about sadness and anxiety. It islinked to our memory. If surgery was excruciatinglast time, that is what you think it will be again andit will be harder for us to achieve pain control.”

Another important skill is to be able to under-

“I would like nurses to be rewarded financially

and in career advancement and to feel supported”

Systems&Services


they have to do at the moment is to run to find ajunior doctor who will prescribe what they want.That is obviously not ideal. We want to bring fastappropriate access to care for patients.”

TEAMWORKIn specialist centres like the Royal Marsden, thehierarchy between professions has largely disap-peared. Dolan says: “We work as part of a multi-disciplinary team, and surgeons, anaesthetists,intensivists and physicians hugely appreciatethe work of the nurses and the nurses hugelyappreciate them. They are all very keen that wework together to improve the system.”

She feels nurses in general deserve greaterappreciation and recognition. “I would want tosee nurses across the world having access tostudy leave and study resource so that morenurses could undertake postgraduate degrees. Iwould like them to be rewarded financially andin career advancement. I want nurses to feelloved and supported in their work. It is a toughjob and junior doctors and nurses do not gohome and switch off. They go home and they

worry. They need to know that they are appreci-ated. That hard-nosed culture – come in, getthe work done and go home again – I don’tbelieve that that applies in healthcare.”

If the nurses have changed, so have thepatients, 80% of whom are cared for at home.Dolan recalls: “When I first came into nursingmany patients would just say ‘that’s fine’ what-ever you say. Until very recently cancer was nottalked about to patients – so people had a ‘lump’or a ‘bump’ or some ‘abnormal tissue’. Nowmany patients come in having studied theInternet. They want to know about options andwhat is happening.

“If someone is going to have a disease for therest of their life, they had better know about it,because they are going to have to manage theirfinances, their family and everything else and weare not going to be there. Health is not just aboutthe medicines you take. It is about the food youeat. It is about whether you stop smoking and ifyou take exercise. The most fundamental areaof healthcare is about getting people morehealthy. It does have to be a partnership.”

Shelley Dolanwith student nurse,Lai Man Chan.Dolan argues thatnurses who carefor patientswith complexdiseases like cancer,and are expectedto deliver toxicdrugs, need to beeducatedto degree level


Bookcase

➜ Raphaël Brenner

Portrait of palliative medicine as a young art

This is an excellent reference book for anyone involved in

palliative care. It covers every aspect of the specialty, and is

accessible to medical professionals and lay readers alike.

Since it first appeared 12 years ago,the Oxford textbook of palliative

medicine has become the gold stan-dard text in its field. But palliativemedicine is a fast-developing subject,and much has happened in the inter-vening period, as we can see in thisnew paperback edition.From a mere handful of palliativecare services, there are now over8000 worldwide. The subject is beingtaught in many more medical schoolsand has acquired specialty status inseveral countries including the UKand Romania.However, there is still a long way togo. Even in the affluent West, “forevery person who receives good pal-liative care there must be hundredsor even thousands who need it andhave no access to it,” write theauthors.They argue that the skills of palliativemedicine depend first and foremoston attitudes, and they insist that achange in attitude is needed on thepart of doctors “towards theirpatients, their needs and their care.”On every page, the book reaffirms theinterrelation between the threegroups involved in palliative care –patients, their families and health-

care providers – the importance ofpluridisciplinarity and the need forrespect. “If people know they arerespected as part of the human fami-ly (and here developing countrieshave much to teach us), the endingof life can be a final fulfilment of allthat has gone before,” notes CicelySaunders, while a patient tells us“Loneliness is not so much a matterof being alone as of not belonging.”

This latest edition contains so manychanges and innovations that itshould almost be seen as a new book.Its 21 sections, written by authorita-tive, international contributors, dealwith every aspect of palliative medi-cine: from the cultural, spiritualaspects of palliative medicine tosymptom management of cancer,from paediatric palliative medicine tocomplex ethical and emotionalissues.

