Cancer Education & knowledge through people & factsstand the test of time. Some US-based breast cancer advocacy organisations agree with this assessment and have chastised cancer experts

Education & knowledge through people & factsNumber 10, January-February 2006

➜ Michael Baumann: the dynamo of Dresden ➜ Herceptin: the hope and the hype➜ Lost in translation: why promising drugs fall by the wayside ➜ Gynaecologicaloncology: Hungary has a word for it ➜ Can science win back public trust?

Michael Baumann

CancerWorld 10

JANU

ARY-FEBRUARY 2006

Contents

CANCER WORLD ■ JANUARY-FEBRUARY 2006 ■ 1

3 EditorialHope or hype?

4 Cover StoryMichael Baumann: the dynamo of Dresden

12 Grand RoundLost in translation What’s coming up in colorectal cancer?

24 MasterpieceGynaecological oncology: Hungary has a word for it

32 Spotlight on...Can science win back public trust?FECS opens its doors to organ-based oncologistsComing out for breast cancer, country by country

46 Impact FactorRadiofrequency ablation in hepatocellular carcinomaRelapsed Hodgkin’s lymphoma: new twist to the standard regimenNewsround

56 FocusTwo sides to every study

60 Bookcase

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantMariarita Cassese

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

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Contributing WritersMarc Beishon, Raphaël Brenner, Nahum GoldbergFredrick Hagemeister, Peter McIntyre,Margaret McCartney, Mary Rice, Anna Wagstaff

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Copyright ©2006 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


Decades of experiencehave taught us to guardagainst the temptation totrumpet early impressiveresults as breakthroughs.Yet some of the com-

ments over the promising results from tri-als testing Herceptin (trastuzumab) inearly-stage breast cancer raise questionsabout how well that lesson has been learnt.In a glowing NEJM editorial, GabrielHortobagyi, a breast cancer specialist atthe MD Anderson Cancer Center inTexas, described the results as “revolu-tionary”, “simply stunning” and “maybeeven a cure”. Jo Anne Zujewski, directorof breast cancer research at the US NCI,said the findings support her belief thatbreast cancer has become curable inincreasing numbers of women.Predictably, these statements fuelleddemand for early access to Herceptinfrom patients concerned that they woulddie without this drug and, not surprising-ly, sections of the popular press gave overtheir front pages to champion theircause. Such was the pressure in the UKthat the government instructed localhealth authorities that they should notrestrict use of the drug in patients withearly breast cancer on the grounds ofcost, even though the drug was notlicensed for use in this setting, andindeed the manufacturers had yet to sub-mit an application to EMEA.This decision may return to haunt the

➜ Kathy Redmond ■ EDITOR

UK government when equally compellingand emotional situations arise, as theyinevitably will. In a tough editorial, the Lancet’s editor,Richard Horton, voiced strong criticismof decisions in the UK and othercountries to bypass official approvalprocedures. He pointed out that availableevidence on the drug’s safety and efficacyin the adjuvant setting is insufficient tomake reliable judgements, particularlysince interim results are prone to show-ing large treatment effects that may notstand the test of time.Some US-based breast cancer advocacyorganisations agree with this assessmentand have chastised cancer experts forusing the word “cure”, because such pre-mature confidence may fuel unrealisticexpectations. We cannot overlook the situation facingeither the women newly diagnosed withHER2+ breast cancer right now who aredesperate to optimise their chances ofsurvival, or the doctors who must tell theirpatients that only those who can afford topay will get the drug. But should we acceptthat complex decisions on access to cancertherapies are made in haste, in reaction tosensationalist media campaigns?Faced with the challenge of spirallinghealthcare spending there is a need forbalanced debate to tease out when, if ever,it is acceptable for a cancer drug to bepaid out of the public purse prior to thedrug’s approval for a specific indication.

Hopeor hype?

CoverStory

Michael Baumann:the dynamo of Dresden

Michael Baumann went into radiation oncology because it has all the biological interest of

medical oncology with added technical excitement. He claims the new targeted therapies

will only come into their own when combined with radiotherapy, and last year he cofounded

OncoRay, a state-of-the-art research facility, to help find out how this can best be done.

Last October, dignitaries flocked toDresden to witness the reconse-cration of the Frauenkirche, thegreat church reduced to rubble inWorld War Two, and rebuilt remark-

ably quickly after the reunification of East andWest Germany. Meanwhile, another projectwas taking shape that is far from a reconstruc-tion of the past – a new medical school at thecity’s University of Technology, the youngestand possibly the most progressive school in thecountry.

After reunification, federal funds pouredinto the old East Germany for many such proj-ects – and attracted professionals such as radia-tion oncologist Michael Baumann, who in 1995seized the opportunity to help carve out a newinterdisciplinary cancer centre at the CarlGustav Carus medical faculty and universityhospital. Fast-forward 10 years, and he’s now adirector of the centre, professor of radiationoncology and has recently taken on the presi-dency of ESTRO, the European Society forTherapeutic Radiology and Oncology.

➜ Marc Beishon

4 ■ CANCER WORLD ■ JANUARY-FEBRUARY 2006

Both Baumann and the work he’s set up inDresden – including for example a new researchfacility called OncoRay – are becomingimportant markers in the European cancercommunity, and especially in radiation oncology– a specialty that despite its long history of effec-tiveness has suffered from lack of recognitionand investment. While Baumann hammershome time and again the absolute imperative forall specialties to work far more closely together,there’s no doubt that he’s a champion of theradiation oncologists’ cause through long-stand-ing involvement in ESTRO’s education andtraining committee, and a forensic knowledge ofthe key role of radiotherapy in cutting-edge can-cer research.

“I believe radiotherapy is the optimalenvironment to bring in new molecular targetedsubstances, which are far from being curativethemselves,” he says. “We can prove that radio-therapy is extremely effective in eliminatingcancer cells. If we fail, a recurrence could bedown to just a few surviving cells – that’s all. Thecombination of a weak biological agent and a

CoverStory


“Radiotherapy is the best setting to bring in targeted

drugs, which are far from curative themselves”

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At the openingof the OncoRay Centre,Dresden, June 2005.Baumann is a foundingfather of thisstate-of-the-art radiationresearch facility,which does pioneeringwork on molecularand biological imagingand targeting

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very strong local modality in radiotherapy is verypromising.”

Radiotherapy, he adds, is also the most costeffective of all treatments, borne out for examplein a recent ESTRO study called QUARTS(Quantification of Radiation TherapyInfrastructure and Staffing needs – see alsoCancer World 9, October 2005). “That shouldconvince anyone to invest – but they’re notdoing it,” says Baumann, who points to a widediversity in radiotherapy provision and practiceacross Europe.

The cost of the machinery, competingdemands on health service budgets, and thetrend to make short-term purchasing decisionsare clear factors that contribute to this ‘blindspot’ about radiotherapy, comments Baumann.But it also suffers from a poor image among thepublic and politicians – especially in countriessuch as Germany, where there is a strong anti-nuclear power lobby that muddies the waterswhen it comes to discriminating between ‘good’and ‘bad’ radiation.

All this can also feed back into the educa-tion system and deter young doctors and otherscientists from pursuing a career in radiationoncology and related topics such as radiobiologyand radiation physics. In Baumann’s case, as inmany others who get turned on to a particularspecialty, it was by chance that he found himselfinspired by a good teacher of radiobiology at anearly stage at medical school in Hamburg.

“I wanted to do medicine because it com-bines biology and social science, and it has astrong component of interaction with people –although I could also have been an historian,and I’m still very interested in history.” At med-ical school, Baumann opted early on to combinescience and research in his training and tobecome a ‘doctor’ (in Germany, those who trainonly as physicians are plain ‘mister’).

“What really stimulated me about radiobiol-

ogy was not the radiation protection side but itsapplication to cancer research. At Hamburg, theradiation biology lab was already working ontumour models directly related to cancer –whole tumours, not single cells – and bringingthese complex tumour models into a clinical set-ting. They were doing fractionated radiotherapy[breaking up the total dose into many shortersessions], for example, and it was very easy toexplain to students why it had a direct impact onclinical practice.” The scene was also set forwork on perfusion, hypoxia and imaging,although molecular targeting was not yet on thetable.

Apart from the facts about radiotherapy –that for example 50% of patients cured of cancerhave a radiotherapy component (a figure that isrising) – Baumann found it more diverse thanmedical oncology as a specialism. “You have thesame biological principles relevant to medicaloncology, but also all the technical issues suchas imaging, and the possibility of not onlyadministering drugs intravenously and over dif-ferent times, but also to shape your agent bylocal or spatial means. It’s a fascinating way oftreating cancer – you have to know as muchabout your patients as a medical oncologist, butthose extra technological aspects are turning outto have a real resonance today.”

In Germany, as in several other countries,radiation oncologists also administer chemo-therapy in conjunction with radiotherapy, butthe term ‘clinical oncologist’ is not used – whichdoes add to the problem of knowing who doeswhat around Europe, comments Baumann.

As a specialty, radiation oncology is not veryvisible in many medical schools, he feels. “It’s nottaught at some schools – students may just beshown a linac [linear accelerator], which is hard-ly very interesting.” Needless to say, at Dresdenthere’s an interdisciplinary oncology course inthe medical school that lasts eight weeks.

“You have the same biological principles relevant

to medical oncology, but also all the technical issues”

CoverStory


Baumann’s interest in research at Hamburg sawhim leave for a two-year laboratory spell atHarvard Medical School almost immediatelyafter graduating and before he started work as aradiation oncology resident at the Hamburg-Eppendorf University Hospital. It’s a path welltrodden by many high flyers featured in CancerWorld – as Baumann reiterates, it’s very hard tobuild even a small research interest while work-ing long hours in the clinic if you don’t have thegrounding in setting up lab projects, writingpapers and obtaining grants.

It’s also a great opportunity to makecareer-long contacts – it’s no surprise thatBaumann cites as his key mentors not only hisHamburg thesis supervisors but also radiationoncology luminary Herman Suit, who is nowofficially retired from Harvard andMassachusetts General but who continues toimpress with a ‘can do’ attitude and ability to getprojects moving.

Commenting on the strengths of the US, henotes that some European centres are actuallyahead of America in the use of certain clinicaltechniques, such as Heidelberg with ion thera-py. Regarding possible controversies in the useof radiotherapy, for example the different appli-cation in rectal cancer in various countries, heconsiders that historical treatment regimens andstrengths are often key factors. Germany, forexample, has a track record in highly skilledhead and neck surgery, which means less radio-therapy is used for these tumours than in the USand elsewhere.

In many cases, he adds, there just aren’tenough data to make hard and fast judgementson the increasingly complicated treatmentoptions, and he points to the increasing avail-ability of European cancer statistics as a goodfirst step in highlighting the wide variations inoutcomes among countries, which will hopeful-ly fuel more large-scale trials.

What Baumann is certain about is the need forall specialties to have the best grounding andup-to-date knowledge in their fields. Thisbecame apparent in his specialty during his res-idency at the University Hospital in Hamburg,in the early 1990s, when a serious problemcame to light regarding late damage to a largenumber of patients who had received radiother-apy at that hospital during the 1980s. Baumannsays the problems, which mainly affectedpatients treated for prostate and rectal cancer,were largely the result of a lack of clinical radio-biology understanding, and the whole episodehad a profound effect on him.

“It brought home to me that radiation oncol-ogy is a very specialised field and you need avery sound education to be a good clinician,

Some European centres are actually ahead

of the US in the use of certain clinical techniques

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ing abroad. But it was clear there was going to bea boost to science and medicine in the old EastGermany and there were plans to really putDresden on the map with support for academicresearch.” Dresden is also a nice city, he adds,and his wife Bettina, a nuclear medicine spe-cialist, had already moved there in advance.

It’s certainly the case that Dresden’s medicalfaculty has picked up a reputation for beingrather less stuffy than the more traditional insti-tutions in Germany, with younger senior staff(Baumann arrived aged just 33), and a progres-sive attitude. “Dresden’s medical faculty hasbeen ranked as the most dynamic in Germany,”he says (and the medical faculty’s dean has beenquoted as saying, “Our main principle is to makeunconventional things happen.”).

There are two paths that the medical schoolis pioneering in general. One is a change toproblem-based learning for students, anapproach developed in partnership with HarvardMedical School. The idea is to give students farmore work to do on their own initiative ratherthan passively attending lots of traditional lec-tures. As Baumann explains, they are set prob-lems such as ‘theoretical’ patients presentingwith certain symptoms, and have to spend timeresearching and discussing the implications insmall tutor groups.

“Now I don’t have enough lecture slots toteach a systematic approach to radiotherapy – Ican only give a couple of examples. At first wewere worried that students would be less good attheir exams – which are common to all Germanstudents – but they have been much better thanaverage.”

The upshot is that students are more tunedin to both clinical bedside issues and research.Indeed, Baumann says that, increasingly, realpatient data will be introduced to a model that isactually more radical at present than Harvard’s.“But you still need some systematic lectures,

“Dresden’s medical faculty has been ranked

as the most dynamic in Germany”

particularly if you are applying new treatments.I also learnt that to make changes in clinicalpractice you must do them in formal study set-tings, and most importantly you need good fol-low-up of patients who are treated with anythingother than completely standard therapy.”

As Baumann adds, late damage is unique toradiotherapy – or at least we don’t know yet ofvery-long-term effects of chemotherapy. Sincethe Hamburg incident, all radiation oncologytreatment has to be followed up in Germany –possibly the only country with such a require-ment, he reckons.

Meanwhile he completed his residency atHamburg while also running an experimentalradiotherapy lab, where among the hot topicswas modified fractionation, later to appear inclinical practice. It was there that he laid thegroundwork for his present clinical specialties:treatment of head and neck, lung and sarcoma.Then – it being usual to move on in Germancareer progression – Baumann chose to move toDresden, although the problems at Hamburggave added impetus.

“I did have several options, including mov-

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and we’ll be putting more in as the curriculumdevelops,” he adds. Academic staff are alsotrained in the new approach – “It’s not usual forus to receive teacher training,” he says.

The other trend is to fast track the right stu-dents into research, especially clinical research,and to help young doctors avoid the conflictbetween training and research that is as acute inGermany as in other countries, according toBaumann. The idea is to give doctors the kind ofbreak that he enjoyed at Harvard – time out inthe lab at an early stage, either at Dresden orabroad, and either for long spells or for, say, oneweek in every four.

There is also a strong emphasis on buildingup opportunities for translational researchthrough close-knit interdisciplinary working,which Baumann says is critical to the success ofthe clinical side of the cancer centre.

For Baumann’s work, early success in bring-ing in grants for experimental radiotherapy andradiation biology have led, 10 years later, toDresden being one of the world leaders in pre-clinical testing of new radiotherapy approaches.“That’s true for normal tissue research, run by acolleague, and tumour research, run by mygroup,” he says. The approaches include modi-fied fractionation, identifying mechanisms ofresistance to radiotherapy, testing molecular tar-geted substances in combination with radiother-apy, and developing imaging modalities.“Hopefully in a couple of years we’ll be able tostratify patients for particular treatments,” hesays.

One of the recent highlights for Baumannhas been the establishment last year of theOncoRay centre – a snappy title that helpedraise the visibility of its work from the start, hefeels (its full title translates as Centre forInnovation Competence for Radiation Researchin Oncology). This is one of six such federallyfunded science centres. It has several research

programmes in train on the core topics of molec-ular and biological imaging and targeting, withstate-of-the-art equipment in place, enablingthe combined use of CT and PET (positronemission tomography), and four-dimensionaltechniques – moving radiotherapy throughspace and time. OncoRay is seeded with fund-ing of some 12 million euros for five years, afterwhich its results may enable it to become self-funding.

Baumann adds that other oncology researchspecialities are also strong in Dresden – he men-tions a medical oncology colleague who hasrecently obtained a grant for stem cell work inconjunction with a branch of the Max PlanckInstitute in the city.

Much has gone according to plan inBaumann’s research aims. The hard work to gainvisibility in the early years has definitely paid offwith large-scale funding today. However, therewas one huge setback – a flood in 2002, whenthe river Elbe burst its banks and the basementlabs in the hospital grounds were inundated. “Ittook about a year to set it up again,” he says.“There was a lot of sympathy from funding agen-cies – but that only goes so far.”

Baumann is also very happy with the waythe cancer centre and clinical work has devel-oped. He’s currently director of the universitycancer centre, a position that rotates among theoncology specialties so that no one feels theirdepartment is less valuable. A system of inter-disciplinary tumour boards is in place, meetingat least three times a week to plan treatment.“Our feeling is that we should provide a servicebefore treatment and even before diagnosticprocedures – we have joint guidelines on how toproceed, so it doesn’t matter who sees a patientfirst.”

Such multidisciplinary working has, howev-er, come fairly late to Germany, he adds, but allacademic centres are going in this direction in

“It should be a European right to talk to both

a urology surgeon and a radiation oncologist”

CoverStory


the country. However, the psychological barriersand competition between specialties are toughto break down. As he says, a prostate cancerpatient should have equal access to both a urol-ogy surgeon and a radiation oncologist to make adecision about a choice of effective treatments.“It should be a European right to talk to both –but it’s not European fact. Competition is onlygood if you talk about it and put forward thearguments. Quality for a department is oftendefined by quantity – say the number of surgicalprocedures performed – and that’s not alwaysmedically driven.”

