cancer world 36

� Jaap Verweij: an intelligent approach to drugs � He took Herceptin and Sutent frombench to bedside, but Axel Ullrich still wants more � Who needs what? The search forbiomarkers that predict response � Assisted dying: a simple matter of patient choice?

Jaap Verweij

Education & knowledge through people & facts

Number 36, May-June 2010

CancerWorld

36M

AY-JUN

E2010

CANCER WORLD � MAY/JUNE 2010 � 1

Contents

3 EditorialWhen the trial you need is just over the border

4 Cover StoryJaap Verweij: an intelligent approach to drugs

15 e-Grand RoundThe treatment of gastrointestinal stromal tumours (GIST)

24 Cutting EdgeWho’s who in the world of personalised cancer treatments?

34 MasterpieceBlazing a trail in a new type of research

42 Impact FactorTrials and tribulations in primary CNS lymphomaAndrogen deprivation therapy for prostate cancer: true love or heartbreak?Newsround

57 Systems & ServicesShould you respect a dying wish?

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantCorinne Hall

Editorial AdvisorsJacques BernierFatima CardosoFranco CavalliAlberto CostaVincent T. DeVita

Contributing WritersStephen Ansell, Marc BeishonSimon Crompton, Jason EfstathiouSusan Mayor, Vincent RajkumarWilliam Shipley, Matthew SmithAnna Wagstaff, Anthony Zietman

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonChatrina Melcher

Art EditorJason Harris

ProductionHarrisDPIwww.harrisdpi.co.uk

Printed byGrafiche Porpora

Cover photographFrank Van Beek/Capital Photos

Published byEuropean School of Oncology

Direttore responsabileAlberto Costa

Registrazione Tribunale di RomaDecreto n. 436 del 8.11.2004

All enquiries about Cancer Worldshould be made to:ESO Editorial OfficeVia del Bollo 420123 Milan, Italye-mail: [email protected]: +39 02 8546 4522Fax: +39 02 8546 4545All correspondence should be sentto the Editor at [email protected]

Copyright ©2010 European School of Oncology.All rights reserved

Cancer World is published six times per year by the European School of Oncology.It is distributed at major conferences, mailed to subscribers and to Europeanopinion leaders, and is available online at www.cancerworld.org


Editorial

The bureaucratic obstacles thatoften prevent European cancerpatients from joining clinical

trials in other Member States came underthe spotlight recently in the case of a youngwoman with melanoma. Belgian-basedPatricia Garcia-Prieto has stage IVmelanoma which is positive for the BRAFV600mutation.When her disease started toadvance she decided her best chance ofliving longer, with a better quality of life, layin joining a phase III trial with PLX 4032that is running in France. Her oncologistagreed that this would be her best option,and the French investigators deemed hereligible for the trial.The trial does not require hospitalisation

and the only costs that her Belgian insurerswould have to cover would be some follow-up tests (such as PET scans andMRIs).Allshe needed from her insurers was an E-112form – the EU administrative mechanismthat gives citizens access to pre-authorisedcare in anotherMember State. The insurersrefused the request, however, stating that itwas the patient’s own personalmotivation tojoin the trial – not a need to secure health-care abroad. PatriciaGarcia-Prieto launcheda campaign to get that E-112 form, using asmany contacts as possible to get the deci-sion overturned. Her story was covered inthe respected French-language newspaperLe Soir (http://tiny.cc/patriciastory).As a result of concerted pressure, the

insurance company gave her an E-112 formvalid for threemonths. She started the trial

� Kathy Redmond � EDITOR

on 31 March, knowing that she has only a50% chance of receiving the trial drugPLX 4032, but happy that she has doneeverything in her power to give herself thebest chance of living longer – a key consid-eration for any mother of two youngchildren.With European citizens becoming ever

moremobile, issues surrounding their rightsin relation to cross-border healthcare needurgent attention. At the end of last yeartherewere strong hopes an agreement couldbe reached that would have paved the wayfor an EU Directive that would allowpatients like Patricia to join trials in otherMember States.Unfortunately, that agreement is being

held up by concerns covering a broad spec-trum of issues, none of which should beimpossible to resolve. These include pro-tecting the principle of subsidiarity, defini-tional confusion about what constituteshospital care, worries about clinical over-sight and liability, issues surrounding patientconfidentiality and lack of agreement aboutwhat can be reimbursed.Efforts continue to clarify these out-

standing concerns, and the few MemberStates that are stalling the process are underpressure to sign up to revised proposals.The European cancer community can con-tribute to the current debate by highlightingthe problems patients and clinicians face ingetting access to cross-border healthcare,and suggesting workable solutions thatwould be quick and easy to implement.

When the trial you needis just over the border

CoverStory

4 � CANCER WORLD � MAY/JUNE 2010

� Marc Beishon

As head of medical oncology and an early-phase trials expert at one of Europe’s most dynamic

cancer centres, Jaap Verweij has a lot to say about how drug developers are using the wealth of bio-

logical information they nowhave access to. Butwith therapies increasingly aiming to control rather

than cure, he says, an intelligent approach to drugsmust also be about tolerability and affordability.

Medicaloncologists see themselvesatthe forefront of researchand treat-ment not because of any superior-ity, but because of the very natureof cancer. As first-line treatment

has improved greatly, the shift to cancer mortalitybeingmainlydue tometastaticdiseasehas thrown thespotlight on systemic treatments that reach thewholebody, and only drugs can do that.

But with this remit comes great responsibility, asJaapVerweij, headofmedical oncologyat theErasmusUniversityMedical Centre in Rotterdam, is the firstto point out. Not only are medical oncologists dutybound toknowthoroughly thealready-hugearsenal ofcancer drugs in the pharmacy from a clinical stand-point, but increasingly they also need to think aboutthe cost of their treatment decisions.

“And those involved inclinical researchhaveapar-ticular responsibility about whether we are investi-gating the right functionality, and using the right trialdesigns, regulationsandsoon.Further,medical oncol-ogists must not confine themselves to knowledge ofcancer drugs– interactionswithothermedicines and

withcomplementary substances suchasherbal reme-dies can also be crucial to clinical practice.

“My view is that the level of knowledge you nowneed to be a medical oncologist and administer sys-temic therapies isenormous, given that the therapeuticwindowcanbe sonarrowbeforewegoover the edge,and that side-effects can be so difficult tomanage.”

Verweij, who has headed the medical oncologytranslational pharmacology unit atErasmus formorethan 20 years, speaks from long experience in early-phase clinical trials and a deep interest in the phar-macologyofdrugs. “I’mnot formally apharmacologist,but all my research is pharmacology driven,” he says.“You must have this expertise to bring new drugs tothe clinic, using pharmacokinetics and pharmaco-dynamics to understand bothwhat a drug is doing tothe body, andwhat the body is doingwith the drug.”

While only some oncologists are involved in thissharp end of trials, Verweij is concerned that far toomany are not even receiving the level of training inpharmacology thathe feels is necessary forday-to-daywork in theclinic, for instance indealingwith adversedrug interactions as well as the therapeutic window.

Jaap Verweij:an intelligent approach to drugs

CoverStory


FRANKVANBEEK/CAPITALPHOTOS

“I’m also worried that we are not training enoughoncologists in howdo to research at any stage of drugdevelopment, and in particular it is becoming muchharder to attract people into an academic career.”

While the Erasmus has an international reputa-tion for cancer research, Verweij has also spent a lotof timehelping to raise awareness of best practice anddevelopworld-class tools.Notably hewas one of thefounders of theRECIST (ResponseEvaluationCri-teria In Solid Tumours) ‘language’, which sets outcommon ground for oncologists to describe howtumours change, or not, in trials. He is also a spe-cialist in sarcomas, the complex and difficult-to-treat rare cancers that includeGIST (gastrointestinalstromal tumours), and so is an expert now in the useof Glivec (imatinib), which continues to be a keymodel in what to do – and what not to do – in chas-ing the functionality of targeted therapy. (The newtreatment paradigms now emerging for GIST are

explored in this issue’s e-grandround article, p15.)But earlydrug investigation inall its aspects isVer-

weij’s key topic, andoneonwhichhehas spoken andwrittenextensively, in trenchanteditorial commentsondrug development as well as highly technical exami-nations of the challenges for trial design. The phar-maceutical industry and regulators have been in hisfiring line, as indeedhavesomeoncologists,notably fortheuseofGlivec as anadjuvant therapy inGIST. “Myclinical practice is based on hard scientific evidence,but somedoctors seemtobase their practicemoreonbeliefs,” he says.

Unlikemanydoctors, Verweij’s career choicewasnot basedon someearly deepconviction–hehad ‘noclue’what to study after finishing high school. It washis father who forced him to tour university intro-ductorydays, andof all things, itwasamodelof anele-phant’shearthe sawwhen touringonemedical facultythat decidedhim.He studied atUtrecht. “Thenaftertheusual phases ofwonderingwhat to specialise in, Isettled on internal medicine, as it offered the broad-est andmost holistic approach.”

Training inEindhoven,heworkedon theoncologyward. “Ibecamevery frustratedby theattitude that, ‘It’scancer, there’s nothingwe can do.’ I thought thatwasterrible – even if therewas no treatment, we could atleasthelppatients.Mymentors there,WimBreedandHarryHillen,wereof the sameopinionandwere veryimportant in shapingmy future.

“I sat with a woman who had non-Hodgkin’slymphoma– she knewwecouldn’t treat her but I lenthermy ear during a night shift. I could see hermen-tally gaining strengthwhile I listened.Aftermy inter-nal medicine training, I wanted to be a medicaloncologist.”