Marking the importance with whichthe subject is regarded by theauthors, the section on educationand training has been almost entirelyrewritten, and includes new chapterson the role of humanities in palliativemedicine and on new technologiessuch as Internet learning.Also new are chapters on comple-mentary medicines (aromatherapy)and alternative medicine, and on thecontribution to palliative medicine of

allied health professions (musictherapy, psychology, etc.).While cancer remains at thecentre of palliative medicine,much space is also devoted tonon-malignant diseases and tonew approaches to neurologicaldisorders.

Finally, an excellent section on pallia-tive medicine in the home remindsus that there are still a fortunate fewwho die in their own homes (24% inthe UK, 56% in Italy). While this is clearly a medical text-book, non-physicians will also find init a wealth of knowledge. It is stimu-lating, thoughtful, and has an open-minded global approach. My onlyregret is that the layout could havebeen less cramped.

Oxford textbook of palliative medicine3rd editionEdited by Derek Doyle, Geoffrey HanksNathan Cherny and Kenneth CalmanOxford University Press, 2005, 1269 pp£59.95 (paperback)


Bookcase

T he editors and 24 co-authors ofthe second revised edition of this

textbook of clinical neuro-oncologyhave managed a pedagogical tour-de-force. They have made the complex issuesinvolved in their discipline accessibleto physicians, general practitionersand oncologists alike, without com-promising on either depth or detail –the bibliography contains more than2000 references. Their approach is practice-orientedand up-to-date – they use the WHO2000 classification for description oftumours.The comprehensive content is com-plemented by a clear and well-designed layout. Plenty of pictures,diagrams and tables, together withthe use of two-tone printing andboxes, combine to make it very user-friendly. The authors also deal with variousaspects of interdisciplinarity inneuro-oncology, including the treat-ment of tumour-induced pain andpsychosocial rehabilitation.This book is part of the ThiemeReference Series in neurology.

“T o find oneself from one day tothe next in hospital because

one has just been diagnosed withleukaemia is like undergoing punish-ment, except that no one has doneanything wrong,” writes MarianneAlmira at the beginning of her book.Better than any textbook on psycho-oncology or supportive care writtenby scholarly physicians, Sam is aunique, first-hand testimony of a 13-year-old girl who was diagnosed withleukaemia.To pass the time during the year shespent in hospital, Marianne drew herdog Sam as the cancer patient sub-jected to treatment by nurses anddoctors. The result is an amazingstrip-cartoon book illustrated andwritten with wit, sensitivity and intel-ligence.It is a kind of hospital diary that is atthe same time moving, funny (aswhen the physician prescribes thepatient a blood test in an incompre-hensible technical language), deeplyinstructive and full of hope. ThroughSam, Marianne reveals to readers theunintended inhumanity of somemedical staff.Her book is a graphic portrayal of thefeelings and needs of cancer patients.A must for everyone involved inoncology.

NeuroonkologieEdited by Uwe SchlegelMichael Weller and Manfred WestphalGeorg Thieme, 2005, 492 ppeuro 99.95

Sam à l’hôpitalMarianne AlmiraGallimard jeunesse/Giboulées2005, 48 ppeuro 12.50

W ritten by the Children’sOncology Group, the world’s

largest cooperative study group forchildren’s cancer, this third edition ofSupportive Care of Children withCancer is a highly useful, ready-refer-ence handbook for nurses, medicalstaff and oncologists involved in pae-diatric oncology care. It can be con-sulted for quick reviews at a patient’sbedside and is fully up-to-date. Today,three out of four children with cancercan be cured. But the downside isthat children with cancer have toundergo increasingly intensive treat-ment regimens. This book details thesupportive care measures needed tosustain children through therapeuticordeals and enable them to achievethe best possible quality of life. A sig-nificant contribution to the improvedoutcome for children with cancer isthe recognition of the infectious,metabolic and haemorrhagic compli-cations that can arise in disease andtreatment interventions. The bookcovers these complications in depthand describes new approaches topain management. It also includes anew chapter on burnout among pae-diatric oncology staff.

Supportive care of childrenwith cancer:Current therapy and guidelinesfrom the Children’s Oncology GroupEdited by Arnold J. AltmanThe Johns Hopkins UniversityPress, 2004, 434 pp, $33.95

cancer education & knowledge through people & facts · responses it evoked, show the power...

Documents