A big obstacle is also the resources needed

to run a multidisciplinary centre “We don’t getany extra funds at Dresden to provide the serv-ice – it needs time and personnel – but ourpatient surveys show how popular it is. Budget-holders must provide money for such services.”

As he says, there is only one chance to getthings right in curative settings, and so manythings that can go wrong, including on the pal-liative side. He adds that, with studies showingthat current best practice would lead to an over-all survival gain of at least 10% even in devel-oped countries, he is keen to take the messagesto the wider platforms of ESTRO and FECS(Federation of European Cancer Societies).

As president of ESTRO, there are pressinginvestment and image concerns about radiother-apy to address. The recent enlargement of theEuropean Union, in particular, has exposed awide variability in radiotherapy provision – notsurprising, when you consider the costs oflinacs, radiation protection buildings and imag-ing facilities, and competing demands for othermachinery such as MRI scanners. “Most health-care budgets are too short term – a linac needsto be costed over 10 years or so,” says Baumann.

The lobby for radiotherapy is much weakerthan the drugs lobby, he adds, and equipmentmakers have relatively little clout compared withtheir pharma counterparts. Outdated equip-ment is a real problem, given the advances inimaging, planning software and dosimetry kit.

Personnel is another issue – apart from ashortage of radiation oncologists in some coun-tries, Baumann points out that radiotherapy isalways inter-disciplinary in itself, “We can’tafford the shortage in radiation physicistseither.” He warns too of a trend towards havingtoo many small centres – which is the case inGermany. One linac and a very low number ofradiation oncologists simply can’t provide goodspecialist care for curative treatment, he says.

But he picks out the image and importance

A big obstacle is also the resources needed

to run a multidisciplinary centre

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of radiotherapy as probably the key issue, andsays there is a lot of excitement when he dis-cusses in lectures the very promising pathwaysfor combined radio- and molecular-targetedchemotherapy.

His priorities for his two-year ESTRO pres-idency are to expand the society to properlycover all European countries, and to build upthe education and training work further(ESTRO has made good progress in establishingEurope-wide training records to aid professionalmobility, for example).

He sees no contradiction between promot-ing radiation oncology as a strong specialty andimproved interdisciplinary organ-based subspe-cialisation envisaged by FECS. If anything, dis-cipline-based specialism will only increase asbranches of oncology become more complex,and there’s no way that ESTRO is going to stoparguing the case for, say, more linacs per head ofpopulation. What’s needed at a higher level, hefeels, are clear aims before any discussion ofstructure takes place, given the premise thatthere can only be a set of strong specialties inoncology.

“The question of whether we need a federa-tion or a single society is not too interesting forme – we should first define aims, which I feelshould include providing a good lobbying instru-ment for patients, good conferences and foster-ing oncology research at all levels.” The aims hehas in mind are really a scaling-up of the kind ofinclusive, interdisciplinary cancer centre workhe’s involved in at Dresden. Good PR and‘branding’, and concerted efforts to make thegeneral population more aware of treatmentalternatives, should also be cultivated atEuropean level, he says.

That said, “I feel though that a federationcould work well, and we should look at whyFECS doesn’t appear at the moment to be theunambiguous voice of oncology.”

To some extent the debate will be shaped byboth medical and technological progress, andradiation oncologists have no shortage of excit-ing tools either in action now or on the horizon.All important, as Baumann restates, is molecu-lar targeting, either protecting normal tissues orfor sensitisation of tumours, by integratingradiotherapy with molecular targets. Biologicalimaging using PET and MRI “will offer a host ofinformation on how tumours are reacting” and isclearly a major step up from conventionalanatomical imaging.

IMRT (intensity modulated radiation thera-py) is also now in play, while more equipmentsuch as proton and ion machines might beworthwhile, although some commentators aresceptical about possible gains. “The investmentis huge – but that can’t be an argument not todo it. For specialised indications – such as forchildren – reducing the volume of irradiatedtissues say at the base of the skull is clearlyadvantageous.”

Baumann doesn’t have 100 million euros foran ion machine in the OncoRay unit at present,but few would bet against the Dresden team’sability to come up with the grants. In any case,he’s keeping an eye on other possible routes,such as laser technology, which is developingapace (and for which the last Nobel prize inphysics was awarded).

At home, Baumann likes to get away fromwork – classical music including opera is amonghis interests, as are reading history, biographiesand mystery novels. He has no plans to movefrom Dresden but doesn’t rule anything out.

At work, he says his team works on closepersonal terms – but he considers himself to bea demanding boss. “I see nothing wrong withthat. If you don’t move you are dead.” The wholeset up brings to mind the name, if not the cur-rent performance, of another feature of the city– its football team, Dynamo Dresden.

“Discipline-based specialism will only increase

as branches of oncology become more complex”

GrandRound


With all the amazingimaging technolo-gies now available,we should be ableto design drugs to

intervene with surgical precision inpatient populations identified by pre-dictive biomarkers. So why is it thatmost of the targeted drugs that havemade it to the market have been lessthan spectacular successes?

Is it that cancer cells are too devi-ous – they will always be one stepahead, finding little known back waysor creating new ones when their mainpathways are blocked? Or is it simplythat drug developers are having trou-ble getting their science right?

Heinz Zwierzina, chairman of theBiotherapy Development Association(BDA), is convinced it is the latter.He cofounded the Association in2002 in order to promote the effectivedevelopment of the new generation of

cancer biotherapies. Zwierzinabelieves effective new therapies arebeing discarded at an early stage ofdevelopment because of failings inthe translational research and trialprotocols. By the same token, heargues that many drugs that havemade it to the market could be usedto far greater effect if further workwere done to establish the most effec-tive dose and schedules, and to definethe most responsive patient groupand the most appropriate treatmentsetting.

One answer lies in bringingtogether drug developers, clinicalresearch organisations and companiesinvolved in diagnostics with regula-tors, translational and clinicalresearchers, and patient organisa-tions, to try to develop a commonapproach to getting effective drugs tomarket. To that end, the BDA organ-ises select conferences every 18

months, where representatives fromall these areas meet in a secludedatmosphere, mull over the implica-tions of recent developments and talkabout lessons for the future.

UNCHARTED TERRITORYThe second such conference tookplace in Innsbruck at the beginningof October, under the title“Harmonisation of next-generationoncology drug development”.

The need for harmonisation hascome about because new imagingtechniques have effectively torn upthe traditional drug development rulebook. Not only is this uncharted ter-ritory, there is not even agreement onhow to conduct the exploration.Which of the burgeoning alternativetests and technologies are mostappropriate for measuring what?Which biomarkers have a real clinicalrelevance and what do they tell us?

➜ Anna Wagstaff

Lost in translation

Cancer drugs often deliver less than they promise. The BDA believes the

problem may lie not in the drugs themselves, but in the way they are targeted,

tested and used. It organises regular get-togethers where the main players can

share information and discuss strategies for the future.


GrandRound

Which protocols are most appropri-ate for drawing out the informationwe need to use a drug to maximumeffect? These conferences aim toestablish and expand commonground. And some common groundthere certainly is.

For instance, it is commonlyaccepted that targeted drugs are gen-erally very much less harmful thancytotoxics, which means less need forphase I trials – many trials are nowcollapsing the phase I into a singlephase I/II.

Phase II trials, however, are nowseen as absolutely essential. Nolonger are they just pilot studies tosee whether it is worth investing in aphase III. They should be exploratorytrials using translational research to

try to establish proof of the principleof the mechanism of the drug inhumans, to identify the characteris-tics that predict which patients willrespond best, and to establish themost effective dose and schedule.Well that’s the theory anyway.

Nick Botwood from AstraZenecatalked about the lessons they hadlearned from the development ofIressa (gefitinib) – a drug for non-small-cell lung cancer (NSCLC) thatAstraZeneca withdrew from review bythe European Medicines Agency(EMEA) very early in 2005 becausesome impressive evidence of tumourregression in early clinical trials didnot translate into a statistically signif-icant increase in survival compared toplacebo in the overall population.

Iressa had been designed to work inpatients with NSCLC exhibitingEGFR over-expression identifiedusing an immuno-histochemistrytest.

However, it has since transpiredthat there are at least four communi-cating receptors, some more impor-tant than others, and 14 possiblemutations have been identified, eachassociated with different levels ofresponse. It now turns out that Iressaactually works best in patientsexhibiting an amplified EGFR whichdoes not show up using immuno-his-tochemistry, but is detectable by theFISH (fluorescence in situ hybridisa-tion) test. However, in the meantime,Roche got approval for a rival drug,Tarceva (erlotinib), whose phase III

Not only is this uncharted territory, there is not even

agreement on how to conduct the exploration

We are only just beginning to mapthe complexity of cell signalling pathways

Source: Reprinted from D Hanahan and R Weinberg. The Hallmarks of Cancer. Cell 100:57–70. © 2000, with permission from Elsevier

GrandRound

survival benefit was significant atp=0.001.

Bob Milsted, AstraZeneca’s globalhead of regulatory affairs for oncology,accepts that there is a problem get-ting the science right, but he stressesthat people must have realistic expec-tations about what can be achievedwithin a given time period. He arguesthat it will always be the case thatwhen a new drug is ready for the mar-ket, researchers will only just havebegun to understand how it works,and he points out that methotrexate,which is targeted at a specificenzyme, has been on the market for agood 40 years and there are still novalidated biomarkers to indicatewhich patients respond best to it.What many people don’t realise abouttargeted drugs, he says, is that youneed a drug capable of hitting a giventarget before you can start to look atwhat the effects of hitting that targetmight be.

“When a new drug appears on thescene it is two things. One is a drug indevelopment. The second is a phar-macological tool. It is not until I havethe drug that I can shut down thatsignalling pathway and see what hap-pens and start to explore the science.


cisely how it works. There is no rea-son to believe that we can tell foreach patient what this drug is actual-ly doing or not doing.” But his col-league Bertil Jonsson emphasisedthat this does not mean we give uptrying to understand. “I believe it isour duty to try to understand what ishappening. Of course we will alwaysmake mistakes, but a purely empiri-cal approach cannot be the wayforward.”

Industry representatives, howev-er, seem fairly relaxed in the face ofthis dawning recognition that we maynever know the precise mechanism ofdrugs. A senior executive from Merck(KGaA) voiced strong optimism aboutthe potential of intelligent combina-tions of targeted drugs. Merck, hesaid, is already working with otherpharmaceutical companies to test theeffectiveness of approved drugs usedin combination. One example is a trialof Erbitux (cetuximab) used in com-bination with Iressa.

Issues of commercial confiden-tiality, competition and legal liability,once seen as serious obstacles tocooperation, are being circumventedby using non-commercial third parties– in this case it is José Baselga’s team

That is when I can start to tease outwhether the pathway is driving themalignant phenotype in all patients,or only in some of them, and if it isonly some, can I recognise them?”

Rachel Humphrey from Bristol-Myers Squibb, cast doubt on whetherit would ever be possible to identifyprecise mechanisms, or indeed toestablish whether a given drug isactually hitting its target rather thansomething else. Tyrosine kinases, forinstance, are all so similar in struc-ture, she said, that it is very likely thatwhichever pathway you aim at, youwill end up blocking other pathwaysas well, and there is no way of know-ing which is the pathway of greatestsignificance. The best chance ofprogress, she suggested, now lies inusing combinations of inhibitorsaimed at multiple targets.

MISSING THE TARGETWhat does this mean for our dreamof the perfectly targeted anti-cancerdrug? Jan Liliemark from theSwedish Medical Products Agencyfound Humphrey’s message realisticbut depressing. “For a drug that hits20 different kinases or pathways,there is no point in investigating pre-

IMPACT OF VEGFR-2 INHIBITORS ON OTHER TYROSINE KINASES

Compound Phase VEGFR-1 VEGFR-3 C-Kit PDGFRB c-Raf b-Raf Src Flt-3 FGFR-1 EGFRVatalanib III 2 18 13.5 13.5 - - - - - -Sorafenib III - 0.1 0.53 0.3 0.07 0.24 - 0.64 6.4 -Sunitinib III ≤ 1 ≤ 1 ≤ 1 ≤ 1 - - - ≤ 1 90 10,000AZD-6474 III 40 - - 27.5 - - - - 90 12.5CP-547632 II - - - 79 - - - - 0.8 545CEP-7055 I 0.8 1 - - - - - 0.3 27 -Axitinib I 1.4 - 0.5 ≤ 1 - - - - 12.8 -GW-786034 I 5 1 - - - - 150 - - 590Chir 258 I 1 1 0.15 2 - - 508 0.008 1 169Courtesy of Renzo Canetta, Bristol-Myers Squibb

The compounds in the left column are all designed to block VEGFR-2. The data show how selective each compound is for a rangeof other tyrosine kinases compared to its intended target (fold-selectivity vs VEGFR-2)


in Barcelona that is doing the work.Interestingly, Merck is also looking atcombinations in which either one orboth of the drugs are still in phase I orII (within their own developmentpipeline). One example is an angio-genesis inhibitor still in development,which had shown unimpressive clini-cal response in phase II. “We askedthe German Cancer Centre inHeidelberg to do some clinical mod-els combining this drug with Erbitux,and they were extremely excitedabout the synergistic effects,” he said.

The new approach to drug devel-opment has had a profound effect onthe approval process. As targeteddrugs tend to be far less harmful thantraditional cytotoxics, there is pres-sure on the regulators to speed uptheir decision making.

Raj Puri from the US regulatorybody the Food and Drug Administra-tion (FDA) talked about new guide-lines issued in April 2005, designed tomake it easier for drug developers to

obtain important pharmacokineticinformation at a much earlier stage ofdevelopment. Using the new‘exploratory IND [investigational newdrug] studies’, US investigators cannow combine preclinical data with‘first-in-human data’ (phase 0) to helpthem select the most promising drugsbefore moving into phase I/II trials.

“Rather than doing a full phase Itrial, they are directed towards phar-macokinetics and pharmacodynamicsas a way of getting into clinical trial.They can gain insight, for instance, onhow to dose, based on preclinicaldata. This option was not open tothem before,” said Puri.

Questions were also raised aboutwhether regulators are right to with-hold approval of a drug that carrieslow risk and had been shown to be ofvalue to some patients, even when thebenefit failed to reach statistical sig-nificance at phase III. Milsted saidthat the phase I/II evidence of aresponse to Iressa in some patients

was so dramatic that when hereceived the CT scans he askedwhether there was any doubt aboutthe original diagnosis, because “thetumour looked more like a lymphomathan NSCLC.” He believes thisshould have been enough to tip thebalance in favour of approval, despitethe phase III survival figures fallingjust short of significance.

CONDITIONAL APPROVAL?A number of delegates pointed outthat the FDA had in the past grantedapproval on the basis of phase IIresults alone, under their ‘acceleratedapproval’ procedure, and asked whythe same could not be done in Europe.

Jonsson from the SwedishMedical Products Agency replied thatEurope is generally more cautious inits approach to novel medicines thanthe US, and he defended EMEA’sapproach, arguing that the FDA isitself uneasy about the way accelerat-ed approval has worked in practice.

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EFFICACY PROFILES IN RENAL CELL CARCINOMA: ANTIBODIES (Abs) vs TYROSINE KINASE INHIBITORS (TKIs) vs COMBINATION

Agent or Combination Known Targets Observed Objective Observed Rate of “Clinical Benefit”Inhibited Response Rate (Phase II) (CR+PR+SD) (Phase II)

Bevacizumab (Abs) VEGF 10% -Gefitinib (TKI) EGFR 0% 38%Sorafenib (TKI) Raf, VEGF, PDGF, Flt-3, 14% (Ph III: PFS doubled) 89%Sunitinib (TKI) VEGFR, PDGF, Flt-3, c-KIT, FGF 40% 68%Axitinib (TKI) VEGFR, PDGF 40% 86%Bevacizumab plus VEGF plus

Erlotinib (combo) EGFR 21% 86%CR, complete response; PR, partial response; SD stable disease. Courtesy of Rachel Humphrey, Bristol-Myers Squibb

Intelligent combinations of monoclonal antibodies and tyrosine kinase inhibitors may be the way forward

You need a drug capable of hitting a given target

before you can look at the effects of hitting it

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The procedure was introduced to givepatients with serious or life-threaten-ing diseases quicker access to drugsthat appear to offer a meaningfulimprovement over anything alreadyavailable. The applicant has todemonstrate that their drug has aneffect on a surrogate endpoint that is‘reasonably likely to predict clinicalbenefit’, and approval is granted onlyon condition that further studies aredone to verify that the predictions ofclinical benefit are borne out by theevidence. However, the FDA havefound poor compliance with the con-ditions, because once the drug is on


the market, it is not in the interests ofthe company to devote its resourcesto further research – particularly ifthat research indicates the drug is notas effective as predicted, or is effec-tive only in a very limited group ofpatients. Though the FDA has theright to take the drug off the market ifthat research is not done, or indeed ifthe drug turns out to be less effectivethan predicted, this has proved hardto do in practice.