Verweijwrote toBobPinedoat theFreeUniversityMedicalCentre inAmsterdamandgaineda fellowshipthere.Pinedowas the first professor ofmedical oncol-ogy in theNetherlands, andagreatpioneer and lateralthinker, saysVerweij. “He’s theonewhotrainedmeandmany others in research, and taught me the rele-vanceof themultidisciplinary–andlateral–approachesto treatment. Whenever we said, ‘This is the besttreatmentoption,’he’d say, ‘What’s anotherpossibility?’”

After that experience, therewas little possibility ofVerweij returning to a general hospital as an ordinarymedical oncologist, and he duly secured a post at theErasmus where he could carry out cutting-edgeresearch aswell as do clinical work. “I set up an early

CoverStory


A LANGUAGE FOR RESPONSE

Verweij and colleagues at the EORTC (European Organisation for Research andTreatment of Cancer), the NCI (National Cancer Institute in the US) and in Canadadeveloped RECIST in 2001 as a way for researchers to describe what they wereseeing, particularly in phase II studies.Essentially, RECIST is a way to make the life of researchers easier by applyingvalidated criteria from a large and growing database of adult solid tumours, toassess objectively shrinkage and progression, which are both used as endpointsin trials.The database started with 3000 patients from industry and EORTC trials withvalidated data, so it had been shown to be reliable, and now it’s up to about10,000. “Of course if we could also build a database with PET scans we couldprobably come up with something much more precise, but we do not have vali-dated data yet for this.”Just as previousWHO response criteria were subject tomodification, and in anycase were not validated, the much more robust RECIST has also been revised– Verweij and colleagues issuedRECIST 1.1 in 2008, with changes such as reduc-ing the number of lesions to be assessed (see www.eortc.be/recist), while oth-ers have worked to address some anomalies. An important one is the responseof GIST to Glivec (imatinib), where tumours can appear to progress when in factthey are responding to treatment (see also e-grandround p 15). As anotherresearcher has titled a paper: ‘We should desist using RECIST at least in GIST’.More generally, Verweij believes that shrinkage is not a particularly useful waytomeasure response. “Expertsmay not be so great at assessing tumour shrink-age, but they are really good at assessing the timepoint where a tumour grows.If we used only that endpoint we could make our life even more simple.”

patientswhowere at anend-of-life state andwhohadvolunteered for altruistic reasons.Wepickedone thatwent on tobecomecapecitabine (Xeloda)–an impor-tant drug for colorectal, breast and gastric cancer.”

He adds that many other successful drugs havealso been among those trialled at the Erasmus, suchasDocetaxel (taxotere) andCampto (irinotecan), andindeed Glivec, which in Europe was trialled by hisgroupalongwith teams inLeuven(Belgium), andLon-don. “Buteven thoughwe’vealways tried tokeepacrit-ical eyeonwhatweweredoingandwhateveryoneelseis doing, Imust say thatduringmycareer I’vemadeallthemethodologymistakes you can do in trials.”

Hepoints to crucial shifts inunderstanding, suchas learning thatdrugscouldbe ineffective formetasta-tic diseasebutworkwell for adjuvant therapy, suchas5FU. “Sowe learnt thatmetastatic disease is very dif-ferent fromthesituationafter surgery.And we’ve foundfrommolecular biology that drugs can approach thecancer cell in completely different ways.”

Verweijworkedhiswayup tobecomeprofessor ofexperimental chemotherapy – one of the very few inEuropewith this title. “Most of those who do similarwork are clinical pharmacologists andbasedmostly inthe laboratory. Iwasunusual inbeingclinicallybased.”Now, after stepping up to headmedical oncology, hissuccessorhas the titleofprofessorof experimental sys-temic therapy: “That reflects the fact thatwedon’t justgive chemotherapy anymore.”

Verweij and colleagues had been tracking theemergence of the targeted era since the 1990s. “Webecame aware that targeting signal transductionwascompletely different from targeting DNA and wasgoing tobe important for cancer.But it’s also importantfor what itmeans for clinical practice as we also nowhaveacompletelydifferent viewofwhat is tolerable forpatients, as inhibition of a molecular target requireslong-term therapy andnot the intermittent treatmentwewere used towith chemotherapy.”

As he adds, with chemotherapy, patients mayhave vomiting and nausea for a day but can feel wellfor 20 days until the next treatment. “But sufferingfrommildnauseadaily for21dayswitha targeteddrugis awful.” He also makes a point that may not beappreciated bymany – that theway cancer is turninginto a long-term, chronic condition as a result ofnewer therapies is because thedrugs areby their verynaturemostlynot completely eradicatingcancer cells,and we have largely left the idea of a cancer cure

clinical trials unit and a pharmacology lab. We didphase I trials for chemotherapy drugs, starting in1986, and also for supportive drugs such as anti-emetics – ondansetron started here and became astandard of care for patients on chemotherapy,among others.

“Wealsodid the first phase ‘0’trials, before anyonehad heard the term – that’s where you just test thepharmacology of drugs in a small number of people,and not treatment benefit. We had two oral 5FU‘prodrugs’ to test on their pharmacological basis on

CoverStory



behindafter the successesof anumberof chemother-apydrugs. “Ifwecancurecancerweshouldof course,and theremaybesomecureswithnewagents tocome,but turningcancer into achronicdisease is also agreatachievement.”

For oncologists, he says, healthcare is nowmuchmore of a business than before. “Money is a muchmore important issuewhenyouhave tomakechoicesabout whether to give very expensive drugs thatmayonly have a very limited benefit. And I do see drugsprescribednowwhere Iwonderwhether it is the rightthing to do, given the cost. It means we sometimeshave to thinkmore likebusinesspeople thandoctors.”

But he is not a great fan of the UK’s NICE(National Institute of Health and Clinical Excel-lence) for holding up recommendations for somedrugs. “I believe it is almost unethical to do so, butwe do owe it thanks for driving down drug costs –the price of Tarceva (erlotinib), for example, hascome down by 70%.”

That said,under theNetherlands’health systematpresent only 13% of his department’s budget goes ondrugs. “By far our biggest cost is personnel. But if wedo spend a lot more on drugs, we would have to firepeople.Thathasn’t happenedand itwon’twhile I’m incharge, but the risk is there.”

Risk is also the key word in Verweij’s thinkingabouthowtoaccelerate the introductionofnewdrugsandcut thehugewaste in themanyphase III trials thatprove ineffective. Simply observing that an agentinhibits expression of some receptor or enzyme of acancer cell doesnotmean itwill stop the tumour fromgrowing, and chasing ‘innocent bystanders’ all theway from laboratory to the clinic has been a majorweakness of drug discovery, he says.

“Clearly, ifweunderstand the functionalityof a tar-

get, our success ratewith drugswill behigher.Glivecis the key example, although we did make mistakeswith it.Weare seeingother fascinatingdevelopmentsnow, suchas the ‘hedgehog’inhibitor forbasal cell car-cinomaof the skin, andanALKinhibitorwhereweareseeing fascinating activity in lung cancer. PARPinhibitors for breast cancer also look very promising.

“But the problem is that if you wait for survival ittakes far too long to know whether the drug is trulyeffective, so we could look at using biomarkers – butwhich ones are predictive?We still have to wait untillater trial phases oruntil thepatient dies fromdiseaseto know, and that’s the Catch-22 we’re in right now.We’ve spent a huge amount on biomarkers but onlyreceivedminimal benefit for drugdevelopment.” (Formore on this seeCutting Edge, p 24.)

The aim, he adds, must be for new drugs to bemuchmoreeffective thanmanyarenow. “Twoweeks’extra survival – that’s a not a drug in my terms. Twoyears’ extra survival certainly is.”

In recent talks,Verweij has suggested that certainthresholds of tumour shrinkage in a phase I studycouldpave theway formore speedydrug registration.“If saywe see 60%of patientswith tumour shrinkageinaphase I study, there is littledoubt thatdrugwill getregistered, andwith20%–60%it likelywill aswell, butonce we drop below 20% it becomes much less cer-tain. I don’t have the answer aboutwhat level of activ-ity you need in a phase I trial to be sure a drug willbecomeastandardofcare,butwecertainlycould raisethe current bar.”

Preclinical animal models are clearly inadequateat present, he says. “We can hardly use them now aspredictors of behaviour in human tumours.” Muchgreater use of pharmacology could supply moreanswers, hebelieves, starting at thephase0 stage and

“Chasing ‘innocent bystanders’ from laboratory to the

clinic has been a major weakness of drug discovery”

“We’ve spent a huge amount on biomarkers but only

received minimal benefit for drug development”

CoverStory


going to remainextremelydifficult though tomeasuredirectly the level of a drug in adeeply located tumour,as formost solid tumours. But we are rapidly gainingknowledge andwill have the ability toworkwith spe-cific drug levels to individualise treatment of ourpatients in the future.”

Verweij is especially critical of the role of phar-maceutical companies and regulators inearly-stage tri-als. “Money and time are obviously critical forcompanies, so they often go to doctorswho can offerthe patients but not necessarily the detailed knowl-edge ofwhat they are doing.”Almost all phase I stud-ies are done by industry, he adds, and there is atendency to spread trials aroundseveral sites to try andspeed them up, which can result not only in theinvolvement of less experienced investigators andpossible increased patient risk, as safety informa-tion isnot communicated, but canalso lead to a longeraccrual time– theopposite ofwhatwas intended.Henotes also that quite often clinicians are offered trialson a take-it-or-leave-it basiswithnoopportunity to beinvolved in the trial design and so become ‘perform-ers rather than investigators’.

working forward to establishwhether drugs are actu-ally reaching the targetedcancer cells andwhatdosesaremost effective, even in individual patients.