Jonsson said that while he recog-nised that the biggest hurdle foreffective drug development is identi-fying good predictor markers, if the

regulators allow too many drugsthrough without insisting that thecompany first identify how their drugcan be used to best effect, the marketcould fill up with very expensive drugsthat have only marginal clinical bene-fit in an unselected patient popula-tion, and there is a danger that faithin the whole system will collapse. Hesaid that EMEA would soon havesimilar powers to the FDA to grantconditional approval, and that thereneeds to be a lot of discussion abouthow these powers should be used.

Some voices argued that it maybe only after the drug has been widely

New FDA guidelines aim to make it easier to obtain

vital pharmacokinetic information much earlier

This secluded spot in the Austrian Tyrol provides the perfect setting for informal discussions between industry, academics and the regulators


used for a number of years that itbecomes possible to define whichpatients respond the best. They madethe point that, had Iressa failed to getapproval in the US and Japan as hap-pened in Europe, then the informa-tion we now have about the particularmutation that predicts a strongresponse would quite possibly neverhave come to light.

One delegate came up with anovel suggestion for giving trialsteams access to previously untreatedpatients on the scale needed for moredetailed phase II analysis. As a molec-ular response is often apparent withindays, they argued, it should be possi-ble to administer the drug in the neo-adjuvant setting to newly diagnosedpatients during the normal waitingperiod between diagnosis and surgery.

Another suggested that ifresponse could be detected so quick-ly, even if companies had failed toidentify which patients would bemost likely to respond, every patientcould be given the chance to try allpossible drugs at least for a week orso, without too great a burden onhealth budgets.

Commenting later on the wholediscussion, Milsted said, “The ideathat we can solve all the problems ina few years is unrealistic. But someacademics and regulators don’tunderstand that. They say ‘You musthave developed a biomarker that willtell me who will benefit from thisdrug.’ And you have to say, ‘I’m sorrybut the science is not available for usto do that. We can only start to dothat now because we have treated

3000 patients and we have somedata.’ ”

Jonsson, however, clearlybelieves companies could do more inphase II to analyse how their drugsperform in real tumour tissue, andsaid he had taken the opportunityprovided by the conference to havean informal discussion with delegatesfrom one of the companies about theuse of breast tumour samples.

“I don’t understand why the com-pany doesn’t use them more to comea bit closer to the real cancer,” hesaid. “You can only treat a patientwith one compound, not ten. In alaboratory, however, you can treat thecells with ten compounds and lookfor markers and look for activity.

“Perhaps from these in-vitroexperiments you can find the pheno-type that makes it more likely thatyou have activity.”

The problem, he said, lies not somuch in the logistics of setting upgood-quality tissue banks, but gettingaccess to that tissue – not just for aca-demics but for the industry as well.

APPROVING COMBINATIONSBut it is when we start looking at theapproval process of combinationtherapies that things get really com-plex. Would two drugs approved foruse separately need to go through aseparate approval process to be usedin combination? Yes they would, saidthe regulators, because we need toknow both the combined benefitsand the combined side-effects.

What about combining experi-mental drugs? Would each drug have

to be approved for use separatelybefore approval could be sought forthe combination? If so, what if one orboth the drugs proved too toxic whenused alone, but were far less toxic incombination?

Hmm… said the Swedish regula-tors. We’d have to see the data. Ifthere are clear benefits for patients,we should be able to find ways toresolve the regulatory issues.However, no drugs developer has yetbeen brave enough to come forwardwith a test case, so we can’t say….

So what about Merck? Wouldthey be up for trying a test case? “Iam encouraged at least by theSwedish authorities,” said a Merckexecutive. “I think with these author-ities we can talk, and as they men-tioned, go for scientific advice. Youwould not go all the way throughphase III trials, and then go and askthem to approve. You would do itstepwise. Initially share the concept.Then ask specific questions, whereyou get scientific advice. Then comeback when you have data. And thendiscuss the phase III design. It needsa dialogue always.”

That dialogue, and step-by-stepapproach, is exactly what the BDAconferences hope to achieve in termsof developing an agreed overallapproach to effective drug develop-ment. When it meets again in March2007, lessons from the first trials ofcombinations of exploratory drugs,and an assessment of the use ofEMEA’s conditional approval instru-ment will be two topics that are like-ly to find a place on the agenda.

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“I don’t understand why they don’t use tissue

samples more to come a bit closer to the real cancer”


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➜ Mary Rice

What’s coming upin colorectal cancer?

A panel of experts is predicting that colorectal cancer patients will soon feel

the benefits of the sort of individualised therapies that are beginning to be

used in breast cancer. More effort is needed to promote a multidisciplinary

approach, improve staging and raise awareness of the benefits of screening.

Some catching up to do com-pared with some othercancers, but otherwisetreatment for colorectalcancer is making good

progress. This was the overall view ofthe experts gathered in Barcelona forthe first Colorectal CancerObservatory, organised by theEuropean School of Oncology.Clinicians and patient representativesfrom Europe and the US were asked topredict how they saw treatment, diag-nosis, screening and patient advocacyevolving over the coming 12 months,so that all participants could see theirwork in the context of a wider arena.

The single most important thingthat could happen to improve col-orectal cancer treatment, saidObservatory chair Mario Dicato, ofthe Centre Hospitalier deLuxembourg, would be improving ourability to predict risk of progression.

“Because we are not as advanced inthis field as they are in breast cancer,for example,” he said, “it is certainthat a number of patients are stillunder- or over-treated. We are stillunable to delineate clearly betweensub-groups at different risk. We donot have predictive markers for theuse of Avastin [bevacizumab] in thesame way breast cancer patients havefor Herceptin [trastuzumab], and thisis bad both for patients and forhealthcare systems, which have to

foot the bills for treatment that weknow is sometimes unnecessary. Thecurrent problem is knowing for whomit is unnecessary.”

Europe-wide guidelines for colo-rectal cancer were called for byCornelis van de Velde, of the LeidenUniversity Medical Centre in theNetherlands. Some countries have noguidelines at all, he said. For a start,multidisciplinary treatment planningshould be made mandatory for every-one. Staging is also a big problem.

OBSERVATORY PANEL

■ Mario Dicato (chair), medical oncologist, Luxembourg■ Lynn Faulds Wood (co-chair), patient advocate, UK ■ Philippe Rougier, medical oncologist, France■ Hans-Joachim Schmoll, medical oncologist, Germany■ Margaret Tempero, medical oncologist, US■ Cornelis van de Velde, surgeon, the Netherlands■ Chris Verslype, medical oncologist, Belgium

Accurate staging is vital, he stressed,both pre-operatively, by radiology, andpost-operatively by the pathologist.“At the moment it is imprecise.Patients are still mis-staged, particu-larly in stages 2 and 3, and this ham-pers the chances of targeting andoptimising treatment,” he said, addingthat pre-operative MRI, essential for

staging, is obligatory in some coun-tries, while in other countries it issimply not an option.

But despite having some catchingup to do, things are moving at a greatrate, he said. “In 1988 there was aneditorial in JAMA which looked atwhether chemotherapy had a role incolorectal cancer. This was followed

by a study that showed that it had sur-vival benefits in patients with lymphnode metastases. This seems extraor-dinary now, but in fact it was only fol-lowing in the same pattern as breastcancer, and we can expect to see thesame kind of progress both in diagno-sis, treatment, and survival benefits.”

Laparoscopic surgery will becomean integral part of colorectal cancersurgery, he predicted. “Currently somepeople get it and some don’t – and thisis true even within countries, forexample in the UK. The pioneers whothought it would enhance survivalhave found that this is not the case,but with careful technique the resultscan be equal to open surgery, at lessburden to the patient. It takes moreoperating time, but is easier to recoverfrom, and the quality of life benefits tothe patient are considerable.”

Providing better information topatients so that they can be properlyinvolved in the decision-makingprocess could also bring benefits allround, he said. “For example, peopleare very much opposed to the idea ofhaving a stoma. But to avoid this wehave to do highly technicallydemanding operations, which cansometimes make the patient inconti-nent. We need to get better atexplaining to patients exactly what isinvolved when there is a choice ofprocedures, so that they can fullyunderstand and pick the one that isbetter for them. A stoma can avoidmany problems, but because this isnot always properly explained,patients sometimes choose an alter-native that has a far more deleteriouseffect on their quality of life.”

Margaret Tempero, from theDepartment of Medicine, Universityof California at San Francisco, USA,also emphasised the importance ofmarkers for improving decisions onwhether or not to treat. She predicted


“My Ferrari has to be checked out regularly. Me too!”. Michael Schumacher does his bit to promotescreening in this campaign run by the Felix Burda Foundation in Germany, but much more needs tobe done to raise awareness about Europe’s second biggest cancer killer

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that research into the management ofcolorectal cancer will undergo a dra-matic shift as genomic predictors ofoutcome emerge from the analysis ofcandidate biomarkers in bankedtissue. “This will prompt prospectivetrials to validate the biomarkers asdiagnostic indicators to treat or not totreat. A second wave of research onbiomarkers predicting sensitivity orresistance will lead to tailored treat-ment selection,” she said.

Lynn Faulds Wood, representingthe European Cancer PatientCoalition, and a former colorectalcancer patient herself, set out thewish list for patients over the nextyear. Public health campaigns mustbe a priority, she said: it is the secondbiggest cancer killer across Europe,yet there is very low awareness of thedisease and its symptoms. It would

help if agreement could be reachedon a single name for the disease,which, she pointed out, is “confusing-ly known around Europe as colorec-tal, colon, and bowel cancer”.

Widespread implementation ofscreening programmes would be thebest way to save many thousands oflives over the next few years, she said,while better access to various forms oftreatment would bring improvementsfor patients. Some patients have towait months for radiotherapy. Accessto life-prolonging and potentially life-saving drugs is too slow, with officialapproval taking many months longerin Europe than in the US. And betteraccess to carefully targeted therapiesis needed.

Hope was held out on that lastsentiment by Hans-Joachim Schmoll,of the Martin Luther University,

Halle, Germany. He believes that inthe next 12 months combinations ofchemo-therapy and targeted agentswill increase long-term survival ratesin metastatic colorectal cancer. Newdrugs based on oxaliplatin will play anincreasing role in adjuvant therapy.

Such expert predictions are use-ful both in keeping people informedand in giving them a better under-standing of what their colleagues indifferent disciplines are doing, con-cluded Dicato. “I believe that by help-ing us understand what is likely toevolve in the next few years, we canbenefit not just ourselves, but alsopatients and healthcare systems. Inparticular, the promise held out bymicro-arrays and targeted treatmentin colorectal cancer is something thatshould be better known by a widerpublic.”

“In the next 12 months combinations of chemo

and targeted agents will increase long-term survival”

METASTATIC CRC

In metastatic CRC in the coming year Schmoll predicts:1. In chemotherapy backbones■ 5FU/oxaliplatin will continue to be an ideal backbone for chemo/targeted

combinations■ CapOx and XELOX (oxaliplatin/capecitabine combinations in different schedules)

will be used more frequently due to promising data, in particular on safety ■ XELIRI (irenotecan + capecitabine) will disappear■ Data on the relative benefits of CapOx vs FU/oxaliplatin will be available in June2. In targeted therapies■ Bevacizumab will be used more in combination with FOLFOX (oxaliplatin+5FU+leu-

covorin) and possibly also with CapOx in the 1st- and 2nd-line setting ■ Cetuximab will be shown to have strong efficacy when used in combination with

chemotherapy in 1st-line treatment, but it will remain unclear whether it is equallyeffective as FOLFOX/bevacizumab

■ Small molecule vascular endothelial growth factor [VEGF] tyrosine kinase inhibitorswill not yet be on the market

ADJUVANT THERAPY

In adjuvant therapy in the coming yearSchmoll predicts:■ The use of oxaliplatin-based combina-

tions will strongly increase followingsupportive data from the NSABP C07study and 4-year MOSAIC update

■ Safety data suppor t the use ofXELOX, but this combination will notbe used in an adjuvant setting atleast until 2007, when we will haveearly data on its efficacy

■ For patients who are not candidatesfor oxaliplatin, FOLFIRI will still be anoption (better than 5FU alone)

■ Oxaliplatin remains favourable withany 5FU backbone

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Gynaecological oncology:Hungary has a word for it

Péter Bösze, professor, gynaecologist, geneticist, chemotherapist, radiotherapist and teacher,

helped found the Budapest school of radical surgery. Today he is still encouraging young

gynae-oncologists to think radically and practise holistically – and he is helping ensure that

they can do both in their own mother tongue.

Péter Bösze pioneered the development ofgynaecological oncology in Hungary andin Europe, and is a leading figure in a

movement for radical surgery that today seesyoung surgeons from around the world seekingtraining opportunities in his home country.

He is polymath: a surgeon who is also ageneticist, chemotherapist and a board-certifiedspecialist in radiotherapy. He believes that thegynae-oncologist has a holistic role in the med-ical care of women, and should practise with abroad range of skills and tools. He is excitedabout the prospects of a prophylactic vaccine forcervical cancer and looks forward to better drugsto treat ovarian cancers. Yet he upholds, aboveall, the role of surgery in cervical, endometrialand ovarian cancers as being the most likely toprevent relapse and the least likely to causecomplications. He also believes that gynae-oncologists are the natural people to specialisein breast cancer surgery, and has won the rightfor this in Hungary. He believes that there isalmost nothing a skilled surgeon cannot accom-plish, so long as he or she is properly trained,

➜ Peter McIntyre


keeps up to date with the latest research andsees enough patients to be a genuine specialistin their field.

Still a full-time practising consultant at StStephen’s Hospital in Budapest, he devotes timeto publishing, writing and teaching atSemmelweis University, instilling in young menand (increasingly) women the training, skills andconfidence to take surgery forward and bring theresults of basic research into daily practice. Heis also leading a movement to adapt Hungarianmedical language so that everything that needsto be known and understood about cell muta-tion, genetics, surgery and cancer can be said inhis native tongue.

If Bösze has a determination thatgynaecological oncologists will not be compart-mentalised, he probably owes some of hisself-confidence to the pernicious regime that triedto prevent him from following his chosen career.

Bösze qualified from Semmelweis MedicalUniversity in Budapest in 1963, seven yearsafter the Hungarian uprising was put down bythe Soviet army. “I was against the system, as far

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as it was possible,” he says. With no familymembers in the Communist Party, he wasdenied a job in Budapest and the right tobecome an obstetrician and gynaecologist.

Instead, he was sent to the town hospital ofKarcag, 150 km east of Budapest, and told totrain as a general practitioner (GP). This turnedout to be a brilliant mistake on behalf of theauthorities, as the head of obstetrics and gynae-

cology at Karcag was desperatefor help and Bösze was thrownin at the deep end.

THE BASICS“It was a world with no moderntechnology, nothing. Some-times there was no light, andwe used a candle,” Böszerecalls. “The obs and gynaeoperating theatre was 500metres away, and sometimesthere was no ambulance to takea patient. If there was an emer-gency Caesarean section, I justput my hands in iodine and didthe operation in the deliveryroom with the nurse. The boywho was the porter was also theanaesthetist. He was excellentwith ether and chloroform;there were no accidents andeveryone survived.

“Sometimes it happenedthat there was no blood fortransfusions. We took out theblood from the abdominal cav-ity and filtered it and screenedit and gave it back to thepatient. This was 40 years ago,my first experience of auto-transfusion.

“I was on duty 28 days amonth for six years. I was enthusiastic. I wasallowed to do everything. It is no way for a med-ical doctor to be trained, but there was no alter-native. It was a kind of auto-training. I have totell you that I loved it. I really loved it.”

Once a fortnight he was allowed to attendthe medical school at Debrecen University andhe found time to publish 16 papers from Karcag.In 1970, the Director of the Medical

I was allowed to do everything. It is no way for a doctor

to be trained, but there was no alternative

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Postgraduate University in Budapest invitedBösze to join the staff. There he received athorough academic training in obstetrics andgynaecology, and was put in charge of thecytogenetics laboratory, where he worked onstructural chromosomal abnormalities, pursuingan interest in infertility and gonadal dysgenesis.

The awards began to flow, and in 1974 hespent a year in Edinburgh doing geneticresearch. On his return to Hungary, Böszeachieved certification in human genetics, andlater in radiotherapy, and he completed his PhDin primary ovarian failure.

The more he practised, the more he felt thatgynaecological cancer demanded its own sub-specialty. “I wanted to devote all my time togynaecology and genetics regarding malignan-

cies and tumours. Obstetrics and gynaecologytraining was far from enough to treat cancerpatients, and there was a desperate need foradequate surgery.”

In 1988, he was appointed to head thegynae-oncology department at the NationalInstitute of Oncology in Budapest, directed bySándor Eckhardt, later to become President ofthe International Union Against Cancer(UICC). Bösze introduced radical surgery. Histeam was the first in Hungary to carry out apelvic exenteration, to remove the uterus,vagina, ovaries, and lymph nodes, lower colon,rectum, and bladder, and to create stomata forfaeces and urine.

At international meetings, Bösze made apractice of visiting one of his hosts in their oper-ating theatre and learning every technique thatcould push back the boundaries. In six years ashead of gynaecological oncology at the Institute,he not only expanded the role of surgery, butoversaw 1,000 chemotherapy treatments a yearand a similar number of brachytherapy (intra-cavity radiotherapy) episodes.

When Eckhardt was injured in an accidentand stood down as Director of the Institute,Bösze did not see eye to eye with his successorand left. He eventually joined a strong gynaeco-logical oncology team (many of whom he hadhelped to train) at St Stephen’s Hospital, as aconsultant. “We have trainees from all over theworld, and I am really proud of our surgery. I amnot head of this department and it is my col-leagues who do the major work, but I am proudthat I started it.”

RADICAL SURGERYHere, the Budapest school of radical surgeryflourished, for example, extending radical hys-terectomy to remove not only the womb, para-metrium and lymph nodes, but also scatteredlymph nodes beyond the internal iliac veins and

The more he practised, the more he felt that

gynaecological cancer needed its own sub-specialty

arteries that had been considered unreachable,in effect clearing the pelvic side wall.

Bösze says, “With this technique, we totallychanged our five-year survival rate for cervicalcancer in stage 2B. Our five-year survival is over80%, while using combination therapies it isperhaps not more than 60%. We very rarely usecombination therapy in operable cervical cancer.We consider that lymph node dissection is atherapeutic curative approach.”

The department also invented radicalabdominal trachelectomy (ART) to remove thecervix, parametrium and lymph nodes, but pre-serve the fundus of the uterus so that a womancan still carry a child. László Ungár, head of theSt Stephen’s team, recently went to the US tocarry out this operation there.

Bösze believes that genetic advances willshow surgery to be the best stand-alone treat-ment for a range of cancers. “I would say that70% or 80% or higher percentage of early casesof gynaecological cancers are treated with sur-gery with or without adjuvant therapy. If you per-form radical hysterectomy in early-stage cervicalcancer (stage 1B1), you find secondary metasta-tic nodes in no more than 20% of the cases. Buthow can you separate which are the 20% andwhich are the 80%? Genetic research will findout who requires radical treatment and whorequires a simple hysterectomy or amputationof the cervix. In my view, this is the challengeof our time; to individualise treatment andmanagement.”

Specialist surgery can also reduce the needfor radiotherapy. Some endometrial cancers canbe cured by a simple surgery, hysterectomy andbilateral salpingo-oophorectomy (removal of theuterus, ovaries and fallopian tubes). However,some patients have a higher risk of lymph nodemetastases, and Bösze estimates that 50%–60%also require adequate lymph node dissection.General gynaecologists rarely offer this extra

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step, which means that patients receive unnec-essary post-operative radiotherapy.

“The question is whether the risk and thecomplications of lymph node dissection can becompared to the risk of adjuvant radiation ther-apy. I am certainly in favour of lymph node dis-section. Removing the lymph nodes from thepelvis is very rarely associated with any kind ofcomplications in skilled hands, and certainlydoes not have the long-term complications asso-ciated with radiation therapy. Radiation therapyis not a harmless procedure, and it invariablydamages normal tissue.”

Problems associated with radiotherapy aresometimes downplayed, because radiation-induced fistulae and bowel damage rarely occurwithin five years of treatment, which is the timeused as the standard measure of effectiveness.However, Bösze says that some patients die fromradiation complications 15 or 20 years later.

Pre-operative radiotherapy is also being dra-matically reduced. “There was a tradition forpre-operative intracavitary radiation therapy inendometrial or cervical cancer. Now we have cutthis tradition, and established guidelines wheresurgery alone is enough, and sparing radiationtherapy.”

Bösze believes that gynae-oncologists mustkeep themselves up to date with chemotherapyand radiotherapy. “You have to know, in detail,when chemotherapy should be given, howshould it be given, and what are the principles ofwhy it works.

“The same is true for radiation therapy. Ifyou don’t have any idea of the place for radiationtherapy or chemotherapy, when there is a meet-ing of the board, and the radiation therapist says‘yes we should do radiation therapy,’ that is aone-person decision, not a team decision. Evenin highly qualified centres, patients may getradiation therapy because radiation therapywants patients.”

He believes genetics will show surgery to be the best

stand-alone treatment for a range of cancers

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TRADITIONAL TOOLSAs well as keeping up to date with new sciences,Bösze is a great advocate of some traditionaltools of his trade, especially the colposcope. Hedoes not understand why western Europeancountries rely on smear testing alone for screen-ing, sending only women with abnormal smearsfor colposcopy, with all the attendant anxietyduring the waiting period. In Hungary and east-ern Europe, colposcopy is a routine part ofgynaecological examination.

“I use the colposcope all the time. It has alot of advantages. It makes me sure that nothingis wrong on the cervix or the vulva or the vagi-na. When you examine the vagina with a specu-lum and explore the cervix with a colposcope aspart of the gynaecological examination, thecervix is in front of you and you look and cansee if it is normal or not. It is an absolutelyharmless procedure.

“If the transformation zone (where pre-cancerous epithelial changes take place) is fullyvisible, you can be 100% sure that nothing iswrong, that there is no cancer. In 99% of cases Ican tell the patient right now that there is noth-ing wrong or that there is some suspicion and wehave to await the result of the cytology.”

Bösze is on the board of the InternationalFederation of Cervical Pathology andColposcopy (IFCPC), which is seeking tobalance out the benefits of cytology andcolposcopy. Cytology is associated with a highfalse-negative rate, missing 10%–15% ofabnormal cervical intra-epithelial neoplasia,while perhaps half of the suspicious findingsidentified by colposcopy turn out to be benign.

Ovarian cancer, known as the silent killerbecause of lack of symptoms in its early stages,gives least grounds for optimism. Research intoCA-125 screening (a blood test) and transvagi-nal ultrasound is discouraging. The US-basedProstate, Lung, Colorectal and Ovarian Cancer

Screening Trial reported in the American Journalof Obstetrics and Gynecology in November 2005that, of 570 women who had surgery followingscreening, 541 did not have cancer.

Bösze says, “This is a nasty cancer and,unfortunately, the vast majority are found in anadvanced stage. It is important to treat thesepatients in centres that can remove all thetumours from the abdominal cavity and retro-peritoneum, taking out and sectioning abdomi-nal organs. Once the tumour is out of the ovary,the only chance is to remove all visibletumours.”

About 5%–10% of ovarian cancers occur inwomen with BRCA 1 or 2 mutation – the samegenetic susceptibility that gives a higher risk forbreast cancer. Women who carry this genemutation can have their ovaries removed.Younger women can go on the pill until they areready to conceive, and have their ovariesremoved after they complete their families.

Bösze is one of the founders of theHungarian Cancer Genetic Service, which henow heads. He believes that the common genet-ic link strengthens the case for gynae-oncolo-gists treating breast cancer. The HungarianColleges for Surgery and for Oncology haveaccepted this, and gynaecological oncologists atSt Stephen’s operate on more than 200 womenwith breast cancer each year.

This fits Bösze’s belief that gynaecologicaloncologists should be holistic and multi-skilled.“I started the practice that the gynae-oncologistshould treat breast cancer. Breast cancer surgeryis simple compared with radical hysterectomy orexenteration. The gynaecologist deals with allkinds of benign diseases of the breast, and agynae-oncological examination cannot be madewithout palpating the breast. The importantthing is you should be trained well enough andsee enough patients. Patients should be treatedin centres, but whether they are called breast

“Genetic research will find out who requires radical

treatment and who requires minor surgery”

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cancer centres or gynae-oncology centres doesnot matter.”

RECOGNITIONBösze fought to win wider recognition for gynae-cological oncologists during his presidency ofthe European Society of GynaecologicalOncology (ESGO), from 1997 to 1999. Heapproached the European Board and College ofObstetrics and Gynaecology (EBCOG) which,“after many debates”, accepted that gynaecolog-ical oncology should be a sub-specialty – thefirst time that the European Union of MedicalSpecialists (UEMS) recognised a sub-specialty.EBCOG and ESGO also developed trainingguidelines for gynae-oncologists. He also affiliat-ed ESGO as an associate member of theFederation of European Cancer Societies(FECS). He describes these two steps as “break-throughs” that allowed the Society to becomethe voice of gynaecological oncology in Europe.

Bösze is the founding president of theHungarian Society of GynaecologicalOncologists and editor of its journal, theHungarian Journal of Gynaecological Oncology.Publishing takes an increasing share of hisattention. He is joint editor in chief (withAntonio Annis) of the European Journal ofGynaecological Oncology, and Eastern Europeaneditor of the European Journal of Obstetrics andGynaecology and Reproductive Biology.

In 1999, he founded the EuropeanAcademy of Gynaecological Cancer (EAGC) tosupport learning. The Academy now publishesthe CME Journal of Gynaecological Oncology,which he also started, in collaboration with theEuropean School of Oncology. Bösze explains,“Practising clinicians very much like review arti-cles that give an insight into a topic, but reviewarticles usually have a page limit. My idea was toestablish a journal with chapters, each devotedto a particular topic, as a kind of in-depth sym-

posium from basic principles to latest results.” The journal, now in its tenth year, goes out

to gynae-oncologists all over the world threetimes a year, with contributions from specialistsin many countries. In his career, Bösze hasattended more than 200 congresses as speakeror chairman, and many academic gynaecologi-cal-oncologists became his friend. He laughs,“When I send an e-mail saying, ‘please write anarticle for me,’ they don’t say no!”

An EAGC Course Book on Colposcopy, edit-ed by Bösze with David Luesley fromBirmingham, UK, was published in 2004 with

He believes the common genetic link strengthens

the case for gynae-oncologists treating breast cancer

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an impressive list of 35 international contribu-tors. What gynaecologic oncologists should knowabout chemotherapy, edited with MaurieMarkman of the MD Anderson Cancer Center,Houston, was published in December 2005, anda third title will follow, on cancer and genetics.

Bösze recently founded the journalHungarian Medical Language (Magyar orvosinyelv), to ensure that whatever happens ingenetics, oncology or gynaecology, Hungarianshave a word for it. Otherwise, he believes thatdoctors will lose touch with patients.

“The molecular biology of medicine is a rev-olutionary one with new terms every day, all inEnglish. Doctors in Latin America, France, Italy,Hungary and everywhere realised that we weretalking to each other in English. Our duty is toexplain to a woman what we think about her dis-ease and what management is available, so we

can make this decision together. You have toexplain this to her in her own language. Butmany terms have not got a Hungarian transla-tion. This journal keeps the Hungarian medicallanguage up to date and preserves the structureof the sentences.

“Medicine is science, art and language, andlanguage partly determines your way of thinking.If you cannot use proper words, it is not only aproblem for patients, you mislead your col-leagues and cannot give instructions to nurses.Your national language is the key to your person-al and national identity.

“This has nothing to do with chauvinism.Europe is a colourful continent because of dif-ferent nations, languages and cultures with1,000 years or more of history. I am not againstspeaking English – we should have a commonlanguage to understand each other. But anEnglish-speaking Europe would be a terriblecopy of the continent on the other side of theocean.”

This 21st century concern about the down-side of globalisation reflects the tradition of theHungarian Academy of Science, from whereBösze received his doctorate in 1992. TheAcademy – originally the Hungarian LearnedSociety – was founded in 1825 for ‘the study andpropagation of the sciences in Hungarian’.Much of its early work was spent defining tech-nical terms for the new sciences of the 19thcentury. Hungarian writer and poet János Aranydescribed its activities as “bee-like busy collec-tion of dialectal words and technical terms … inshort, aspirations to improve and expand theHungarian language, to propagate science inHungarian.”

Just as 19th century Academy memberswanted to keep up with the latest learning andat the same time to assert a national identity, sotoday in the 21st century Péter Bösze is leadinghis colleagues to do the same.

Hungarian language must keep abreast of science,

or doctors will lose touch with their patients

ITmust have been along time since themagnificent Doge’sPalace in Venicehosted such a bold

piece of diplomacy. VictorChernomyrdin, plenipotentiary min-ister in Russia’s government, was atthe top table with Kathleen KennedyTownsend, niece of the assassinatedUS President John F Kennedy, by his side.

Despite appearances, this wasnot a summit looking to reconcile dif-ferences between political powers.This was the grand opening of theFirst World Conference on theFuture of Science, organised by theUmberto Veronesi Foundation.Among those present were govern-ment ministers, a representative ofthe Vatican and other religiousauthorities, and the director of theUnited Nations Educational,Scientific and Cultural Organization

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Can sciencewin back public trust?Venice Charter starts the dialogue

Confidence in science is becoming dangerously eroded in the face of a rise in religious

fundamentalism and a general scepticism that scientific advances will be used for the good

of humanity as a whole. Will a global alliance for science win back some respect?

(UNESCO) regional bureau forscience.

The differences this conferencesought to reconcile concerned a breachbetween science and society thatseems to be widening in communi-ties across the globe. The alliance ithoped to forge was a global alliancefor science, “involving scientists,philosophers, theologians, politicians,industrialists, jurists, and all interestedparties.”

There was even a declaration – theVenice Charter – which affirms theimportance of science as a force forprogress and human well-being. Ittalks of the need for scientific progressto be fully and openly debated bysociety, particularly the areas ofgenetics, astrophysics and informationtechnology – and it commits thesignatories to promoting andparticipating in such dialogue.

Given the grandeur of the settingand the stature of the top table, one

might have expected a document res-onating with the sort of visionKennedy Townsend’s uncle used torally the people behind the US spaceexploration programme. Yet, theVenice Charter is essentially a cau-tious document, reflecting not somuch a lack of ambition, as a recog-nition that attitudes towards sciencehave changed, leaving it feeling belea-guered and misunderstood.

Kennedy Townsend talked abouthow the US, the super-power thatlanded the first man on the moon andhas led scientific and technologicalinnovation for half a century, seems tobe turning its back on science. Almosttwo-thirds of US Americans now saythey are open to the teachings of‘intelligent design’ – a bible-basedexplanation of the origin of life,touched up with a quasi-scientificveneer. One third would like to see‘intelligent design’ replace evolution-ary theory in the school curriculum.

➜ Anna Wagstaff

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Decisions over issues such as stemcell research or the withdrawal of lifesupport where brain death hasoccurred are turned into emotive arti-cles of faith by the Christian funda-mentalists who make up PresidentBush’s electoral base, making rationaldebate very difficult.

A parallel rise in religious funda-mentalism in the Islamic world,where the arts and sciences were forcenturies nurtured with pride, isexerting an increasing influence overcultural and social life. Interestingly,however, Darius Atighetchi, professorof Islamic Bioethics at the SecondUniversity of Naples, indicated thatgene therapy, in-vitro fertilisation,cloning and stem cell research –issues that have become flashpointsin the US and in strongly Catholiccountries – have posed less of a prob-lem in Islamic countries. When theUN General Assembly adopted a dec-laration virtually prohibiting all forms

of human cloning, most Islamic coun-tries abstained.

Religious fundamentalism is byno means the only problem. Scienceis also suffering from increasingconstraints on the freedom ofinformation on the grounds of nation-al security, where the concept of ‘dualuse’ can cover a wide area of scientif-ic research. In China, which isinvesting heavily in biotechnology andother sciences, and where religion haslittle influence, progress is held backby constraints on movement and free-dom of information. In Europe, aca-demic clinical research is hamperedby unnecessarily bureaucratic regula-tions designed with pharmaceuticalcompanies in mind.

THE THREATSThe conference looked at the waygovernments increasingly see scienceas simply a part of their economicdevelopment policy. Funding for basic

science, where researchers have free-dom to follow their own leads, isbeing squeezed in favour of project-based funding concentrated onpotential economic growth areas.

The free exchange of ideas isbeing threatened as universities areencouraged to patent their researchfindings to earn extra revenue – a prac-tice that started in the US and is nowspreading to Europe. Increasinglyintense competition for fundingbetween academic institutions detersan open and collaborative approach. Apolicy of cutting back on tenured posi-tions means that by the time sciencegraduates can settle down to work ona permanent contract they are oftenpast their most productive age. Havingconstantly to compete for jobs andfunding means they become slave totheir impact factor, and the need topublish may bias their choice ofresearch.

Drug development, once seen as

Science rejected. The Cincinnati Museum of Creation presents as historical factthis tableau of children playing alongside dinosaurs

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part of a state’s social responsibility, isnow left almost entirely to the privatesector. With huge sums of privateinvestment riding on what academicresearchers and journals publish aboutthese drugs and what clinicians pre-scribe, public trust in the integrity ofthe system has been undermined. As aresult, there are plenty of people whosuspect that bird flu is a scare inspiredby the pharmaceutical industry. Thewidespread distrust of geneticallymodified crops is another example.

Genetic scientists talked of theirastonishment at the public rejectionof what they see as a technologicaladvance with the potential to addressthe food needs of the world’s poorestpopulations. This was a public argu-ment between industrial scientistsand the western environmental lobby– and the public sided with the envi-ronmentalists against the weight ofscientific opinion.

Attempts by the US governmentto give credibility to scientific theoriesthat dispute the overwhelming evi-dence of global warming were alsomentioned as helping to discredit sci-ence in the eyes of the public as anobjective method of investigation.