“Forexample, in theGlivecstudiesweshowedhowthe body coped with the drug – the side-effects andexposure to the tumour and normal tissues – andwealso learnt that patientswith a certainmutation [KITmutation] were less sensitive to the drug, and somight benefit fromahigher dose.Wehadnever seenbefore that specific target characteristicswere impor-tant for selecting the dose of a drug.”

As he notes, the old concept of just ramping upchemotherapy to barely tolerable levels must bereplaced with far smarter approaches for identifyingoptimal, not maximum, doses for targeted therapiesand indeed several approaches arebeing investigated.PETscanningwith a labelleddrug is one, but has theproblem that the ability to label drugs for radiationemission is still at an early stage.

“Oneother techniqueweare researching ismicro-dialysis, where wemeasure the exposure of the drugin tumour tissue–mostly skinmetastases– insteadofblood plasma and extrapolate from that. It’s probably

CoverStory



With later trial phases, RECIST has added much-needed rigour todetermininghowdrugs areworking,he says. But there are still big problemswith thewayresearchers are advancing knowledge and haltingunproductive paths. “We need to be much better atwriting up studies with negative results so we don’tmake the same mistakes,” says Verweij. “This is notabout bad drugs but bad research and bad writing.There isn’t a single trial I’ve done that hasn’t taughtme something.”

One example is learning that shrinkage is not asimportant as progression in driving treatment deci-sions.Another is givingGlivec for theKITexpressionwithoutmutations, which has not proved fruitful, hesays, noting that this has not stopped other investiga-tors trying Glivec on other tumours expressing non-mutated KIT, such as prostate and non-small-celllung cancer, with no success.

“Expression is not the same as functionality,” hecomments, adding, “We’ve done a very good trial onEGFR-expressing synovial carcinomawith anEGFRinhibitor and have not seen any positive effect, butagainwe have learnt we should not chase somethingthat isn’t functional. The trouble is researchers aren’talways goodmessengers.”

Hehas alsonoted thatHerceptin (trastuzumab)iswidelycontinuedbeyondprogession, simplychang-ing the cytotoxic drug added to it, without any ran-domisedevidence that thisworks. “Unfortunately, onetrial that did randomise continuedHerceptinwith achemotherapy drug was stopped prematurely. It isnow unlikely we will ever learn whether such anapproach truly enhances outcomes andwhether it iscost effective.”Andagain, he’s spokenout about theapplicationofHerceptin tocancersother thanbreast,where there is no evidence of HER2/neu being afunctional target.

Another concern for Verweij is bringing drugs forsupportivecare intoclinicalpractice. “This is about reg-ulation and measurable endpoints for drug trials.While it’s easy tounderstandevaluations forbreastcan-cer – say, patients live longer or the disease stops

“Academic research needs to be funded much more

for applications such as interactions between drugs”

CoverStory


“Regulation is also driving up costs. I used to be ableto manage 120 patients with one data manager, butnowIneedsixandamonitor, and then there is anaudi-tor above them and possibly another above that, andthey all need salaries. Protocols used to takemea fewhours to write. Now they can take months.” A rareexception, he notes, to the current industry-drivenagenda is the studies ledbyCancerResearchUK,oneof the largest research charities in the field. He con-siders thepresentcontributionof theEuropeanUnionto cancer as ‘peanuts’.

While drug companies have becomemore inter-ested in rarer cancers following the success ofGlivec,says Verweij, academic research needs to be fundedmuch more for applications such as interactionsbetween drug combinations and with other treat-ments such as radiotherapy. “The companies tend toback off as this is too complex and the registrationpaths too difficult,” he says. From experience withchemotherapy, where in most cases more than onedrugworksbetter,more investigationsofcombinationswith the newagents could be very beneficial, but thecomplexity of investigation can be very high. “A lot ofwhat has been done has been more or less alchemy.Just putting drug A with drug B without detailedpharmacological investigation is not science.”

The strict labeling of drugs for certain treatmentsalso severely restricts researchersheadds, as insurancecompanies won’t pay for other uses. “In the past wewereable touseadrugsuchasdoxorubicin inanycan-cerwe found itworked in.NowIcanonly giveGlivectopatientswithCML[chronicmyeloid leukaemia] orGISTandwith theKITmutationandnot for anyotherpatients, based on scientific evidence.”

As he notes, the group of companies thatmarketErbitux (cetuximab) did take the riskwith investigat-ing it in conjunctionwith radiation for head andneckcancer. “But there are only very few other industry-funded studies onother agents known tobe synergis-ticwith radiationsuchasAvastin [bevacizumab]– theyare mostly academic studies but they are slow andshort of finance.”

be looking at overall survival – that’s the aim of anyadjuvant treatment, not prolonging time to recur-rence, which is all this trial has yet shown. Based onthe published absence of improved survival at fouryears it can be estimated that the cost per life yeargainedmay run intomanymillionsof euros and is sim-ply unaffordable.”

Verweij flies small planes as ahobby– sometimestomeetingswhen theweather’s good– andhas threechildren, one of whom is studying to be a molecularbiologist,whichheconsiders is altogethermorecleverthanbeing a clinician.Hiswife,Monique, runs apri-mary healthcare organisation in Eindhoven.

In the nine years he has until retirement he sayshe’ll behappywith a fewmoredrugs likeGlivec–he’snot expectingmajor breakthroughs – and progress intrial design. “I’d like to seemoreEurope-wide studiesto show theworldwe’ve survived theEuropeanClin-ical Trials Directive,” he adds. “I’d like also for us toshowmorealtruismoutsideourdrive tomakeourownnames, and work together more closely. It will take alot ofmotivation but it can be done.”

growing for longer – how dowemeasure a conditionsuchas fatigue? I talk to a lot of pharmaceutical com-panies and they are coming up with interesting sup-portivedrugs, but they are struggling tobring themtomarketbecauseof the lackofendpoints and regulationto guide them. So instead they focus on the under-lying,majormalignant diseases.”

Along with the dangers of drug interactions (seebox) it all reinforcesVerweij’s alreadystronglyheldviewthat medical oncologists need to be well trained inpharmacology, and if they do not have access to thistraining in acancerdepartmentwhen they start out inthespecialism, it shouldbeofferedelsewhere.But fewcancer centreshave thekindof cancer pharmacologyexpertise of the Erasmus – hementions theNether-landsCancer Institute, theRoyalMarsden inLondon,and centres in Newcastle, UK, and Chicago andPittsburgh in theUS, as of similar standing.

“I want also to seemore oncologists trained to beresearchers, not just in the science but how to man-age regulations.Wehave somany studies thatneed tobe done, but a survey in theUS shows that the num-ber of academic researchers is going down there –salaries of courseare justnot ashighas inprivateprac-tice or industry. But hopefully not toomany of uswillbemotivated bymoney alone.”

Verweij says he tries to keep out of what he calls‘onco-politics’. He is pleased that the major cancersocieties have came together in ECCO (EuropeanCanCerOrganisation), but laments the lack of fund-ing for theEORTC. “Its budget has only been about14million euros a year and theNCI hasmuchmore– but even so we have had three times as manypatients in trials. We have been pretty creative andefficient.” In theNetherlands he chairs the scientificadvisory council of theDutchCancer Society.

BobPinedo, andalso sarcoma ‘godfather’AllanvanOosterom (a former EORTC president), are his keymentors andarenodoubt supportiveof a current con-troversy where Verweij has made a big stand, on theapproval ofGlivecasanadjuvant therapy inGIST. “Weshouldnotbecomparingearlywithdelayed treatment,aswe’dbegivingGlivecon relapseanyway.Weshould

CoverStory


“We should be looking at survival – that’s the aim of any

adjuvant treatment, not prolonging time to recurrence”

BEWARE OF INTERACTIONS

The large number of patients who also take herbal products that are not regu-lated as drugs is seen by Verweij as an alarming trend. “In the Netherlands 40%of patients are taking other pills without telling us. Research we’ve done showsthat some interactionswith cancer drugs can be dangerous.” The commonly takenSt John’sWort, for example, can decrease the activity of drugs, while other sub-stances can increase the toxicity to lethal levels.Prescriptionmedicines can have similar effects – a recent study in theBMJ hasfound, for example, that womenwith breast cancer who take the antidepressantparoxetine at the same time as tamoxifen are at an increased risk of death owingto a suppression of the cancer drug. This type of interaction can be overlookedby doctors who have had little or no training in drug treatment.“Most doctors, however, are not routinely asking about the complementary prod-ucts people are taking, and we have published several papers that show whateffects they can have,” says Verweij. Patients, he adds, are accessing a hugeamount of information on the Internet – much of it wrong – and tend to regardherbal products as natural and harmless.

e-GrandRound


The treatment of gastrointestinalstromal tumours (GIST)

A better understanding of the different mutations that drive GIST is leading to new

paradigms of tailored treatment that break many of the traditional norms of chemotherapy,

particularly with respect to management of progression.