The image of science as a meansto resolve the major problems afflict-ing mankind is also undermined by theallocation of resources. Vast sums ofmoney are ploughed into finding waysto keep the world’s wealthy popula-tions healthier, looking younger andliving longer, and into technologies ofwar. Meanwhile, the world’s poorestdie from preventable malnutrition,malaria, and lack of clean drinking

water and sanitation, and future gen-erations are threatened by lack ofattention to issues of sustainability.

But this remarkable gathering inVenice, which included philosophers,theologians, jurists, economists andpoliticians in addition to scientistsversed in genetics, bio-informatics,neurology, climate change, bio-agricul-ture and energy, had not been con-vened just to bewail the low position ofscience. It aimed to examine ways torestore public belief and confidence inscience, the scientific community andscientific methodology.

THE DEBATESThe first session, including theolo-gians of several religions and a chem-istry professor, looked at whether it ispossible to bridge the gap betweenreligion and science, or at least find acommon language to discuss issues oflife, death and humanity. No conclu-sions were reached, and evidence forany intellectual basis for commonground was hard to detect. Perhapsthe most pertinent contribution camefrom Kennedy Townsend, who has tobuild bridges as a politician. Sheemphasised that people are more opento rational argument in an atmosphereof tolerance and mutual respect. “Theimportant thing is not to fan flames offear,” she said. “Scientists should saynice things about God.”

There was, however, a recognitionthat advances in neuroscience andgenetics present an unsettling chal-lenge not just to the religious conceptof the soul, but also to the deepersense of individual identity. Much of

the world has had trouble enoughcoming to terms with the concept ofevolution – that mankind is separatedfrom the animal kingdom chiefly by itslevel of intellectual development. Nowwe are asked to accept that who weare, how we perceive and understandthings and what actions we take are alldetermined by our genetic make upand neurophysiology. And to cap it all,with advances in cloning, even ourgenetic make up can be reproduced.

Daniel Dennett, Director of theCenter for Cognitive Studies at TuftsUniversity, Massachusetts, and PhilipPettit, Professor of Politics andHuman Values at PrincetonUniversity, New Jersey, presentedfascinating accounts of what sciencehas uncovered about the relationbetween a person acting and thatperson willing that act, and offered acomforting philosophical treatiseabout what all this means for thewhole concept of free will.

In a nutshell, our brains give theorder to act split seconds before weare aware of willing the action.However, our own neurophysiologicalmake up is constantly evolving as weinteract with our surroundings, so weare not stuck with some predeter-mined and unchanging hardwiring;we develop in a unique way. So longas we can accept that our millions ofneurons are what we are, and don’tinsist on having some intermediary ‘I’giving the orders, then the perceptionthat our actions are our own is stillphilosophically viable, and humandignity can remain intact. “We are notin the loop – we are the loop.” Or in

The super-power that landed the first man on the moon

seems to be turning its back on science

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the language of attempted bridgebuilding, “Yes we have a soul, but it ismade of trillions of tiny robots.”

The threat posed by scientificprogress, however, goes beyond prob-lems of philosophy and self-identity.Advances in genetics hold the key totackling many of the diseases andhereditary conditions that havedefeated traditional medicine, butthey also threaten to open the way tonew forms of discrimination andsocial exclusion.

Women with a family history ofBRCA-related breast cancer, forinstance, could jeopardise theirchances of qualifying for a mortgageor insurance if they follow medicaladvice to be tested for the BRCAmutation. Some countries have nowintroduced legislation to prohibitcompanies from requesting informa-tion on any genetic test results whenthey ask potential clients to divulgetheir medical history.

But the implications of a knowngenetic predisposition go beyond the

interests of one individual. In a recentcase in Iceland, a court upheld amother’s request that the hereditarycause of her partner’s death shouldnot be given on his death certificatebecause the information could jeopar-dise their daughter’s interests.

This is a foretaste of what is tocome. Research into the genetic riskfor alcohol and drug addiction ormental health problems is opening upthe potential for discriminationagainst entire gene pools. The newknowledge is also open to selectiveinterpretation and misuse by peoplepursuing racist or sectarian agendas.

Advances in neurology are alsofraught with ethical dilemmas. Thedevelopment of drugs to combat, forinstance, memory loss in the elderly,opens question about whetherhealthy people who can afford to buythe drugs privately should be allowedto use them, for instance, to boosttheir exam performance.

Amedeo Santosuosso is based atthe Department of Law at Pavia

University and is a founding memberof the European Network for LifeSciences, Health and the Courts(ENLSC, www.unipv.it/enlsc/). Hetold the conference how, in recentdecades, lawyers all over the worldhave had to find ways of respondingto these new scientific develop-ments. Western law, he said, hastraditionally taken as its startingpoint the concept of the ‘privatesphere’ and ‘the social sphere’ devel-oped by John Stewart Mill back inthe mid-nineteenth century. Asadvances in genetics have blurredthat distinction, jurists have had tothink on their feet and search aroundfor other reference points.

Unlike scientists, said Santo-suosso, jurists tend to work within theirown legal systems – and also in theirmother tongue. He told of what a reve-lation it had been when the ENLSCcalled an international meeting in Paviato see how other countries were dealingwith these issues. Fifteen nationalitieswere represented, and it soon became

Crossing boundaries.Judges at the ENLSC seminardonned lab coats and picked uptheir pipettes to get a feelfor the realities of scientificinvestigation

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apparent, he said, that all of them hadbeen taking the same basic approach,using universal reference points thattranscend national boundaries, such asself-determination and liberty.

“As we started to discuss caseswithin the Network for the first time,we realised that in practice we weredrawing up a sort of ‘universal charterof rights’,” said Santosuosso. “And wethought: ‘Who are we to do this?’ Butthere is no other process.”

THE REMEDIESWhat the jurists were doing goes tothe heart of what this conference wasall about. On the one hand, profes-sionals were engaging in a welcomedebate, grappling with the implica-tions of scientific advances for societyand its laws. On the other hand, theyalso recognised that such debate hasto take place in a far wider forum.

Exactly how this will happen wasthe subject of the final session, whichconcluded that scientists have aresponsibility to engage with the pub-lic. “You have to get actively involved,”

said Kennedy Townsend, “Learn to bearticulate, explain what you are doingand don’t talk in code.”

This session was chaired byGiuliano Amato, a veteran politicalcampaigner who at various times hasserved as Italy’s prime minister andchancellor, and vice-president of theEU Convention in Europe. In themonths leading up to the conference,Amato had been a leading voice,together with Umberto Veronesi, call-ing for a ‘yes’ vote in the Italian refer-endum on stem cell research, whichwas lost because of a high level ofabstentions. He believes that theresults of the referendum might havebeen different “if scientists andphilosophers and so on spoke directlyto the people, instead of leaving it tothe politicians, who had only learntabout the subject a short whilebefore.”

He urged scientists to trust thepublic judgement. “People can learn toevaluate the significance of researchwithout understanding all the details.”But they have to be given the opportu-

nity. “Scientists should speak morewith the public.”

He joined many other speakers inthe session in calling for science to betaught better, and for more and bettercoverage in the media. But he alsostressed that supporters of sciencemust use the institutions of participa-tory democracy – polls, referenda,consensus conferences, and citizens’juries – to argue their case.

Veronesi, the renowned Italianoncologist and prime mover behindthe Venice Charter, was delighted bythe response to the VeniceConference, but says it is only thebeginning of a global project. “Theproblems and dilemmas of unrelentingtechnological progress are not beingadequately discussed in society as awhole. Hopefully, through setting upan alliance, we can move in a directionto change this. We are now planning topromote the Charter worldwide, as wedid last November with the presenta-tion to the New York Academy ofScience. Next step will be the presen-tation to the European Commission.”

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An Alliance for Science. Left to right: Giuliano Amato, veteran Italian/European political campaigner; Federico Mayor, chair of the European ResearchCouncil Expert Group, Janez Potocnik, EC Commissioner for Science and Research and, far right, Conference President Umberto Veronesi

Following a year of intenseinternal debate about thefuture of the Federation ofEuropean CancerSocieties (FECS), a

FECS council meeting held at thebeginning of November at the ParisECCO conference decided FECSwould open its doors to organ-basedsocieties. It described the decision aspart of its “One Voice, Once Vision”approach, which seeks to provide astrong and united voice for oncologyin Europe, that is as representative aspossible of all parts of the oncologycommunity.

According to this decision, organ-based societies that are alreadyaffiliated to FECS can join as fullmembers. This would include themastologists’ society (EUSOMA) andthe gynaecological and neurologicaloncologists’ societies (ESGO andEANO). The declared intention,however, is to go well beyond theranks of existing affiliates to find waysto bring in important groups like the

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The rocky roadto unity

As FECS prepares to welcome organ-based societies through the front door, the medical

oncologists threaten to leave by the back.

urologists, coloproctologists, pneu-mologists and gastroenterologists,which have traditionally had little todo with either FECS or ECCO (theFECS congress), despite the fact thatmany – often the majority – of theirmembers treat cancer patients.

Much of the talk during the pre-ceding year had focused on the possi-bility of dissolving the societies in theFederation and moving towards a sin-gle membership-based European can-cer society, but the council meeting inParis decided that such a move wouldbe premature.

Speaking shortly after the FECScouncil meeting, John Smyth, incom-ing president of FECS, said, “It wasincredibly frenetic at the Paris confer-ence, there was a huge amount ofdebate and discussion, but I was verypleased with the outcome of theFECS council meeting, which wasbased on listening to all the discus-sions. There is a greater need forcoordinating things than ever before.What we are going to explore is how

to open the Federation to other soci-eties, particularly what are nowreferred to as the organ-based soci-eties, because a lot of meetings and,more importantly, clinical practice,are very much specialised around dif-ferent types of cancer – breast cancer,colorectal and neural and so on.”

Initial responses from some of theorgan-based societies have beenwarm. Ignace Vergote, outgoing presi-dent of the European Society ofGynaecological Oncology (ESGO) –a FECS affiliate since 2000 – said,“We have been trying to get this deci-sion for five or six years. It will makea big difference. We will be moreinvolved in all the important thingsthat FECS is doing. Not only the con-gress [ECCO], where we will have agreater influence, but also in thepolitical work, where it is important toact with the other societies.”

ALL ABOARDNot all organ-based specialists havetheir own oncological societies,

➜ Anna Wagstaff

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however, and the question of how bestto draw in these practitioners is one ofthe issues a newly established FECS‘strategic committee’ was assigned tolook at. Urologists, for example, playthe central role in treating the major-ity of prostate, bladder and testicularcancer patients in Europe, but only atiny proportion of them specialiseexclusively in oncology.

Hein Van Poppel, Chairman ofthe Department of Urology at theUniversity Hospital Gasthuisberg,Katholieke Universiteit Leuven,Belgium, says, “Most urologists dosome oncology – many do tumours ofthe bladder and kidney, and they alldo prostate cancer, but for most ofthem oncology is not their only activ-ity”. Van Poppel himself treats onlycancer patients, but he says there areprobably no more than ten other peo-ple like him in the whole of Belgium.

This situation is reflected in theway urologists are organised. Thoughthere is a body named the EuropeanSociety of Oncological Urology(ESOU), this is not an independentmembership-based organisation likethe gynaecologists’ ESGO, but one of13 sections of the EuropeanAssociation of Urology (EAU). VanPoppel says that the EAU is keen tolook at how it may be able to cooper-ate with FECS, and is likely torecommend some form of liaison orcoordination via the ESOU board.

Vergote and Van Poppel are them-selves convinced of the importance ofgetting all cancer practitioners moreinvolved in multidisciplinary forumsas a way of raising standards through-

out Europe. However, they cautionthat there is much work to be done.As the trend towards organ-speciali-sation has spread, many strongnational and European societies havebeen built, each with its own con-gress and hierarchy of ‘must-attend’meetings.

“I only go to ECCO for one ortwo invited talks,” says Vergote,“because the ESGO meeting is threeweeks before, and this is more specif-ic – five days only on gynaecologicalcancers, where we have not onlygynaecologists but also medicaloncologists, radiation oncologists, andtranslational researchers who areinterested in gynaecological cancers.”

“It is not the congress where Isubmit my research,” says VanPoppel. “I submit it at the EAU or theAUA [American UrologicalAssociation], and we are not absolute-ly sure that FECS is going to changeits attitude, because it is always radi-ation oncologists and medical oncolo-gists going to that type of meeting,and surgeons are not involved. Sohow is FECS going to be successfulin organising an attendance fromoncologic urologists – that is thequestion.”

That said, both of them acknowl-edge that attempts to attract moreorgan-based specialists by includinghot organ-specific topics and speakerson the ECCO agenda are beginningto pay off. “Urologists are more andmore involved, and the urology ses-sions are now better attended,” saysVan Poppel.

The fact that, as a full member,

ESGO will now have a strong say over‘its part’ of the ECCO agenda, willalso make a difference says Vergote.And as for the timing of conferences,and content overlap, that can alwaysbe sorted out. “I think the goal ofECCO should be that it becomes asimportant as ASCO, but for Europe,”he said.

ONE STEP FORWARD,ONE STEP BACKAllowing organ-based societies toaffiliate to FECS would enable theFederation to bring a whole new layerof cancer practitioners under itsumbrella. However, the decision infu-riated the medical oncologists’ society,ESMO – a founding member ofFECS – which says it feels deeplythreatened.

In the closing days of 2005,ESMO announced it was pulling outof FECS activities and would focusinstead on expanding its ownorganisation “into a multidisciplinarymember-based society” with its ownannual congress starting in 2008. Onereason for the decision was undoubt-edly frustration over FECS’ decisionnot to turn the Federation into a sin-gle membership-based society, whichESMO has long advocated as vital forraising the profile of oncology inEurope. But ESMO President HåkanMellstedt also cites FECS’ decision toallow in organ-based societies as animportant factor behind his society’sdecision to disengage.

In many European countries,medical oncologists are still fightingto be recognised as a specialist

Not all organ-based specialists have

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discipline, alongside surgical oncolo-gists and radiation oncologists.ESMO argues that organ-based spe-cialists, whose primary training isusually in surgery, should not be han-dling drug treatments, and that allow-ing organ-based societies to affiliateto FECS undermines the medicaloncologists’ quest for recognition.

Mellstedt said “It is still a prob-lem that medical oncology is notrecognised in many countries inEurope, and we have to protect thatdiscipline for the best interests of thepatients of the future. With the pres-ent decision [by FECS], ESMOwould have disappeared or wouldhave been greatly reduced to a verysmall society. Our judgement is that itis better for us to step out of theFederation, because we have to sur-vive in a milieu where we can defendourselves.”

At the heart of the matter is agenuine difference of approach topatient treatment. The organ special-ists feel they are the ones with theexpertise. “We do the diagnosis, thestaging, the treatment, we use hor-monal treatment, and we use bispho-sphonates, angiogenesis inhibitorsand endothelin receptor blockers, justlike medical oncologists do,” says VanPoppel, adding that while most med-ical oncologists treat many malignantdiseases, urological oncologists treatonly urological malignancies, “Itwould be good to also have medicaloncologists who specialise exclusivelyin urological tumours.”

Mellstedt counters, however, that“You don’t treat the cancer, you treatthe patient. You need supportive care,you may need palliative care, and Idoubt that all these organ specialistshave that spectrum of knowledge.”He also points out that medical treat-ment of cancer patients is becomingincreasingly complex, with new

chemotherapy and targeted agents,new diagnostic procedures, and tai-lored therapies. “All this has to beincluded in the treatment of cancerpatients, and for that you need basictraining both in internal medicine andmedical oncology.”

A BUMPY RIDEThere are areas of common groundbetween medical oncologists andorgan specialists, for those who wishto find them. Mellstedt accepts thatmany smaller hospitals won’t be ableto support their own medical oncolo-gy department, but says there shouldbe specialist medical oncologistswithin every department of internalmedicine.

He says that ESMO is very keento collaborate directly with organ-based societies, but not within theFederation. He even says he is opento the principle of organ-specialist

oncology bodies like ESGO affiliatingto FECS, but draws the line at organ-based societies that include non-oncologists.

Van Poppel, for his part, agreesthat medical oncologists should beinvolved in the multidisciplinary plan-ning of each patient’s treatment, butargues that where the treatment is nottoxic and is easily available, it can bedelivered either by the urologist or bythe medical oncologist.

All the players in this unrollingsaga know full well the price to bepaid in terms of the clout and stand-ing of oncology in Europe if theycannot come together in a unitedfront.

The question remains, however,what shape that unity will take.Judging by recent events, there is stillsome way to go before a solution isreached that everyone can live with,and we may be in for a bumpy ride.

FECS

The Federation of Cancer Societies is a multidisciplinary umbrella group for Europe’smain oncology societiesIt has six full members:■ European Association for Cancer Research (EACR)■ European Oncology Nursing Society (EONS)■ European Society for Medical Oncology (ESMO)■ European Society of Surgical Oncology (ESSO)■ European Society for Therapeutic Radiology and Oncology (ESTRO)■ International Society of Paediatric Oncology, European Branch (SIOP Europe)It has eight affiliated members■ European Association for Neuro-Oncology (EANO) ■ European Group for Blood and Marrow Transplantation (EBMT) ■ European Organisation for Research and Treatment of Cancer (EORTC) ■ European Society of Gynaecological Oncology (ESGO) ■ European Society of Oncology Pharmacy (ESOP) ■ European Society of Mastology (EUSOMA) ■ Flims Alumni Club (FAC) ■ Organisation of European Cancer Institutes (OECI) At its council meeting in November, FECS agreed to invite its organ-based affiliatesEANO, ESGO and EUSOMA to join as full members. It also decided to explore how toopen the Federation to non-affiliated organ-based societies

Throughout October tens of thousands of menand women from more than 30 countries acrossthe world took to the streets as part of the AvonWalk Around the World for Breast Cancer.Many of the walks were linked by a Global

Connection Ribbon that was passed on from a survivor inone country to the next in a chain of solidarity. The event,also supported by Novartis, was organised to mark the 50thanniversary of the Avon Foundation, set up to supportinitiatives to improve the lives of women, with a particularfocus on breast cancer.

The Avon Foundation prides itself on taking an intelli-gent, needs-based approach to supporting the fight againstbreast cancer. It focuses on promoting medical research,

Spotlighton...


Coming out for breast cancercountry by country

Walks to raise awareness of breast cancer are established traditions in many countries. But in

many more, breast cancer remains hidden from public and political agendas. Avon’s Walk Around

the World helped connect everyone fighting to raise the profile of breast cancer across the globe.

CHINA

GERMANY TO BULGARIA

MEXICO

FRANCE

awareness, and access to care, screening and high-qualitydiagnostics, and on supporting community-based groupsthat can reach the most poorly served populations.

Though the Avon Foundation is based in the US, Avonphilanthropy is active worldwide. In Europe, it supportsorganisations like Mamazone in Germany and Amazons inPoland – two very effective advocacy groups, both heavilygeared towards helping patients get the information theyneed. The Foundation is also funding fellowships for breastcancer doctors from eastern Europe to study in the US.

Walk Around the World for Breast Cancer provided anopportunity to show solidarity between breast cancer sur-vivors in different parts of the world fighting for greaterawareness of breast cancer under very different conditions

– from the US, where women put breast cancer on thepolitical map decades ago, to countries in central/easternand southern Europe, China and East Asia, in many ofwhich breast cancer remains a taboo.

Wang Boaling is a 58-year-old breast cancer survivorfrom Beijing, who joined the Chinese leg of Walk Around theWorld, up the Great Wall. She welcomed the chance tospeak out about breast cancer. “If women paid more attentionto their health it would be easier to find the cancer and treatit. Here in China breast cancer is still something you do nottalk about easily. After my operation, I reflected a lot on whatI could do. I wanted to show the world that cancer did notstop me and show other women that it should not stop themeither. It was very impressive to stand on such a powerful

Spotlighton...


Walk Around the Worldfor Breast Cancer events took placein more than 30 countries.In Europe, this included Bulgaria, Czech Republic, Estonia,France, Germany, Greece, Hungary,Ireland, Italy, Poland, Portugal,Romania, Russia, Serbia, Slovakia,Spain, Turkey, Ukraine and the UK

POLAND

RUSSIAN SURVIVORS

HUNGARY

CANADA

Spotlighton...


symbolic monument as the Great Wall and look out and seethe hundreds of women with their families and friends whowere also climbing the Wall for the same reason.”

Reluctance to speak about breast cancer is alsohampering progress in dealing with the disease in much ofEurope. Patient organisations in Romania talk ofdifficulties in securing local authority grants, because ofthe assumption that people with cancer are going to dieand there is nothing anyone can do about it. The Avon walk– the first ever in Bucharest – therefore offered a welcomeopportunity to raise the profile of breast cancer. “Thewhole initiative, from the press conference to the walk andafter-walk festivities was a success,” said Judy Zerwitz, a65-year-old breast cancer survivor representing the US,who had flown over to join the Romanian walk. “About

500 lively and energetic people turned up to show theirsupport for breast cancer. There was music and peoplewere having fun; it was all out in the open – both literallyand figuratively speaking.”

Avon has organised walks to raise breast cancer aware-ness in a number of countries for many years. LastOctober’s Walk Around the World for Breast Cancer pro-vided the impetus to organise walks for the first time inplaces that do not have this tradition, and the GlobalConnection Ribbon focused on the importance of solidar-ity between advocacy groups in different countries. This isimportant because levels of cancer awareness differ sub-stantially across Europe, and it is only when cancerbecomes a significant public issue that politicians anddecision makers start to do something about it.

ROMANIA TO GERMANY

PORTUGAL

USA - SAN FRANCISCO

UK TOIRELAND

ARGENTINA

I wanted to show the world that cancer did not stop

me and it should not stop other women either

ImpactFactor


absence of five-year survival data[1–3].

Lencioni et al. provide an initialreport of promising longer follow-updata, as they demonstrate five-yearsurvival similar to surgical series forsimilarly stratified patients (seeopposite).

The authors performed aprospective, intention-to-treat clinicaltrial in patients with hepatic cirrhosis(Child-Turcotte-Pugh class A or B)and early-stage HCC in whom percu-taneous image-guided RFA was theonly first-line anticancer treatment.

In total, 206 nonsurgical patientswith either a single HCC ≤5 cm indiameter or up to three HCCs ≤3 cmeach were enrolled. RFA was per-formed in 187 patients (91%).

Safety of the procedure wasdemonstrated, as there were noperiprocedural deaths and only 2%had major complications. Overallsurvival was 97% at one year, 67% atthree years, and 41% at five years, byintention-to-treat analysis, with a48% five-year survival rate for thoseundergoing RFA. Median survivalwas 57 months.

Overall, the one-year, three-year, andfive-year recurrence rates were 14%,49%, and 81% respectively for theemergence of new tumours, high-lighting the noncurative nature oflocal resection, and 4%, 10%, and10% for local tumour progression,confirming that RFA in skilled handscan be effective at eradicating focal,but not distant, disease. The authorsfurther confirmed prior intervention-al oncology literature, noting thatChild-Turcotte-Pugh class andtumour multiplicity were additionalpredictors of survival.

These results suggest there isprobably enough evidence to justifyusing image-guided RFA as a first-line treatment for cirrhotic patientswith early-stage HCC with limited,well-defined tumour burden. Indeed,this is the practice at our institution,where RFA is also used as an adjunctto liver transplantation.

Nevertheless, the need forfurther studies, including largerand longer series and ideally arandomised direct comparisonbetween surgery and image-guidedablation (RFA and other), must be

Over the past decade, therehas been increased interestin image-guided radiofre-

quency ablation (RFA) of focaltumours using needle-like applica-tors, because of the minimalmorbidity and mortality comparedwith conventional surgical resection[1]. Clinical interest has focusedupon treating hepatocellular carcino-ma (HCC), because most patientshave underlying liver disease and/orcoagulopathies, which substantiallyincrease surgical morbidity, and mostpatients develop additional foci ofdisease [1–4].

The use of heat energy in theform of localised radiofrequency tocoagulate and ablate tumour hasbegun replacing prior methods, suchas ethanol injection. This is becauseof the reduced number of treatmentsrequired and at least equivalent effi-cacy of RFA compared with ethanolinjection [2,3]. Although there aremany optimistic preliminary reportswith short-term follow-up, RFA hasnevertheless been criticised by someas ‘untested’, owing to a paucity oflong-term results, particularly the

➜ Nahum Goldberg*

Radiofrequency ablation in hepatocellular carcinoma

A new study supports the use of image-guided radiofrequency ablation as a first-line

treatment for well-selected cirrhotic patients with early-stage hepatocellular carcinoma.

Cancer World has reached agreement with the Nature Publishing Group for the reprinting of articles from the Practice Points section of Nature Clinical Practice Oncology. This and thefollowing article first appeared in the September and July 2005 issues respectively


acknowledged, because the studywas of short follow-up duration, witha mean of two years, with widevariation.

Furthermore, the best way toperform tumour ablation in terms oftechnique, device selection, andpotential combination with othertherapies, such as chemoembolisa-tion and adjuvant treatments toimprove local and distant diseasecontrol, requires further study. Each

of these variables can potentiallyinfluence the study outcome.

Better definition of indicationsand treatment guidelines is also need-ed, with caution being urged againstoveroptimistically translating thesepromising data for the treatment ofmore advanced HCC (i.e. largertumours) or other types of tumour(e.g. intrahepatic colorectal metas-tases), which are more difficult totreat with ablative techniques [1,4].

Details of the references cited in this article can beaccessed at www.cancerworld.org/cancerworld

* Nahum Goldberg is director of AbdominalIntervention and Tumor Ablation and directorof the Minimally Invasive Tumor Therapy Laboratoryat Beth Israel Deaconess Medical Center,and an Associate Professor of Radiology at HarvardUniversity, Boston, Massachusetts, USA. Competing interests: Dr Goldberg receives sponsoredresearch support and is on the advisory boardof Valleylab, USA, a manufacturer of radiofrequencyablation devices. He also receives research supportfrom the NCI

First published in Nature Clinical Practice: Oncology2005, vol 2 no.9. © 2005 Nature Publishing Group

ImpactFactor

The study

patients given RFA (70% male; mean age 67 years), 61 weretreated using a 50 W generator and 126 were treated usinga 150 W or a 200 W generator. After one or two sessions ofRFA, complete tumour regression was observed in 169 of187 patients (90%) and 222 of 240 tumours (92%) at1 month. Respective survival rates in the intention-to-treatpopulation and in the RFA-treated patients were 97% and97% at 1 year, 67% and 71% at 3 years and 41% and 48% at5 years, respectively. Survival did not differ significantlybetween the two groups (P=0.5094). Among patients treat-ed with RFA, survival was significantly greater in those withChild-Turcotte-Pugh class A cirrhosis than in those withChild-Turcotte-Pugh class B cirrhosis (P=0.0006), and inthose with one tumour compared with those with severaltumours (P=0.0133). Local tumour progression occurred in4% of RFA-treated tumours at 1 year, 10% at 3 years and10% at 5 years; metastasis was seen in 14%, 49% and 81%,respectively. Serious adverse events (including one case oftumour dissemination via the needle track) occurred inthree patients, and minor complications were reported innine patients.Conclusion. First-line anticancer treatment with percuta-neous image-guided RFA is effective in patients with cir-rhosis and early-stage HCC for whom surgical resection isnot indicated.Acknowledgement. This synopsis was written by Jean-Francois Geschwind, associate professor and director ofvascular and interventional radiology, Johns HopkinsHospital, Baltimore, MD, USA.

Background. Patients with cirrhosis are at high risk of devel-oping hepatocellular carcinoma (HCC). Radiofrequencyablation (RFA) is a promising treatment for early-stage HCC,but there are few data on its long-term efficacy.Objective. To assess long-term survival rates in patientswith early-stage HCC and underlying cirrhosis treated withpercutaneous image-guided RFA as a first-line therapy.Design & intervention. This prospective, single-arm trialrecruited consecutive patients with Child-Turcotte-Pughclass A or B cirrhosis and early-stage HCC between June1996 and January 2003. Patients who were suitable for livertransplantation or tumour resection were excluded.Percutaneous sonography-guided RFA was performed usinga 460 kHz generator of 50 W, 150 W or 200 W. Target intra-tumoural temperatures were 95ºC for the 50 W generator,and 105ºC for the 150 W and 200 W generators. Needletracks were ablated after all procedures. Patients with CTevidence of incomplete tumour ablation 1 month aftertreatment received a further dose. Patients who failed toimprove after two sessions or who developed metastaseswere offered segmental transcatheter arterial chemo-embolisation. Patients were followed up and tumourrecurrence was monitored by 3-monthly ultrasonographyand 6-monthly spiral CT, for a mean follow-up period of 24months (range 3–78 months).Outcome measures. The primary outcome measure wasoverall survival.Results. Of 206 patients (69% male; mean age 67 years)who entered the study, 187 (91%) underwent RFA. Of the

R. Lencioni et al. (2005) Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results ofpercutaneous image-guided radiofrequency ablation. Radiology 234:961–967

ImpactFactor


High-dose chemotherapy fol-lowed by autologous stem-cell transplantation (ASCT)

has been the standard care for patientswith relapsed Hodgkin’s lymphoma formany years, achieving better resultsthan MINI-BEAM (low-dosecarmustine, etoposide, cytarabine, andmelphalan) and DEXA-BEAM(dexamethasone, carmustine,etoposide, cytarabine and melphalan)in randomised studies. However, manyquestions remain regarding the con-duct of such a programme for relapsedand refractory disease, including thebest selection of patients, optimalchoice and sequencing of drugs priorto high-dose treatment, and value ofallogeneic stem-cell sources.

In a large multicentre study by theGerman Hodgkin Lymphoma StudyGroup, reported by Josting et al. (seeopposite), patients with primary refrac-tory and relapsed Hodgkin’s lymphomareceived two cycles of DHAP (dexam-ethasone, high-dose cytarabine andcisplatin), and responders underwentsequential high-dose chemotherapyfollowed by standard and high-doseBEAM chemotherapy (carmustine,etoposide, cytarabine and melphalan)and ASCT.

Most patients were in first relapse

following primary therapy, and allpatients were considered in the finalanalysis. Overall results of this trialwere good: at 30 months, freedomfrom second treatment failure (FF2F)and overall survival rates were 59%and 78%, respectively. Results forFF2F were strongly affected by stageat relapse, type of remission at entryinto study, and sensitivity to DHAP.

For overall survival, response toDHAP, type of remission, and pres-ence of anaemia were strong determi-nants of outcome. The investigatorshave planned a large multicentre ran-domised study in which all patientswith relapsed Hodgkin’s lymphomawill receive two cycles of DHAP fol-lowed by either BEAM and ASCT orsequential high-dose therapy andBEAM with ASCT for patients with acomplete response or partial responseafter DHAP.

The Goldie–Coleman hypothesis,according to which non-cross-resist-ant drugs should be used at lowerdoses in combination for initial treat-ment of chemo-sensitive lymphomas,has been challenged by this study.The results lend support, instead, tothe Norton–Simon hypothesis, whichsuggests that maximum doses ofsequential agents should be delivered

to overcome potential resistance inpatients with relapsed disease.

In general, investigators haveused two methods to select patientswith Hodgkin’s lymphoma for ASCT.In one method, patients are inducedinto remission and then undergopheresis with a regimen differentfrom that used for induction; in theother, the same regimen is used forinduction and pheresis [1,2]. Jostinget al. used the former model, but witha twist: patients undergo the sametype of sequential high-dose therapyfor cytoreduction as employed byGianni et al. in relapsed aggressivelymphomas and Hodgkin’s lymphoma[3,4], with the added benefit ofimproving the quality of stem-cellproducts obtained.

In those reports, results were veryfavourable, although critics could notconclude that there was any benefit ofsuch an approach in these single-armed trials. Nonetheless, Josting etal. have confirmed the feasibility ofsuch a programme in a multicentrestudy, and have reported results inways that strengthen support for thisapproach. Others have also demon-strated that this approach is feasiblein therapy of follicular lymphomasand relapsed Hodgkin’s lymphoma, in

➜ Fredrick Hagemeister*

Relapsed Hodgkin’s lymphoma: new twist to the standard regimen

Results of a multicentre study show that a sequential high-dose chemotherapy variant of

the standard treatment is safe and effective in relapsed Hodgkin’s patients.


ImpactFactor

favourable relapse but also for thosewith unfavourable disease. Are regi-mens employing etoposide, gem-citabine, or other drugs better thanDHAP at inducing remission? Areallogeneic stem cells useful? Willantibodies play a role in treatment?Investigators may have to utilise morenovel approaches to significantly

single-armed multicentre studies[5,6]. A randomised study will be nec-essary to demonstrate that the FF2Fachieved by Josting et al. using thisapproach is better than resultsachieved with standard methods.

Finally, questions remain overwhether one could improve on theseresults, not only for patients with

improve results for patients withrecurrent Hodgkin’s lymphoma.Details of the references cited in this article can beaccessed at www.cancerworld.org/cancerworld* Fredrick Hagemeister is a Professor of Medicine andInternist in the Department of Lymphoma andMyeloma at the University of Texas, MD AndersonCancer Center in Houston, Texas, USA

First published in Nature Clinical Practice: Oncology2005, vol 2 no.7. © 2005 Nature Publishing Group

The study

response (PR) or complete response (CR) then received anHDSCT regimen comprising 4000 mg/m2 cyclophosphamide– after which peripheral-blood stem cells were harvested bypheresis – followed by high-dose methotrexate (8000 mg/m2),vincristine (1.4 mg/m2), high-dose etoposide and myeloabla-tive treatment with BEAM (carmustine, etoposide, cytara-bine and melphalan). Patients then underwent ASCT.Follow-up assessments took place 100 days after ASCT, every3 months for the first year, then every 6 months. This wasreduced to once a year after 5 years.Outcome measures. The primary endpoints were free-dom from second failure (FF2F) and overall survival.Toxicity of DHAP and HDSCT were also assessed.Results. Of the 102 patients enrolled in the study, 88%showed some degree of response (PR 67%, CR 21%) aftertwo cycles of DHAP, and went on to receive HDSCT. Aftera median follow-up time of 30 months (range 3–61 months)the overall response rate was 80% (PR 8%, CR 72%),including patients who had failed after DHAP. The FF2Fand overall survival for all patients were 59% and 78%,respectively. Disease progression accounted for 23 deaths(22%), and two patients (2%) died from septic shock duringneutropaenia. Significant prognostic factors for FF2F wererelapse status (P=0.0051), stage at relapse (P=0.0358) andchemosensitivity after DHAP (P<0.0001). Duration of firstremission (P=0.0017) and anaemia at relapse (P=0.019)were significant for overall survival.Conclusion. Salvage therapy with DHAP, followed by theprescribed HDSCT regimen, is safe and effective inpatients with relapsed and refractory Hodgkin’s lymphoma.Acknowledgement.This synopsis was written by AlexandraKing, Nature Clinical Practice.