Gastrointestinal stromal tumours(GIST) are rare tumours, withan incidence of 10 new cases

per million population per year, giving4000–5000 new cases in the EuropeanUnioneachyear.GISTwas thought tobeextremely rare, but the discovery of thespecific molecular alteration that wasdriving these tumours in the late 1990srevealed itwas slightly less rare thanhadbeen thought. This work showed that amutation in the KIT gene drives thetumour. Themolecular characterisationof GIST is at the centre of this review.GIST can be detected in all organs

of the digestive tract: the stomach, thesmall bowel, the rectum, the oesopha-gus and, in some rare cases, themesen-tery. Mutation can occur in differentparts of the KIT gene, and this canaffect where the tumour develops. KITexon 9 mutations occur most often inthe small bowel lesions. Mutations inthe PDGF receptor-alpha (PDGFRα)gene occurmost often in gastric lesions.This interesting parallel between themolecular anatomy of this tumour andthe location ofGIST needs to be kept inmind, because it will drive the treat-ment of patients in the future.

The European School of Oncology presentsweekly e-grandrounds which offer partici-pants the opportunity to discuss a range ofcutting-edge issues, from controversialareas and the latest scientific develop-ments to challenging clinical cases, withleading European experts in the field. Oneof these will be selected for publication ineach issue of Cancer World.In this issue, Jean-Yves Blay, of the CentreLéon Bérard, Lyon, France, who is director ofthe Conticanet network of excellence andpresident of the EORTC, provides an updateon the latest evidence for the treatment ofGIST. Daniel Helbling, of the OnkozentrumZurich, Switzerland, poses questions thatexplore the issues further. The presentationis summarised by Susan Mayor.

The recorded version of this and other e-grandrounds is available atwww.e-eso.net/home.do

The majority of GIST lesionshave mutations in KIT, withmost occurring in the jux-tamembrane region of thekinase (just inside the cellmembrane). These mutationshave functional consequences,including a constitutional acti-vation of the kinase, which canbe blocked by tyrosine kinaseinhibitors (TKIs).More recently, it was dis-

covered that another gene –PDGFRα – can be mutated inthis tumour. This occurs lessfrequently than KITmutations– approximately 5% in themetastatic setting but proba-bly 20% in localised tumours.The two mutations are mutu-ally exclusive, with a GISTtumour having only one mutation tostart with. However, additional muta-tions occur in the case of resistance.

THE IMPACT OFIMATINIB ON SURVIVALThe introduction of imatinib (Glivec)for the treatment of metastaticGIST substantially increasedoverall survival, showing themost dramatic impact of anovel treatment on the out-come of patients with solidtumours in the last 20 years.Imatinib significantly improvedsurvival compared to the previ-ous treatment, doxorubicin.The large increase in overallsurvival led to the approval ofimatinib for GIST without theusual requirement for a ran-domised controlled trial.Results from the Conti-

canet network’s series of GISTpatients show the overallmedian survival in GISTpatients treated with imatinib isaround five years, while the

median progression-free survival isapproximately 24 months. This is ofinterest because it is the longest serieswe have to date on the treatment ofGIST, and includes patients frombefore the imatinib era. It shows thatimatinib is able to improve not only


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progression-free survival butalso overall survival evenbeyond the time of progression.This is very important for thetreatment strategy for GIST.

Question: The curve is not flatat the end, so does this meanthat there is no cure in GISTwith Glivec?Answer:We do not have a finalanswer to this question. We donot knowwhether there will be aplateau at the end.We know thatsome patients have not progressedafter 10 years of treatment, sothat is reassuring, but this pro-portion of patients is relativelysmall, at less than 25%.However,this takes into consideration dif-ferent GISTs with different

mutations, and survival is probably dif-ferent between mutations.The development of a new treatment

that is extremely effective in improvingoutcomes for these patients has led to anumber of evolving paradigms.

EVOLVING PARADIGM 1Double the imatinib dosefor a patient progressing onthe standard doseThe best treatment for a patientwith metastatic GIST who isprogressing on 400 mg/day ofimatinib is probably to doublethe dose. This is, to my knowl-edge, the only example inoncology of a treatment wherethe dose is increased in the caseof progression. This approachwas tested in the EORTC62005–S0033 trial, whichcompared 400 mg/day with800mg/day in advanced GIST,with patients on the lower dosebeing given the opportunity tocross over to 800 mg/day onsigns of tumour progression.

MUTATIONS VARY BY SITE

Understanding which gene mutation drives the GIST in a givenpatient will determine treatment choice in the future

Source: C Corless, Presentation at the GOLS meeting 2008

IMATINIB GREATLY IMPROVED SURVIVAL IN GIST

Results from the Conticanet series of GIST patients demonstratedthe huge survival benefit conferred by the new therapy

Source: Adapted from J Verweij et al. The Lancet 2004, 364:1127–1134

is particularly sensitive to imatinib(100% for the fourth quartile,P=0.009).

Question: This is the only situationwhere a dose increase is recommended inoncology. Is that because the tolerance ofthe drug is good?Answer: Tolerance to dose escalation ofimatinib is good compared to usual cyto-toxic agents, but it is not always very easy.Even though you have fewer side-effectsby escalating the dose rather than start-ing with 800mg/day, some patients havedifficulty maintaining the 800 mg/daydose.Question: How long do patients bene-fit from the dose increase?Answer: The median progression-freesurvival after dose escalation is proba-bly in the range of 3–4 months, andonly 20% of the patients have not pro-gressed at one year. However, we stillhave some patients on an escalateddose who are doing well after severalyears. This is very rare compared toother treatments. Some patients have

The results showed that about one-thirdof patients achieve tumour control sim-ply by doubling the dose of imatinib.Approximately 20% of the patients willnot progress in the years following adose escalation.Why is that?Investigation of the pharmacoki-

netics of the drugmeasured the troughlevel of imatinib after one month oftreatment and showed that patients inthe lower quartile of exposure had alower response rate and a higher risk ofprogression than those in the upperthree quartiles (GD Demetri et al.2008,ASCOGastrointestinal CancersSymposium, abstract 3). This sug-gested that exposure to the agent iscorrelated to the outcome. This haspreviously been observed in the treat-ment of chronic myeloid leukaemia,which is the other disease targeted byimatinib. There was a trend to higherrates of clinical benefit with higherimatinib exposure (67% in the firstquartile vs 84% in the fourth quartile),with greater clinical benefit for patientswith the KIT exon 11mutation, which

shown sustained tumour control on800 mg/day for more than two yearsafter progression on 400 mg/day. Thisshows that exposure of the tumour tothe agent is critical in understandingwhy these patients are responding.

EVOLVING PARADIGM 2Never stop systemic treatment inthe advanced phaseHow long should we continue to treatwith imatinib? This is an importantquestion, and one that patients oftenask after three to four years of treat-ment. To address this question, theFrench Sarcoma Group BFR14 trialrandomised GIST patients to imatinibthat was either stopped after one yearand then restarted on progression ortreatment was continued until pro-gression. Results showed the medianprogression-free survival for patientsstopping treatment at one year was sixmonths, which was very significantlyinferior to that in patients continuingtreatment. The good news is thatall patients, apart from one who died

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ONE YEAR IS NOT ENOUGH

The BFR14 trial showed much shorter progression-free survival in patients randomised to stop imatinib therapy after one yearSource: Based on JY Blay, A Le Cesne et al. JCO 2007, 25:1107–1113

from an unrelated side-effect,responded to restarting imatinib.This showed that treatment forone year does not kill all tumourcells, because all patients whostopped imatinib relapsed,although this occurred afterthree years in one patient.The same trial went on to

randomise patients to stop orcontinue at three years, with thesame result. The median pro-gression-free survival is sixmonths, which was significantlyinferior to the continuation arm.Again, all patients respondedto restarting imatinib, whichis reassuring.What is more worrying is

that the median progression-free survival is exactly the same ingroups stopping after one year as afterthree years, showing that during thefirst three years the treatment is simplydelaying progression. It is stopping theproliferation of cells, and not killing thelast cancer cell. Therefore, we shouldprobably treat with imatinib for morethan three years. We are just complet-ing a five-year randomised trial, withresults being presented this year.

EVOLVING PARADIGM 3Response does not equal reductionin tumour volumeThe idea that response cannot beequated with a reduction in tumourvolume is a very important change inthe way we are used to seeingresponses to cancer treatment.We areused to thinking that to have a responsewe need the patient’s tumour to shrink,and that the tumour increases in vol-ume when progression occurs. This isprobably not true for the treatment ofGIST with imatinib, and is probablynot true for other targeted agents inother cancers. Response does not nec-essarily mean reduction in tumour vol-

ume, and progression does not neces-sarily mean a volume increase.False progression can be seen in

GIST patients treated with imatinib.The figure above shows CT scans for apatient treated in the early days of ima-tinib.After threemonths, there appearsto be new lesions. However, these arehypointense lesions caused by thetreatment, typical of a false progres-sion. Conversely, you can also have afalse response. Even though the patienthas a response according to RECISTcriteria, the disease is continuing toprogress.We should be aware of this, aswe should probably be ready to changeour practice in years to come.We should assume that aCT scan is

the gold standard. It is also important tolisten to the patient. If a patient has apartial response but is feeling unwell,we have to suspect that a partial or lim-ited progressionmay possibly be occur-ring. On the other hand, if despite anincrease in tumour volume on a scanthey say they are feeling well and havenomore pain, this could be a false pro-gression. In such a case, it is importantto weigh up the level of suspicion.