Background. The current treatment of choice for patientswith relapsed or refractory Hodgkin’s lymphoma is high-dose chemotherapy followed by autologous stem-cell trans-plantation (ASCT). In line with the Norton–Simon hypoth-esis, sequential high-dose chemotherapy (HDSCT) –where non-cross-resistant agents are administered at briefintervals – is suggested by the authors of this study as analternative to conventional high-dose chemotherapy inthese poor-risk patients.Objectives. To determine whether a dose-intensified andtime-intensified HDSCT regimen improves outcome inpatients with relapsed or refractory Hodgkin’s lymphoma.Design. This phase II study enrolled patients agedbetween 18 and 65 years (median age 34) with biopsy-con-firmed, relapsed or progressive Hodgkin’s lymphoma from34 treatment centres in Germany. Among other criteria, eli-gible patients had an Eastern Cooperative Oncology Groupperformance status of ≤2, were free of infection and nega-tive for HIV. All patients had undergone first-line poly-chemotherapy with one of a number of standard regimens,such as COPP/ABVD (cyclophosphamide, vincristine, pro-carbazine and prednisone, alternating with doxorubicin,bleomycin, vinblastine, and dacarbazine) or BEACOPP(bleomycin, etoposide, doxorubicin, cyclophosphamide,vincristine, procarbazine, and prednisone).Intervention. Upon relapse or progression, all patientsunderwent initial cytoreduction with two cycles of DHAP(dexamethasone, high-dose cytarabine and cisplatin), 14 daysapart, accompanied by ondansetron on the first and secondday of each cycle to minimise nausea and vomiting.Granulocyte-colony-stimulating factor was also administeredto aid haematologic recovery. Patients who showed a partial

A. Josting et al. (2005) Cologne high-dose sequential chemotherapy in relapsed and refractory Hodgkin lymphoma:results of a large multicenter study of the German Hodgkin Lymphoma Study Group. Ann Oncol 16: 116–123

ImpactFactor

New tumour biomarkers may help toidentify outcomes for patients with

neuroblastoma, a form of childhood cancer,according to a study published in the NewEngland Journal of Medicine. Neurobla-stoma is one of the most common cancersfound in babies or young children, withtwo-thirds of cases diagnosed in childrenyounger than five years of age.

The disease originates in the adrenalmedulla or other sites where sympatheticnervous system tissue is present. There aredifferent types of neuroblastoma tumours.Some are highly aggressive and requireassertive treatment, others will remainslow-growing and can spontaneouslyregress.

Treatment for neuroblastoma variesgreatly, depending on the stage of the dis-ease and its ferocity. It is important thatdoctors can identify the strain of neuroblas-toma so that patients can be given theappropriate treatment.

Scientists in the latest published studyexamined over 900 different samples ofneuroblastoma, and looked at the abnor-malities of chromosomes 1p and 11q. Theresults suggested that abnormalities inpatients with the disease are associatedwith worse outcomes. Three-year event-freeand overall survival rates were worse forthose with the chromosome abnormalities.In the future, scientists will be able to screen

tumours for the presence of abnormalities,to determine the appropriate form of treat-ment for the cancer patient. In some casesmore aggressive chemotherapy and imme-diate bone marrow transplant may beappropriate to improve chances of survival.■ Chromosome 1p and 11q deletions and out-

come in neuroblastoma. EF Attiyeh, WB

London, YP Mossé, et al. NEJM 24 November

2005, 353:2243-2253


N E W S R O U N DS e l e c t e d p r e s s r e p o r t s c o m p i l e d b y t h e E S O C a n c e r M e d i a C e n t r e

betes. Previous studies have indicated thatmen with diabetes may be more at risk; how-ever, the study proved that the link betweencolorectal cancer and diabetes did not differsignificantly by sex or by cancer sub-site.

The study also revealed that peoplewith diabetes are more likely to die fromcolorectal cancer. Scientists are unsure whatcauses the relationship between diabetesand the increased risk of colorectal cancer. Itseems that the high sugar levels found indiabetics may hold the key; or alternativelyhormonal changes associated with diabetescould promote tumour risk. Further researchis needed to fully understand the link. ■ Diabetes mellitus and risk of colorectal cancer:

a meta-analysis. SC Larsson, N Orsini, A Wolk.

JNCI 16 November 2005, 97:1679-1687

Diabetes is associated with an increasedrisk of colorectal cancer according to a

meta-analysis published in the Journal ofthe National Cancer Institute. Previousstudies have been inconclusive about thelink between the two conditions.

Colorectal cancer is the most commonform of cancer in the European Union, butit is one of the most curable cancers ifcaught early enough. Diabetes currentlyaffects 5% of the world’s population andoccurs when the body cannot break downsugar in the normal way. Obesity is a riskfactor for both conditions and may provideevidence for the link.

Scientists examined 15 published stud-ies including just over 2.5 millionparticipants. The meta-analysis found thatpeople with diabetes were at a higher risk ofcolorectal cancer than those without dia-

Anew study published in the Journal ofClinical Oncology has found that

chemotherapy improved survival forpatients with advanced endometrial cancerwhen compared to radiation therapy.

Women who take tamoxifen for breastcancer are at increased risk of endometrialcancer, as are women taking oestrogen(without progesterone) as a type of birthcontrol or to treat menopausal symptoms.

The US study compared the two typesof treatments currently given to endometrial

Chromosome alterationsin neuroblastomasmay help predict survival➜New England Journal of Medicine

Diabetics have a higher riskof colorectal cancer➜ Journal of the National Cancer

Institute

Chemotherapy improvessurvival for patientswith endometrial cancer ➜ Journal of Clinical Oncology


ImpactFactor

cancer patients – irradiation of the abdomenversus chemotherapy with doxorubicin-cisplatin. Nearly 400 women (average age63) with advanced endometrial cancer (stage3 or 4) took part in the study. Approximatelyhalf of the study population was given radi-ation and the other half chemotherapy. Thepatients were then monitored and followedup for a number of years.

The study found that, at five years,after adjusting the results to take intoaccount the different stages of the disease,50% of the patients receiving chemother-apy were predicted to be alive and diseasefree compared to just 38% of patientsreceiving radiation therapy. Moreover, 55%of women treated with chemotherapy werepredicted to be alive compared to 42% ofpatients treated with radiation therapy.

The results clearly showed thatchemotherapy with doxorubicin-cisplatinsignificantly improved progression-free andoverall survival compared with radiationtherapy. However, scientists did find thatthere was greater acute toxicity seen withchemotherapy, and further advances areneeded in reducing the levels of toxicity. ■ Randomized phase III trial of whole-abdominal

irradiation versus doxorubicin and cisplatin

chemotherapy in advanced endometrial carci-

noma: A Gynecologic Oncology Group Study.

ME Randall, VL Filiaci, H Muss, et al. JCO,

published online 5 December 2005, doi:

10.1200/JCO.2004.00.7617

Researchers at the University ofCalifornia at Los Angeles Jonsson

Cancer Centre have identified key charac-teristics in certain fatal brain tumours thatmake those tumours more likely to respondto a specific class of drugs than tumourswhere the specific molecular signature isabsent.

The discovery of this molecular signa-ture (the expression of a mutant protein anda tumour suppressor protein called PTEN)will allow researchers to identify patientswho are likely to respond to the drug treat-ment, before they embark on therapies thatmight not work.

According to Paul Mischel, an associateprofessor of pathology and laboratory med-icine and a Jonsson Cancer Centerresearcher, the discovery of this treatmentcould change the way doctors treatglioblastoma, which is the most commontype of malignant brain tumour and one ofthe most lethal forms of cancer. “In abiologically aggressive disease likeglioblastoma, it’s vital to be able to stratifypatients up front so we can treat them withdrugs that they are more likely to respondto…this will help prevent patients fromhaving needless therapies that are toxic andnot beneficial. With the short survivaltimes associated with glioblastoma, this iscritical.”

Quality of life is an important factor, aspatient survival is on average less than oneyear. Although treatment may prolong life,most malignant brain tumours are not cur-able, making the search for bettertreatments even more urgent. Epidermalgrowth factor receptor (EGFR) is commonlyover-produced in glioblastoma, making itthe focus for therapies.

Mischel and his team studied a group

Opioids, such as morphine, have been shownto clearly reduce pain and improve quality oflife in adults. However, little is known aboutthe safety and efficacy of this class of anal-gesics in children. Until recently, childrenwere thought to feel pain to a lesser degreeand have a higher risk of addiction thanadults. Newer information indicates thatchildren experience severe pain and have thesame addiction risk as adults.

They are also at greater risk for psycho-logical disturbances that have an immediateand long-term developmental impact.However, children often have difficulty tak-ing opioids; they may not like swallowingpills and get distressed at injections.

Julia Finkel, of the Children’s NationalMedical Center in Washington DC, and inter-national colleagues, examined 173 childrenfrom between the ages of 2 and 16 years,many of whom were cancer patients andhad a history of chronic severe pain and pre-vious oral opioid use.

They were given the fentanyl patch thatequalled the amount of oral analgesics theyhad received, and were followed for 15 days.The researchers found that subjective painand quality of life improved significantly. Byday 16, the average daily pain intensity scorehad decreased. Many patients elected tocontinue in the study for three months.After one month, quality of life scoresimproved. At the end of three months, aver-age play performance scores also showedsignificant improvement.

There were no more adverse experi-ences than reported in adults, and noadverse experiences specific for the paedi-atric population. The authors conclude:“Results from global measurements of paintreatment, safety and quality of life indicatethat transdermal fentanyl is an acceptablealternative to oral opioid therapy in chil-dren.”■ Transdermal fentanyl in the management of

children with chronic severe pain: results from

an international study. JC Finkel, A Finley,

C Greco, et al. Cancer, published online 14

November 2005, doi: 10.1002/cncr.21497

Anew study has found that using a trans-dermal patch to deliver the opioid

fentanyl is an effective way to control pain inchildren. Results from an international studypublished in Cancer indicate that the fentanylpatch is safe for children aged 2–16 years.

Fentanyl patch is a safeand effective alternativeto oral opioids for children ➜ Cancer

Discovery of molecularsignature will help treatpatients with brain cancer➜New England Journal of Medicine


ImpactFactor

of 26 glioblastoma patients who eitherresponded very well or very poorly to EGFR-blocking drugs, and developed a way to testtheir brain tumours for the presence of bothmutant and PTEN proteins. Mischel’s teamfound that patients with both genetic vari-ations were 51 times more likely to respondto EGFR blockers. They also lived five timeslonger after having the therapy than thosewithout the variation, surviving for 253days instead of 50.

Mischel and his team also took 33 tis-sue samples from brain cancer patientstreated at another facility. They were able toreplicate their results, confirming that thosewith both genetic variations were morelikely to respond to EGFR blocking drugs.The study shows that glioblastoma patientscan respond to targeted agents, and sug-gests that patients likely to benefit fromtreatment can be identified by moleculartesting.

The study also raised the possibilitythat patients whose tumours lacked thegenetic variations in the molecular signa-ture could possibly be treated with drugs tomake them more sensitive to EGFR blockers.“Many cancers have a similar combinationof a mutant cancer-causing protein andeither the expression or loss of the PTENprotein…The interactions of the two may beimportant in determining response to tar-geted agents.”

About 10%–20% of patients have thecombination of the mutant and PTENproteins.

Mischel and his team are also workingto uncover the molecular signatures in thetumours of non-responders, so they candetermine which therapies might be mosteffective for those patients.

“Glioblastoma is still a difficult disease,but the idea that it may be possible toinduce long-term disease suppression givesreason for hope.” ■ Molecular determinants of the response of

glioblastomas to EGFR kinase inhibitors. IK

Mellinghoff et al. NEJM 10 November 2005,

353:2012–2024

More patients with stage 3 colon cancerare receiving chemotherapy after sur-

gery, improving their five-year survivalrates, according to a study in the December7 issue of JAMA.

However, women, black patients andthe elderly, are less likely to receive adjuvanttreatment.

The National Institutes of HealthConsensus Conference recommended in1990 that adjuvant chemotherapy (5-fluo-rouracil-based regimen) should be given toall patients with stage 3 colon cancer.Researchers looked at information fromalmost 86,000 patients entered into theNational Cancer Data Base between 1990and 2002 to see whether the Conferences’recommendations had been followed.

The researchers found an increase inthe use of adjuvant chemotherapy for allpatients with stage 3 colon cancers, from39% of patients in 1990 to 64% in 2002.Between 1991 and 1997, the five-year sur-vival rate almost doubled in patients whohad adjuvant chemotherapy compared tothose who had surgery alone.

The study also revealed that the use ofadjuvant chemotherapy was lower infemale and elderly patients. Significantly,3% fewer women than men received adju-vant chemotherapy after surgery, eventhough the treatment is equally beneficialin both.

Elderly patients were also given adju-vant chemotherapy less frequently, despitethe fact that they benefit as much as youngpatients.■ Adjuvant chemotherapy for stage III colon

cancer. Implications of race/ethnicity, age and

differentiation. JM Jessup, A Stewart, FL

Greene, et al. JAMA 7 December 2005,

294:2703-2711

Survival ratesfor colon cancerpatients improve➜ JAMA

Anew study has found that Tamoxifenmay be less effective in treating women

with breast cancer if they have a relativelycommon genetic variation, according toresearch published in the Journal of ClinicalOncology.

Tamoxifen usually reduces the riskof breast cancer recurrence by almost50% in women with oestrogen-receptorpositive breast cancer. However, this studyindicates that women whose CYP2D6 geneis altered have a higher risk of relapse whentreated with tamoxifen for five years com-pared to women who do not have thealtered gene.

The genetic alteration, which occurs inabout one in ten women, affects the level ofCYP2D6, a liver enzyme that is involved inmetabolising the drug. Researchers foundthat normally the enzyme CYP2D6 convertstamoxifen to a metabolite called endoxifen– an anti-oestrogen that is nearly one hun-dred times stronger than tamoxifen itself.However in women with the altered gene,the process does not work as well, and thetamoxifen may be less effective at prevent-ing relapse.

The study looked at 223 tumour andtissue samples from tamoxifen-treatedwomen who took part in the AmericanPhase III North Central Cancer TreatmentGroup adjuvant breast cancer trial.

The results showed that women withthe altered gene tend to have a higher riskof disease relapse and a lower incidence ofhot flashes.

A larger study is needed in order to cor-roborate the findings. ■ Pharmacogenetics of tamoxifen biotransfor-

mation is associated with clinical outcomes of

efficacy and hot flashes. MP Goetz et al. JCO 20

December 2005, 23:9312-9318

Breast cancer treatmentmay be affectedby altered gene ➜ Journal of Clinical Oncology

Focus


We hear an awful lot aboutsome research findings. Butwhat about the research we

never find out about at all? Put itanother way. You may spend severalyears slaving over high-quality, relevantresearch, but fame is never guaranteed.Your study may have been beautiful,statisticians may swoon over your ele-gant way with chi-squares, but if yourresults were indeterminate, or youdidn’t get to disprove your null hypoth-esis, you can probably kiss goodbye to acall from the Today radio news pro-gramme. For we know from detailedinvestigation that “publication bias”shapes what the world hears aboutmost often. Basically, the most widelyread journals, those that make mostmedia impact, carry positive findingsmore often than negative ones. Inother words, if your trial shows that adrug is effective, you will have a betterchance of publishing it in a well-known journal than if your trial hasshown that the drug made little or nodifference. In these circumstances,the chances are that only a small orobscure journal will publish it – if it is

published at all. No Today programme,no headlines; back, my dear, to the lab.This is important because we need‘negative’ studies. In fact, we shouldtreasure them just as much as ‘posi-tive’ ones. If negative studies areignored and not published, we endup with a skew of results sitting –artificially – in a treatment’s favour.We end up with a treatment or drugthought to be better – or less harmful– than it actually is. Yet it is under-stood that about 50% of clinical trialsnever reach publication. Unless wecan be certain that we are in posses-sion of all the research relating to adrug or treatment, we cannot be con-fident in our assessment of it.We can hardly blame the media forover-hyping medical stories whenmedical presses are guilty of much thesame thing. Most medical journals area business – the more popular UKjournals cost between £20 and £360(30–530 euros) for an individual sub-scription. Institutions are charged agreat deal more again, and certainjournals can cost thousands of poundsa year. The big journal names need to

remain in the public eye and need toeffectively ‘sell stories’ in order toremain medical must-reads. This hasto be part of the reason why negativestudies tend not to get the attention ofthe wider media. Then there is theissue of reprints. Small and slenderextracts of favourable research fromjournals are handed out in quantity todoctors at conferences or by pharmareps as a PR exercise. Richard Smith,ex-editor of the British MedicalJournal, this year wrote in Medicine,the online Public Library of Science(Plos) journal, that: “Publishers knowthat pharmaceutical companies willoften purchase thousands of dollars’worth of reprints, and the profit mar-gin on reprints is likely to be 70 percent. Editors, too, know that publish-ing such studies is highly profitableand editors are increasingly responsi-ble for the budgets of their journalsand for producing a profit for the own-ers. An editor may thus face a fright-eningly stark conflict of interest: pub-lish a trial that will bring $100,000 ofprofit, or meet the end-of-year budgetby firing an editor.”

Two sides to every study➜ Margaret McCartney*

If negative studies are not published, the results

become artificially skewed in a treatment’s favour

If research is worth funding at all, isn’t it worth paying a little extra to make the results

– positive or negative – available as freely and speedily as possible?


A GOOD ALTERNATIVEIs there another way? Yes, and themess that is medical research mightactually be beginning to get cleanedup. The non-profit organisation Plos,which mainly publishes online,recently launched another journal,entitled Plos Clinical Trials. Already,there are several Plos titles – Geneticsand Pathogens as well as Medicine –which have attracted a great deal ofattention because of the stark differ-ence between the way they acceptand publish research compared withmost other medical publications.Firstly, the authors or researchers payin the region of $2,000–$2,500(1,700–2,150 euros) to have theirpublications printed in Plos journals.

But this is no vanity publishing.While this fee is waived forresearchers unable to afford it, it islogical that, in the main, the cost ofpublication is simply part of the over-all costing for a piece of research. Ifthe research was important enoughto do in the first place, it is surely justas important to make the results asfreely and rapidly available as possi-ble – no matter what they are.I have started to put references toresearch or papers I mention on theFinancial Times website but, if youclick to the links on ft.com, you willfind that in many cases only theabstract, or summary, of the researchis available free. To gain access to thefull body of research on most jour-

nals, you have to pay. By contrast,Plos aims to make all its publishedresearch – peer-reviewed just like anyother journal – available online for nocharge. As far as publication goes, itis a model of excellence. There canbe no logic in the current situation,whereby you could decide to partici-pate as a patient in a clinical trial,even over several years, spendingtime and effort in undertaking follow-up tests, only to find that not onlymust you pay to access the results butalso that neither the scientific nor themedical communities at large haveimmediate access to the results. Thescientific advances the trial prom-ised, and which you thought you wereaiding, instead end up trickling downto the medical community overmonths and years.Some publishers may feel threatenedby open-access publishing, but organ-isations including the WellcomeTrust have made their support clear.It has said it will include the cost ofopen-access publication in researchfunding. The open-access modelresults in a bigger, faster impact forresearch – better for patients, betterfor funders – whether the resultsmake headline news or not.

*Margaret McCartney is a GP in Glasgow, Scotland.First published in the Financial Times, November 12/132005. ©Financial Times Ltd. Reprinted with permission.

Focus

“Publishers know that pharma companies will often

purchase thousands of dollars’ worth of reprints”

PL

OS

Some of the titles published by the PublicLibrary of Science (Plos).Many funding bodies, including the powerfulWellcome Trust in the UK, support Plosand factor the cost of open-access publicationinto their research grants


Bookcase

➜ Raphaël Brenner

The drownedand the saved

INAugust 2002 Ivan Noble’s lifewas turned upside down.

While working as a science journalistfor BBC News online in London, 35-year-old Noble was diagnosed with amalignant brain tumour. The “strongurge to fight back” against the power-lessness of his condition inspiredNoble to chronicle his struggleagainst the disease in a diary, whichhe courageously decided to sharewith readers of BBC news. Noble’sblog (short for weblog), in which hecombined his knowledge as a sciencejournalist with his personal story,became an instant hit and triggeredthousands of e-mails from readers. Ithas now been published as a booktogether with a selection of the e-mails he received.Noble’s narrative is a straightforwardchronicle of how a rational, atheisticjournalist courageously fought can-cer, while continuing to work andpursue family life with his babydaughter, and of how he finally suc-cumbed. “Dealing with cancerbecame my job,” writes Noble. Thejournalist in him did not preventNoble from expressing his pain – ashe swayed between hope and despair,remission and relapse, life and death. One cannot but feel sympathy when

reading about the clumsy manner inwhich he was told of his illness. “Afew more encouraging words wouldhave made that first week so muchless painful,” writes Noble as he

recalls how his oncologist announcedthe bad news. He suggests thatoncologists spend more time withpatients, explaining to them what is

actually taking place in terms of theillness and what may happen next,and he wishes they would have thecourage to look patients in the eye,rather than looking at their own feet.

He reminds us that “it is easyfor doctors to lose sight of whatit is like to be a patient.” As is evident from the e-mailsreceived by Noble, cancerpatients found his diary inspir-ing and supportive. Noble’s bloghit a chord. It expressed theunvoiced feelings of the silentmass of cancer patients andexposed their need to sharetheir experiences, talk freelyand be comforted by others. All profits from Like a Hole inthe Head go to Médecins SansFrontières.Stéphanie Honoré and CarolynM Kaelin, both mothers of twochildren, were 32 and 42respectively when they werediagnosed with breast cancer.They survived and their booksbelong to the testimonial-cum-guide genre that offers practical

tips and advice to women diagnosedwith cancer. Honoré wrote her book in order toenable women to understand and

Like a Hole in the HeadIvan NobleHodder & Stoughton, 176 pp, £6.99

Cancer du sein. L’annonce, le traitement, la rémissionStéphanie HonoréSeuil, 224 pp, euro 19.00

Living through Breast Cancer. What a Harvard Doctor and Survivorwants you to Know about gettingthe Best Care while Preservingyour Self-imageCarolyn M. Kaelin with Francesca ColtreraMcGraw-Hill, 384 pp, $22.95

Beyond Slash, Burn, and Poison. Transforming Breast Cancer Storiesinto ActionMarcy Jane Knopf-NewmanRutgers University Press, 224 pp, £14.95

In recounting their personal stories, cancer patients are not only sharing their experiences

and feelings – they are providing practical support to others and are gradually influencing

the way cancer is perceived and treated.


Bookcase

express their feelings as cancer vic-tims, as well as to familiarise themwith the coded jargon of the medicalprofession. In concise, easy-to-readchapters, she explains the differentstages of treatment and provides awealth of explanations and usefuladvice on all aspects of the disease,from how to announce the bad newsto one’s family and talk about deathwith one’s children, to the intricaciesof breast cancer imaging and modernforms of treatment, including psy-chological therapies and alternativemedicine.What makes her book noteworthy isits personal touch: Honoré brings aninner dimension to whatever she dis-cusses, whether it is man/woman’ssurvival instinct, the brutalism ofhospitals, the negative way in whichthe medical establishment deals withcancer patients or reconstructive sur-gery. At the end of each chapter, weare given boxes called ‘antidotes’ withadvice on how to survive in the hos-tile environment of hospitals.“Oncologists use many protocols andguidelines,” she writes, “it is nowtime for patients to write guidelinesfor use by doctors.” Like Honoré, Kaelin – one ofAmerica’s top female breast healthspecialists – aims to demythologisebreast cancer by explaining everystep of the disease in plain English.As director of the ComprehensiveBreast Center at Brigham andWomen’s Hospital, Boston,Massachusetts, and surgical oncolo-gist with the Dana Farber CancerInstitute, also in Boston, Kaelin issuperlatively qualified to provide ascientific guide for women undergo-ing breast cancer treatment. Her book, replete with illustrations,offers more in-depth information onbreast cancer, particularly on theside-effects of chemotherapy, sexual-

ity, surgery, reconstructive surgeryand the need to obtain a second opin-ion. She also covers sensitive issuesrelating to women’s body image,which are rarely discussed, such asbreast forms, ways of dealing withloss of hair, eyebrows, pubic hair andteeth, skin care, exercise and nutri-tion. On the negative side, she levelsno criticism whatsoever at her ownprofession, and could have dealtmore thoroughly with the needs ofsurvivors following completion oftreatment – an element also lackingin Honoré.Certain topics will interest only USreaders, nonetheless this highlycomprehensive book makes an impor-tant contribution to breast cancerliterature. The daughter of a breast cancer vic-tim and a professor of English, MarcyJane Knopf-Newman has producedan excellent book (much better writ-ten than the above two) on thehistory of breast cancer, in which shereveals “the deep impact that narra-tives can have on a person’s experi-ence and, in turn the significanteffect literature can have on politicaland public culture.” Knopf-Newman argues that the waybreast cancer is perceived and treat-ed, at least in the US, has beenshaped by the narratives and publicdisclosures of a few key people suchas biologist Rachel Carson’s bookSilent Spring, and her testimony at aSenate hearing in the 1960s on theinfluence of the environment on can-cer. At around the same time, sur-geon George Crile published a bookchallenging the widespread use ofHalsted’s radical mastectomy.In 1974 Betty Ford became one ofthe first major figures to publicly dis-close that she suffered from breastcancer. She was followed by activistRose Kushner, whose watershed

book “led to new relationships andbetter communication between doc-tors and patients.” Kushner’s bookhelped empower women to maketheir own decisions about their bod-ies, and request the specialists andforms of surgery they desired. In hercongressional testimony, Kushneralso noted the economic incentivesthat discouraged surgeons from offer-ing women alternative choices to theHalsted mastectomy.Finally, in the ’80s and ’90s, poetactivist Andre Lorde wrote a bookwhich questioned the dominantmedical practices in breast cancertreatment, galvanised women to takea more active role in their healthcareand helped widen the range of choicesavailable to women – particularlyblack, lesbian and disadvantagedwomen. Lorde’s influence is clearlyfelt in Dr. Susan Love’s Breast Book,the number one bestseller on breastcancer in the US. Although Knopf-Newman’s book iswritten from a US perspective, it hasmuch that is relevant to Europeanpatients. In Europe too, breast can-cer patients have had to fight not onlytheir illness but also the medicalestablishment. To what extentpatient narratives will influence pub-lic policy and medical practiceremains to be determined, but if theUS is anything to go by, patientactivism is a force to be reckonedwith.


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Written by an associate clinicalprofessor of medicine at the

American University of BeirutMedical Center, this is the first bookof its kind in Arabic. Addressing itselfto the lay public, it presents in simpleterms the main medical informationpertaining to the health and diseasesof the breast and provides answers toquestions that can cross the minds ofwomen as well as a list of relevantArab, European and US websites.Saghir’s book offers much usefulinformation, support and guidancefor women with breast cancer, anddiscusses the problems resultingfrom surgery, radiotherapy andchemotherapy. The book also pro-vides instructions for self-examina-tion, with illustrations. Husbands,relatives and friends of cancerpatients will also benefit from it. Thelast chapter deals with breast cancerin men, a subject often ignored andsomething of a taboo in the Arabworld. It is to be hoped that this bookwill help change the way breast can-cer is perceived and dealt with inArab countries.

Cornud’s book depicts theprostate pathologies (including

normal prostate and benign prostatehypertrophy) as they appear in all theimaging techniques currently avail-able: microscopy, ultrasonography,MR imaging, MR lymphography,lymphoscintigraphy, PET-CT, spec-troscopic imaging, etc. It alsodiscusses the indications of thesetechniques for each stage of a malig-nant evolution (for diagnostics andtherapeutics), and analyses the roleof imaging in radiotherapy oflocalised prostate cancers. The bookis lavishly illustrated in four-colourprinting, and each indication isaccompanied by a list of the mostrecent references. For French-speak-ing (radio) oncologists, this is theultimate reference book on medicalimaging of prostate cancer.

The popularity of complementaryand alternative medicine (CAM)

in the western world continues to grow,especially among cancer patients. InEurope, 30% of patients on average useat least one type of CAM, while inGermany and Switzerland the figure isover 50%. Despite the fact that mostphysicians do not approve of CAM as awhole, the practice has become a real-ity. Hence the pragmatism of Ungerand Weis – both professors of oncologyin Freiburg, Germany – and their goalto acquaint physicians and other pro-fessionals involved with cancer withthe fundamental principles of non-conventional therapies.Such knowledge, it is hoped, will helpto ensure professional control over non-conventional methods, protect patientsfrom charlatan practitioners and pre-vent detrimental interactions of plantswith chemotherapy or radiotherapy. The book is thoroughly comprehen-sive: the authors analyse the mostpopular CAM methods, explainingtheir indications, pharmacology andside-effects, and discuss the available

Alif Ba Amrad At-ThadiyeABC of Breast Diseases: fromPrevention to TreatmentNagi SaghirArab Scientific Publishers232 pp, $10.00

Imagerie de la prostateEdited by François CornudSauramps médical292 pp, euro 125.00

Psychotherapie bei somatischenErkrankungenKrankheitsmodelle undTherapiepraxis –störungsspezifischund schulenübergreifendEdited by Hermann FallerThieme, 240 pp, euro 39.95

OnkologieUnkonventionelle und supportiveTherapiestrategienEdited by Clemens Ungerand Joachim WeisWissenschaftliche Verlagsgesellschaft,196 pp, euro 24.00


scientific data, with a wealth of refer-ences. The first part of the book dealswith the various therapies – sport andphysical activity, diets (fruits andvegetables), psycho-oncology, andanti-tumour immune response (IL-2,TNF-α, etc.), while the second part isdevoted to non-conventional drugs.Mistletoe (widely used in Germany),anti-oxidants, melatonin, enzymes,thymic hormones, Boswellic acids(against brain tumours) and aloe veraare some of the main remediesreviewed in the book. The authorsnote that these products cannot berecommended according to the rulesof evidence-based medicine, and theycall for more prospective studies, butthey also note that they are not harm-ful and can often improve a patient’squality of life.German-speaking readers interestedin psycho-oncology will find a goodoverview of this discipline in the text-book edited by Hermann Faller.According to Faller, psychologicaltherapy is highly effective for cancerpatients, as it strengthens their abilityto cope with the illness, gives themhope, and facilitates communicationwith their oncologist. Although can-cer causes great psychological stressand suffering in patients and theirfamilies (including depression, anxi-ety and somatoform symptoms), psy-chological therapies regrettablyremain underused.

specific tumours. However, Berger/Prados is more beautifully produced,in four-colour printing, and benefitsfrom a clearer layout and a richericonography than Schiff/O’Neill. Thecontent is also richer, containing amore detailed discussion of rare dis-eases such as glioblastoma multiformeand Lhermitte-Duclos, and is present-ed in a more coherent manner. This isespecially true of the section devotedto paediatric neuro-oncology.For their part, Schiff/O’Neill provideuseful summaries at the beginning ofthe chapters and include an interest-ing chapter on the neurological com-plications of radiotherapy andchemotherapy. Both books deal atlength with cerebral metastases, asubject under-represented in othertextbooks even though metastases arethe most common form of braintumour in adults. The advances in imaging of the centralnervous system (CT, MRI) have beencrucial to the development of minimal-ly invasive neurosurgery (MIS), whichmeans surgery through small openingsor surgery that is minimally disruptiveto the patient. In part I of MinimallyInvasive Neurosurgery, clinical neuro-surgery and neuroradiology expertsreview cutting-edge techniques andtechnologies. They offer a comprehen-sive survey of neurosurgical endoscop-ic equipment, one of the mainstays ofMIS, as well as of gene-based andviral-based therapies. Part II is devotedto the application of MIS in the differ-ent fields of neurosurgery, includingbrain tumours. This is a fast-movingfield. Where image-guided neuro-surgery dominated the advances of thelast decade, laser hypothermia andfocused ultrasound may radicallychange our ability to treat specifictumours in the future. A highly recom-mended book for clinical neuroscien-tists interested in MIS.

Despite the impressive advances inmolecular biology and brain

imaging, these methods are “still shortof achieving major improvements inpatient care and survival”, acknowl-edges Nicholas Vick in Principles ofNeuro-oncology. This is why braintumours remain “the most dreadfulform of cancer”. The two textbooks byBerger/Prados and Schiff/O’Neill pro-vide an encompassing study of neuro-oncology, catering to all those whowish to understand more about braintumours, from neuro-radiologists tostudents. They successfully decipherthe complex issues behind braintumourigenesis and enhance thereader’s intellectual curiosity. Both books cover first the scientificunderpinnings and principles of diag-nosis and treatment, before addressing

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Textbook of Neuro-oncologyEdited by Mitchel S. Bergerand Michael D. PradosElsevier Saunders, 876 pp, £134.00

Principles of Neuro-oncologyEdited by David Schiffand Brian Patrick O’NeillMcGraw-Hill, 768 pp, £95.00

Minimally invasive NeurosurgeryEdited by Marc R. Proctorand Peter M. BlackHumana Press, 448 pp, £103.00

Documents

Cancer Education & knowledge through people & factsstand the test of time. Some US-based breast cancer advocacy organisations agree with this assessment and have chastised cancer experts