Question: If you have a patientwho is doing clinically betterbut you see on the CT scan thatthe lesion is increasing, do youcontinue with the same treat-ment or are you suspicious?Answer: It depends on the levelof the suspicion. One of theaspects that is very important totake into account is the densityof the tumour measured inHounsfield units. Most of theresponding lesions have decreas-ing Hounsfield units. An indexbased on the so-called ‘Choi cri-teria’ enables you to distinguishresponding from non-respond-ing tumours. This needs to bereproduced, but it is quite con-vincing, and it is quite well

accepted that hypointense lesions areresponding lesions.

Concerning treatment, yes, we couldcontinue. If I had doubts, I would prob-ably explore with a PET scan. If I haveno doubts, I would simply see the patientagain within six weeks with a new CTscan and clinical evaluation, instead ofthe usual three-month follow-up.Question: So you do not do PET scansstraightaway, you reserve them for inves-tigating areas of uncertainty?Answer:Correct. There is another indi-cation for PET scan in the ESMOguide-line, which is when you start newadjuvant treatment in large tumoursbefore resection, and you want to makesure the tumour is responding rapidlyand is not a primary resistant tumour,which is rare – only 5%.

EVOLVING PARADIGM 4Understanding the molecularbiology of tumour resistance isimportant for routine treatmentof the patientThemolecular biology of resistance is avery important issue. There are differ-ent subtypes ofmutation, with different


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FALSE PROGRESSION ON CT SCAN

The new hypodense lesions visible on the right-hand scans do notrepresent tumour progression, but are caused by the treatment

Source: Courtesy of JY Blay, Centre Léon Bérard, Lyon

Check exposureThe pharmacokinetic levels of ima-tinib are important, as mentioned pre-viously.

Consider surgerySurgical treatment is very interesting,but still experimental.A small study byCP Raut and co-workers found thatpatients operated on while they hadlimited progression showed a longertime to secondary progression thanthose who had surgery at general pro-gression, and those operated on withstable disease showed even better out-comes (JCO 2006, 24:2325–2331)This is of interest, but it is not yetproven to be superior to treatment withsunitinib.We have started a trial randomising

patients with metastatic GISTresponding to imatinib either to ima-tinib plus resection of their lesion at thetime of best response (within one year)or to continue with imatinib, with sur-gery delayed until the time of progres-sion. This is an extremely importantstudy, but very difficult.

Switch to another TKISunitinib has a broader spectrum ofactivity in terms of kinase inhibitionthan imatinib, so we expected that itcould have an additional effect. Thisadditional effect was demonstrated in atrial comparing sunitinib with placeboin imatinib-resistant patients, showingan improvement in progression-freesurvival. Both blinded and open phasesshowed improved time to progressionwith sunitinib (P Casali et al. ASCO2006, abstract 9513; IR Judson et alESMO 2006, abstract 506). Somewould argue that placebo was not theappropriate control arm, but the trial isvery important because it demonstratesthe activity of sunitinib.Progression-free survival with suni-

tinib differs in patients with exon 9

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of patients, and testing for mutationtype is not available everywhere. Test-ing requires complex technology andgood reproducibility, but this is theway to go forward, certainly for exon 9.

Question: Do we need to test only forexon 9, or for the othermutations as well?Answer: We certainly have to test forexon 9. We suspect that different muta-tions in PDGFRα or exon 11may also beassociated with different prognoses andwe are expecting data on this at ASCOthis year. If this is the case, then weshould have a more exhaustive evalua-tion of the nature of the mutation thanjust a single evaluation of exon 9.

WHAT STRATEGY SHOULD BEADOPTED AT PROGRESSION?There are several things we should doif a patient progresses.

Check adherence with therapyThe first thing to check iswhether a pro-gression is related to non-adherence toimatinib. A study on the number of

packs of imatinib boughtby patients in the USshowed that this wasonly 75% of the amountprescribed, which indi-cates that the adherenceis, at best, three-quar-ters. This is not veryhigh, and we know thatthe exposure to imatinibcorrelates to the out-come. It is not simple totake a pill every day forthe rest of your life. Weneed to try to improvepatient adherence, andwe have to listen to theexperience from otherfields, such as HIV,where adherence tolong-term treatment hasbeen studied extensively.

sites of mutation of KIT: exon 9 andexon 11. A meta-analysis of the twolarge trials mentioned – the US S0033and the EORTC 62005 trials (1640patients) – showed significantly differ-ent progression-free survival treatingexon 9 patients with 400 mg/day (seebelow, blue line), compared to800 mg/day (green line). This does notoccur in exon 11 patients (red and yel-low lines). Information onwhichmuta-tion a patient has is important becausewe need to double the imatinib dose ina patient with an exon 9mutation. Thisstrategy is recommended by the ESMOand the NCCN guidelines in the US.The difference in progression free

survival does not translate into overallsurvival, although the number ofpatients in each group was quite lim-ited. However, 800mg/day is the stan-dard dose for exon 9 patients, and thismeans that we need information onthe patient’s mutation when treating inthe metastatic setting. This is not easybecause information on the type ofmutation is available in less than 50%

THE MUTATION DICTATES THE RESPONSE

Doubling the dose for imatinib-resistant tumours is effective, butonly for tumours with the exon 9 mutation

Source: Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST).Presented at ASCO 2007

next step? There areseveral other TKIs, inaddition to other strate-gies. Nilotinib (Tasigna)is a TKI that blocks theBCR-ABL. It has beentested in a phase I/IItrial in patients withresistant GIST. Theoutcome of patientstreated with a combina-tion of imatinib andnilotinib, or with nilo-tinib as a single agentfor intolerant patients,was not bad in terms oftumour control, as eval-uated by completeresponse (CR) + partialresponse (PR) + stable

disease rate. Progression-free survivalwas comparable with that of patientstreated with second-line sunitinib.Is nilotinib really useful? This is

being explored in a pragmatic trial to bepresented at ASCO 2010, comparingnilotinib versus ‘doctor’s choice’: eitherbest supportive care alone, imatinib orsunitinib. This was a very interestingtrial, but it was complex becausemain-taining TKI pressure using a kinaseinhibitor that has been failing in thepast cannot be described simply in theprotocol – it is the investigator’s judge-ment. Results during 2010 will showwhether nilotinib is an active agent.

Question: Do some patients respondafter imatinib and sunitinib to beinggiven imatinib again?Answer: Yes, this happens in third,fourth, fifth and sixth line.When we sayresponse, we do not always mean tumourshrinkage, but it may be prolongedtumour control and clinical benefit forthe patient and no progression accordingto RECIST.A fourth agent, sorafenib (Nexavar),

was tested in a phase II and compas-

sionate use programme for patientswhohad failed on imatinib and sunitinib. Itshowed a similar control rate of approx-imately two-thirds of the patients, witha median progression-free survival offour to fivemonths. This kinase inhibitorhas a profile similar to sunitinib, but hassome activity in the third- or fourth-line setting in imatinib- and sunitinib-resistant GIST (HS Nimeiri et al.,ASCO Gastrointestinal Cancers Sym-posium 2008, abstract 7). Unfortu-nately, there will be no prospective trialaddressing this question from the phar-maceutical company, but wemay be ina position to try to explore this in the aca-demic setting.The fifth drug being explored is the

heat shock protein 90 (HSB90)inhibitor IPI 504. A phase I studyshowed some level of tumour control ina substantial proportion of patientswith GIST. On the basis of this, theHSB90 inhibitor was tested in a phaseIII trial, but unfortunately this wasstopped because of toxicity in the treat-ment arm. This is definitely a strategythat needs to be further explored.Another pathway that is critical for

the development of resistance ismTOR inhibition. A trial is exploringthe combination of imatinib, sunitiniband sorafenib with RAD 001 –everolimus – which shows long-termtumour control in some patients.About20% of patients greatly benefit from thetreatment at six months. These datawere presented at ASCO 2008, buthave not yet been published. The com-bination is not standard yet, but shouldbe further explored.The figure opposite shows one of

my patients with a huge liver metasta-sis who progressed after treatment with800mg/day imatinib. He was includedin the RAD 001 trial and is still alivemore than three years after resection.This patient would not have been oper-ated on without this treatment.


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mutations compared to other muta-tions. In relapse, patients with exon 9and wild type seem to have a betteroutcome, so this is the opposite towhat is seen with imatinib. The findingdoes notmean that sunitinib is inactiveon exon 11, but rather that we havepossibly selected a resistant clone withadditional mutations.At the time of progression, we have

observed the emergence of resistantclones which are associated with addi-tional mutations of the kinase. Thismutation codes for a protein that isresistant to imatinib and/or to suni-tinib. These additional mutations arelocated on exon 13, 14, 17 and 18 ofthe same kinase. There is a high level ofheterogeneity in these tumours – withmutation of exon 13 and 14 in oneregion, and mutation of 17 in anotherplace. This is a level of complexity thathas not been addressed previously andwhich we do not yet know how to han-dle, but it needs to be characterisedbecause outcomes differ according tothe nature of the secondary mutation.Unfortunately, a lot of patients

progress on sunitinib, so what is the

MOLECULAR HETEROGENEITY AT PROGRESSION

Though GIST starts with only one mutation, multiple mutations candevelop within a single tumour after treatment with imatinib and/orsunitinib, which we must learn how best to manage

Source: CT scan: courtesy of JY Blay, Centre Léon Bérard, Lyon

EVOLVING PARADIGM 5Continuing TKI therapy in caseof progression under TKIHow to respond to progression of atumour being treated with a TKI isstill a changing paradigm. There is noother situation where we would main-tain a treatment demonstrated to beinactive. However, in this case, therationale for doing just this is thatsurvival after progression on imatinibis much longer than expected fromprevious experience with GIST(median overall survival: 58 monthsversus 26 months). The second issueis focal resistance, where the majorityof cell clones remain sensitive, so it isnot logical to stop a treatment that isstill active in a large proportion ofclones. Maintenance of KIT blockadeis probably very logical, based onthese two observations.What about treatment in the adju-

vant setting? This question wasaddressed in the phase II trialACOSOG Z9000. Imatinib treatmentafter surgery showed overall survivalof 99% at one year and 97% at three

years. TheACOSOG phase III Z9001trial demonstrated that exposure toone year of treatment with adjuvantimatinib substantially reduced therisk of progression during and afterthis time period. The magnitude ofrisk reduction is in the range of two-thirds in all populations of patients.Even though patients have

delayed relapse, the majority willrelapse after the end of the treat-ment. There is a high degree of sus-picion that one year of treatment maynot be enough. This needs to be fur-ther explored, but the basic messageis that we do not yet know for howlong we should treat. The Scandina-vian trial, SSG/AIO, randomisedpatients to one year versus three yearsof treatment in the adjuvant setting,while an EORTC trial (62024) isstudying two years of treatment.Results will be available in 2011.The questions on adjuvant treat-

ment that remain include:� Whom should we treat?� What risk level?� What duration?

� What mutational type?� What is the impact on secondaryresistance?

� What will be the impact on overallsurvival?

CONCLUSIONSSurgery and adjuvant imatinib canbe considered standard treatment inlocalised GIST, but a lot of questionsremain about adjuvant treatment.First-line imatinib is the only stan-dard, at a 400 mg/day dose for non-exon 9, and at 800 mg/day for exon 9patients. We should continue treat-ment until progression or intolerance,because patients will experience arecurrence if treatment is stopped.Molecular biology is becomingincreasingly important for prognos-tic and treatment selection.The evaluation of response to

imatinib is not simple, and can bedetermined using the RECIST cri-teria, WHO criteria, and Choi crite-ria. However, we know there are falseprogressions and false responses andthat we should integrate not only

reduction in volume butalso density and prolongedstabilisation as useful cri-teria. Surgery is not ofproven benefit in themetastatic phase; it needsto be explored, and Iencourage everybody toparticipate in the EORTCIntergroup study testingsurgery in the randomisedsetting. The final questionis whether we shouldmaintain treatment inpatients where everythinghas failed. The expertopinion from ESMO andthe NCCN is that weshould maintain treatmentat least to control sensi-tive clones.

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THE ROLE OF MTOR INHIBITION

This imatinib-resistant GIST patient had a huge liver metastasis resected after treatmentwith the mTOR inhibitor everolimus

Source: Courtesy of Pierre Meeus, Centre Léon Bérard, Lyon

bodies, peptide-related things and evensome novel antisense type molecules.All these are in the mix now. The chal-lenge to the drug companies today is nolonger of findingnovel targets,” says John-ston, “it is findingwhere those drugs arelikely to produce most benefit.”

But this is not proving easy. Her-ceptin (trastuzumab) was approved onthe basis of an immunohistochemicalassay thatwasmeant to identify patientswho stood to benefit, but turned out tobe less than satisfactory. “The histo-chemical assays did not correlate wellwith the genomic assays for gene expres-sion thatwewere doing,” says Johnston.“We went forward and marketed thetest even though it hadnever been prop-erly quality assuredwithin the literatureor beyond.” Though it has now largelybeen replaced by theFISH (fluorescent

� Anna Wagstaff

It’s been many years since biolo-gists first offered the tantalisingprospect of a future in whichevery cancer patient could beprescribed a tailor-made treat-

ment aimed at the unique molecular‘signature’ of their particular disease. Inthe intervening years, an ever-growinglist of overexpressions, amplifications,translocations anddeletions has becomepart of the academic oncologist’s vocab-ularywith its ownbewildering dictionaryof acronyms – KRAS, BRAF, VEGFR,EGFR, HER2, ALK, c-KIT, exon 9,mTOR, MEK, PDGFR, BRCA – tonamebut a few. In routine clinical prac-tice, however, only a tiny minority ofpatients are actually tested for these‘biomarkers’ and treated accordingly.

Sowhat’s the hold up?This questionhas increasingly been exercising Patrick

Johnston, head of theCentre forCancerResearch and Cell Biology at Queens’University, Belfast.A specialist in ‘-omics’diagnostics (genomic, proteomic,metabolomic…), he says we now havetargets a-plenty to aim at and awealth ofnew drugs – some in the clinic, manymore in the pipeline – to aim at them.But despite hugely powerful technolo-gies that candowhole-genome sequenc-ing or identify the expression ofthousands of genes in a matter of 24hours, we still do not know which sig-natures (or sets of biomarkers) predictresponse or resistance to which drugs.Thiswork is simply not being done, saysJohnston, or at least not well enough.

“Inmyowndisease, colorectal cancer,there are something like 60–70 newdrugscurrently in variousphasesofdevel-opment.There are smallmolecules, anti-


CuttingEdge

The number of genemutations implicated in cancer is growing at a steady pace

– one cancer centre is now screening for 124 of them.Thenumber of drugs being

developed to target specific mutations is also rising steadily. But finding which

targeted therapieswork best forwhich sets ofmutations is proving an elusive goal.

Who’s who in the world ofpersonalised cancer treatments?

in situ hybridisation test), this too hasnever been validated in a randomisedcontrolled trial and is widely believed tomiss some patients who would benefitfrom Herceptin.

Then there is Erbitux (cetuximab),another important targeted drug, whichwas designed to block the expression ofepidermal growth factor receptors(EGFRs), and was originally approvedfor use in all metastatic colorectal can-cers and in head and neck cancers that

showed positive for EGFR overexpres-sion.Only after the drugwas brought tomarket did it come to light that a sub-stantial proportion of the target group ofpatients (estimated atmore than 25%ofcolorectal cancer patients) receive nobenefit from the drug, due to amutationinKRAS– a gene that plays a role earlierin the signal pathway.

This indicates amethodological fail-ure, says Johnston, in thedevelopment ofboth Erbitux and Vectibix (panitu-

mumab)– a similarEGFR inhibitor, alsoapproved in colorectal cancer. “It is onlyserendipity that has suggested that actu-allyKRAS is adiscriminator.”The impor-tance of KRAS could have beenidentifiedmuchearlier, heargues, if a sys-tematic approachhadbeen takenearly inthe trials of both drugs to measure thevarious components of the signallingpathway–MEK,KRAS,BRAF,EGFR–in parallelwith studying themain target.“This is where the intellectual and the

CuttingEdge


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“The intellectual, preclinical and clinical strategies need

to be thought of together, rather than in isolation”


CuttingEdge

preclinical and clinical strategies need tobe thought of together, rather than inisolation. Sometimes, even so, a drugcandidate will come forward withoutreally having due reference to what hasbeen discovered preclinically.”

“We are trying our best,” is theresponse from the industry. Con-founding the sceptics who won-dered why big pharma woulddedicate resources to identifybiomarkers thatwouldnar-row down the market fortheir therapies, drugs compa-nies really do seem to havespent the last fewyears restruc-turing themselves around thenewparadigmofdeveloping theright drug for the right patient.Most now have teams bringingtogether biologists, preclinical,translational and clinical spe-cialists, with good technicalplatforms and biostatisticalbackup, who try to identify what distin-guishes responders fromnon-respondersanddevelopandvalidate tests that canbeused in the clinic to identify whichpatients will benefit from the drug.

A COMPETITIVE EDGEThey aremotivated in part by increasingdemands from the regulators that, inorder to get approval of new therapies,sponsorswill need to demonstratewhichpatients respond, and come up with atest to reliably identify them.As impor-tant, however, is the recognition that,with somany agents chasing somany tar-gets, market share is now all about whocan identifymost quickly and accuratelythemarker that predicts which patientswill really benefit.

As Wolfgang Wein, head of GlobalOncology at Merck Serono (MerckKGaA) points out, “You have a compet-itive advantage if you are ahead of thegame. If you are a follower, and a bio-marker pops up while your study isalready underway, then you have theproblem that you have to do a retro-spective analysis, which is not much

liked by the regulators.”As far asWein is concerned, the discov-ery that patients with amutant KRAS gene do notrespond to Erbitux – a drug

marketed by Merck Seronooutside theUS– is entirely to thecompany’s benefit. “The KRASallows us to identify thosepatients who are most likely tobenefit from treatment with

Erbitux. This can beshown whether you arelooking at time to progres-

sion, overall survival, responserate or however youwant tomeasure it,”he says. “It strengthened the profile ofthe drug compared to the competition.”

Yet, as he points out, drug companiesare limited by the current state of knowl-edge of the disease. “Biomarker develop-ment somehowemerges fromacademia. Itis anexpressionofwhere academia standsat a certain point in time. You may startyour trial usingonebiomarker, but itmightturn out during the trial to be not a verypreciseone, orbetterbiomarkers comeupin the meantime. I see the problem asoneof validation: to knowwhen it is reallyconfirmedas a goodbiomarker. There areexamples where a biomarker has beenproposed, there are several publications,and then it turned out that they couldnotbe confirmed in a randomised study.”

What critics often don’t appreciate, headds, is that when it comes to exploringhow your drug works in real cancerpatients, you can rarely conduct thestudiesmost likely to answer your ques-tions.Most targeted therapies are devel-oped and approved in combinationwithother, usually cytotoxic, therapies,because the regulatorswould not acceptthat a patient could be denied the cur-rent standard of care. Yet the combina-tion of therapiesmaymuddy the signalsof who is responding to the targetedtherapy and who is not.

It is also in the very nature of cancer,he adds, that youoftenneed tohit severaltargets at once. Four drugs, hitting fourtargets, could give you a very clear signalof response in patients with tumoursrelying on that particular signalling net-work,while anyoneof thosedrugs testedalone might produce no such signal.Again the regulators, for understandablereasons, have resisted giving approvalto more than one experimental drugat a time – though Wein says they areincreasingly open for discussion on such‘novel–novel’ approaches.

“We are therefore limited in whatwe can really do by what can be fundedand what is acceptable in terms of effi-cacy and toxicity,” saysWein. “Evenwiththe best intentions, you can just try togain ground within these limits.” Justhow difficult this can be was mostrecently demonstrated by attempts tofind a marker of response to Erbituxamong patientswith non-small-cell lungcancer – which, as Wein points out, isreally anumbrella term for a collection ofcancers with different histologies. “Wedid anenormous amount ofwork, butwedidn’t find a solution,” says Wein. Last

“You may start your trial using one biomarker, but it

might turn out during the trial to be not very precise”

yearEMEA turned down an applicationfor Erbitux to be extended for use innon-small-cell lung cancer on thegrounds that the added benefit did notoutweigh the additional toxicity in anundifferentiated patient population.

THAT’S SCIENCE FOR YOUDavid Reese, Executive Director ofMedical Sciences at Amgen, whichdeveloped theEGFR inhibitor Vectibix,doesn’t necessarily agreewith Johnston’sassertion that the development of thedrug was flawed and that KRAS waslater identified as a biomarker ofresponse by ‘serendipity’. Reese speaksfrom a certain experience, having bothworked with Dennis Slamon’s team atthe UCLA (University of California,LosAngeles)whenHerceptinwas beingdeveloped, and later helped on the teamthat unravelled the KRAS story.

KRAS, he says, was among the firsthuman oncogenes to be identified.Althoughwehaveknownfor30yearsthat activating mutations in thisgene could drive tumour cells, atthe time of the early trials therewas very little literature delin-eating the role thatKRASplaysin the signalling network thatfed into the target Vectibixaimed to block, says Reese. Inaddition, preclinical modelswere a little misleading,“because there are cell lineswith the KRAS mutation thatappear to respond toVectibix,or other anti-EGFRtherapiesin vitro, whereas in the clinicwe have not really seen that.”

Later on, when a number of

studies “primarily single-arm, single-institution retrospective studies” beganto flesh out the components of EGFRsignalling pathways and flag up mutantKRAS genes as possible predictors ofresistance to drugs such as Vectibix,Amgen went back to the tumour sam-ples it had collected during the phase IIItrial to do its own retrospective analysis.“Wewere able to obtainKRAS status on92%of patients in that study. The analy-sis showed a very strong correlationbetween the presence of KRAS muta-tions and resistance.”

It may not be the ideal way to iden-tify your biomarker of response, saysReese, but that’s science for you.We areall working with an incomplete under-standing of the disease, and the chal-lenge and the art is to identify the rightquestions to ask.

“It is an iterative process,” he adds.“Observations are made in the lab. It isincumbent upon us to try to sort thoseout in our early-phase clinical trials asquickly as possible. Often observationsfrom those trials will then feed back toinform additional work in the lab to

refine our preclinical models.”Where feasible, saysReese, this

will include looking beyond the tar-get to see the wider biologicalimpact of the drug, for example by

obtaining serial tumour biopsies forbefore and after exposure. “One thingthat I think is now apparent is thatyou have to view these as pathwaysand not even pathways but sig-

nalling networks.Under-standing the effect onthe network is criticalin terms of under-

standing what sort of effect your drugmay be having.”

Where he does agree with Johnstonis that the technologies for gatheringthe necessary biological readouts fromsamples are no longer a limiting factor.But the issue thenbecomeswhat you dowith those readouts. “It can alsomisleadyou if inappropriately used, because ofthe massive amount of data that pourout. It is more critical than ever to askvery careful questionswith an extremelywell-defined hypothesis.”

Getting the question right is, how-ever, only the half of it. To find theanswers they must convince cliniciansand patients to take part in what canoften be a logistically complex, time con-suming and sometimes unpleasantprocess – for instancewhere repeat biop-sies or PET scanning may be required.

Itmaybe significant that,whenaskedto name some ‘model trials’ currentlyunderway, Johnston found the questionhard to answer– and the twoat the topofhis list –onebeing runbyECOGand theother by theEORTC–werebothhavingdifficulty accruing patients. “The factthat I can’t point to verywell-defined tri-als that are set up in this way shows theproblem,” he says.

SOME QUESTIONSCAN’T BE ANSWEREDAs Anne-Marie Martin, Director forClinical Biomarkers andClinicalDevel-opment, Oncology R&D, at Glaxo-SmithKline, explains, “Something thatcan be donewith a very controlled set ofexperiments in a lab or with animalsdoes not necessarily translate into theclinical setting. So it is important not

CuttingEdge


“We are all working with an incomplete understanding of

the disease, and the art is to identify the right questions”

only to ask the right questions, but alsoto balancewhat we are able to do in ourpreclinical research with what is clini-cally feasible.”

Identifying patient groups wherethere is a strong unmet medical needremains important for clinical develop-ment, saysMartin, but it is also importantto choose a disease indicationwhere youbelieve a high proportion of patients arelikely to respond. “For instance, in ourearlydevelopmentportfolio,wearedevel-oping a BRAF inhibitor. We know thereare mutations in the BRAF gene andthosemutations are commonly foundparticularly inmalignantmelanoma.”

However, BRAFmutations arealso known to be present in somecolorectal cancers and papillarythyroid cancers, andMartin saystheir teamcould explore the effectof their inhibitor in these cancersaswell, but itmakes sense to startwith malignant melanoma, whereapproximately 50% of patients’tumours have this mutation.

Critical to the whole process,she says, is enabling the preclinicalscientists, the clinicians and thetranslational scientists towork effec-tively together. “My team straddlesthe bridge between basic researchand the clinical groups.Working closelywith the project teams,my teamunder-stands the issues from a basic sciencepoint of view which leads to the ques-tions that we may want to ask in theclinic.”

She accepts, however, that this sortof research requires cooperation at theclinical level with a wider team in addi-tion to the treating oncologist. “In order

for us to be entirely successful in trans-lational research,wewill need to rely onpathologists, interventional radiologistsand maybe even surgeons to access theright samples to perform translationalresearch. We have found that it’s betterto do that little bit of extra legworkupfront, and by reaching out to theseindividuals, explaining the purpose ofthe research and how important it is,usually we are successful in obtainingthe right samples and hopefully on our

way to answering the key questions.”

INVESTING INTRANSLATIONAL RESEARCHThe importance of high-qualitytissue sampling is one of thethings Astra Zeneca is nowfocusing on in a major col-laboration with Cancer

ResearchUK to accelerate thepace of biomarker develop-ment. The initiative is centred atthePaterson Institute ofCancerResearch at Manchester Uni-versity, and coordinated through

the NCRI (National Can-cer Research Institutes).FromAstra Zeneca’s point

of view, it represents a strate-gic attempt to address the single

biggest challenge to realising the dreamof getting the right drug to the right can-cer patient: boosting translationalresearch efforts to understand the basicmechanisms of the disease.

This is how Astra Zeneca’s Head ofEarly Clinical Oncology Development,Andrew Hughes, describes the prob-lem. “Take the targetAkt.You can look inmany different types of cancer and see

thatAkt is upregulated, but as to whichcancers are addicted to that upregulationof Akt versus those that are not, i.e.which cancers aremost likely to respond,it’s an open question, despite the factthatwe have now very potent and selec-tive inhibitors ofAkt.”

The result, he adds, is that we havean increasing number of targeted drugscoming through development withoutunderstanding how best to use them.

“Weare looking verymuch to scienceexternal to Astra Zeneca to help usunderstand the basic biology of humancancer,” saysHughes. “Oncewe under-standwhich part of themolecular lesionin a cell the cancer is addicted to, then ofcourse pharma iswell suited to applyingits high-throughput screening, itsmolec-ular chemistry, its pharmacokinetics, itsoptimisation anddrugmanufacture to gocapitalising upon that innovation. Butpharma I don’t think has the same spec-trum of resources as academia has tounlock the basic understanding of can-cer question.”

The trouble is, says Hughes, thatacademia faces the same challengesobtaining human cancer tissue as indus-try. “There has been an awful lot ofinvestment in yeast, non-mammaliansystems, cell lines because they are easyto acquire. But to ask researchers toresearch on human disease materialrequires them to step out of their labsand into clinics and hospitals to partnerwith a research-minded physician, andappropriately consent patients to usetheir tissue to try andunderstandhumandiseases.” The funding ismore expensiveand themultidisciplinary infrastructurebecomes more of a challenge. “In the


CuttingEdge

“It is important to balance what we are able to do in our

preclinical research with what is clinically feasible”

CuttingEdge


region of translational research therehas been less than we would have likedto have seen.”

Finding ways to reorientate cancerresearch away from the headline-hittingbasic science towards more expensive,logistically demanding translational stud-ies is a challenge that has preoccupiedmany in the cancer research communityover recent years. In collaborating withCRUK’s biomarker programme, AstraZeneca is now looking to give the com-pany the answers it needs to informsomeof its ownclinical trialswhile at thesame timeboosting the general capacityof the academic sector to undertake thissort of research. Amongst other things,the funding goes towards running a joint,co-funded PhD course in translationalresearch, and raising the quantity andquality of tissue available for research byplacing technicianswith the appropriateskills in cancer hospitals.

LOOKING FOR THE BIG RESPONSESEfforts to improve the research commu-nity’s access to quality-controlledbiolog-ical specimens is something everypharmaceutical companywouldapplaud.ButBill Sellers,GlobalHeadofOncologyforNovartis,wants to goone step further.He would like those quality-controlledspecimens tohavebeenpre-screened forbiomarkers known to be of interest.

Sellers is looking for the bigresponses he believes are waiting to befound, and argues that, if andwhen youfind them, all the issues about identify-ingwho is responding, finding biomark-ers and developing a test for thatbiomarker become highly manageable.He cites, as an example, the extension ofGlivec [imatinib] to treat KIT-mutantGIST patients.

“Themutation inKITwasactuallydis-covered by a group in Japan. A secondgroup then showed that cell lines with

those mutations were highly responsive.Patients with GIST were identified bydetection of cKIT by immunohisto-chemistry for anti-CD117(cKTIT) andthen treated with Glivec. At that time ithad not been shown that this specifictest forCD117 identified allKIT-mutantpatientsnor all patientswho responded toGlivec. However, the immunohisto-chemistry test itself showedgood techni-cal performance, and the FDA (USregulators) did not demand validation ofthat test asapreconditionofextending theindicationofGlivec toKIT-mutantGISTpatients. It asked, instead, for apost-mar-keting commitment from Novartis to‘assure the availability of a validated testfor detection of CD117 tumour expres-sion by immunohistochemistry.’”

Far from being a special case, saysSellers, that is the futurewecan look for-ward to. He mentions anALK inhibitorfor lungcancerpatientswith a rearranged

IT'S ALL ABOUT THE TAIL

The tail ends of these curves show that a small minority of patients with non-small-cell lung cancer derive very significant benefit from the EGFR inhibitorTarceva (erlotinib). Progress towards personalised cancer treatments is all about learning how to determine in advance which patients are likely to benefitand which will notSource: FA Shepherd et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. NEJM 353:123–132, reprinted with permission

A. Overall Survival B. Progression-free Survival

ALK gene, and various BRAF inhibitorsformelanomapatientswithBRAFmuta-tions as examples of therapies in thepipeline that are showing promisingresults in their target patient population.

“In the case of melanoma we aredoinga trial of ourdrugTasigna [nilotinib]in KIT-mutant melanoma only, becausegiven the emerging phase II data, whereessentially five out of the first sevenpatients treated with Tasigna haveresponded, there would be noway to dothe trial inKIT-null patients at this point.”

What is holding back progresstowards personalised therapies, saysSell-ers, is the time and effort it takes torecruit the particular patients you needto the trials you want to carry out.

“Imagine you are doing a trial in apopulation of lung or breast cancer, ormelanoma, where only 10% of patientshave the mutation that you want. Youstart the trial and no one out there hasbeen screened for that mutation. Thenevery patient who enters the trial, youhave to consent for the trial, do the testand then tell them you are not eligiblenine out of ten times.”

Tracking down the patient’s tumoursample can itself be a tricky business.“Sometimes that tumourwas isolated ata different hospital, and not at the hos-pital where they are now being treated.You have to find the tumour.You have tomake DNA from the tumour; have itsequenced, so it takes time. And thenthey might not have the right mutationfor your trial.”

Not surprising, then, that cliniciansand patients are not always enthusiastic.Howmuchbetter, suggestsSellers, if thisgeneticprofiling for alterationsconsideredto be important for cancer genetics was


CuttingEdge

“Pharma doesn’t have the same spectrum of resources

as academia to unlock the basic understanding of cancer”

Towards truly tailored treatments. In this translational research laboratory at the MassachusettsGeneral Hospital Cancer Center, specimens from lung and colorectal cancer patients are routinelytested for 124 biomarkers. Prospectively profiling patients in this way should greatly facilitatetranslational research to discover which combinations of biomarkers are significant for whichtreatments in which cancers

KATIE

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Director of the MGH TranslationalResearch Laboratory, points out thatthere’s nothing to stop your average can-cer hospital fromdoing likewise – indeeda number of hospitals across theUS arenow taking part in a lung cancer projectusing the assays developed at MGH.

“We’ve developed assays and soft-ware methods that are easily portablethat we can transfer across differentinstitutions. It makes that equip-ment readily available – plug andplay – to do this kind of clinicalgenotyping.” The beauty of it,says Borger, is that it is becom-ing a routine test for someclinicians. “There is nothingadditional that the patients needto provide. They fill out a con-sent form so they understandthat their tumour will be testedand they agree to that testing.Then after the diagnosis ismade, our pathology depart-ment sends the very same samplethat they evaluated themselves to ourlaboratories, andwe take a little bitmoreof that sample to extract the geneticinformation thatwe test for. Soweuse allthematerial that is currently provided atall institutions to the pathology depart-ments. We don’t need anything extra.”

All the information relating to theassays developed at the MGH CancerCenter will soon be available in the lit-erature, he adds, and other institutionsarewelcome to use or improve on them.Hehopes that companies could developsome assays as kits that would be com-mercially available at a price affordableeven for small institutions.

Currently all lung andcolorectal can-

doneona routineand regularbasis, ratherthanonlywhen theyare about tobecomeeligible for a clinical trial.

Oneway thiscouldbedone is througha lead-in epidemiology trial to profilepatients, so that aheadof timeresearchersalreadyknowhowmanypatients thereareat which centres who are bearing thismutation. Better still, says Sellers, is thepractice thathas recentlybeenadoptedatMassachusetts General Hospital andother cancer centres, where many can-cer patients are now being offered theoption of profiling for sets of mutationsandbeing consented. “When somecom-pany has an interesting drug for oneof those mutations, they will know ifthey are eligible.”

A SIGN OF THINGS TO COMEThe initiative at Massachusetts Gen-eral Hospital (MGH) could signal aninteresting restructuring of cancerresearch efforts, tying the patient careside into the translational research sideon a scale that has never previously beendone. More than that, it would seem torepresent the first rays of the long-awaited dawn of the new era in whichcancer therapies are routinely person-alised in everyday clinical practice.

The hospital is not generating agenetic fingerprint for every cancerpatient – at least not yet. But as part of itsroutine clinical practice, it is now testingsomepatients for the steadily increasingnumber ofmarkers that have been iden-tified in the literature as playing a role indriving certain cancers, and it is usingthis information to direct the patientstowards the therapies that aremost likelyto benefit them. Darrell Borger, Co-

cer patients at MGH can have theirtumours tested for 124 important cancergene mutations, chosen according towhich aremost commonover all cancersas a whole. “In lung cancers we knowwhat the important genes are to lookfor, and of course we look for those,”says Borger, “but by having this broadfingerprint, we are finding that there

is a small number of patients whoalso have uncommon mutations.”

Some of these ‘uncommon’muta-tions couldwell be very commonin other types of cancer, heexplains. “And this is the ques-

tion we will be addressing fairlysoon: Can you take what youknow in a particular cancer witha particular mutation and applythat in another cancerwhere youfind that same mutation?”

Many other institutionsare now also “very very

close” to bringing person-alised cancer therapies to their

patients, according to Borger, in boththe US and across Europe. Interest-ingly, soon to take up his post as Chiefof the Division of Hematology/Oncol-ogy and Associate Director of theMGH Cancer Center is José Baselga,immediate past president of ESMO(European Society for Medical Oncol-ogy). Borger expects the presence ofEurope’s chief champion of transla-tional research will strengthen collab-oration across the Atlantic. “What weare interested in is providing a modelthat many people can benefit from,incorporate and even improve on. Abig collaborative effort, and we all haveour contribution to make.”

“You have to consent every patient, do the test and then

tell them you are not eligible nine out of ten times”

CuttingEdge


Blazing a trailin a new type of research

� Simon Crompton

When confronted with the novel gene technology of the early ’70s, molecular biologist

Axel Ullrich posed the question: what use can this be tomedicine? In doing so, he opened the

door on the era of translational research and a personal career whichwent on to encompass lead

roles in the development of two of the first intelligently designed cancer drugs.

He’s the man behind the first monoclonalantibody drug Herceptin (trastuzumab),and the innovative kidney cancer treat-

ment Sutent (sunitinib). He has come as close asanyone to finding a ‘magic bullet’ for cancer, butAxelUllrich still feels a sense of failure.At the age of 66,with four years to go until compulsory retirement,there’s a deadline for making the really big break-through, the one that will change cancer treatmentforever. The clock is ticking, and the prospect thathe won’t be able to achieve it makes him sad.

“I feel this responsibility…” he says, “Having toretire now, I feel a little bit of a defeat, even thoughthere is no one else who has brought two cancerdrugs to themarket from bench to bedside. I hopethere will be one or twomore. But with cancer, it’sonly a partial victory.”

It’s abattle that startedas an intellectually intrigu-ing skirmish, andhas grown into an increasingly per-sonal war over the years. For all his dissatisfaction,Ullrich stands as one of the living giants in cancerresearch, for 25 years a leader in translating discov-eries inmolecular cloning into usable therapies.

Last year he was awarded the prestigious Dr PaulJanssen Award for Biomedical Research, cited as“one of fewbasic scientistswhosework not only hasinfluenced academic research, but also has helpedmillions of patients suffering frommajor chronic dis-eases.”He is among the top 10most cited biologistsin the world.

How does it feel to have such an influence onpeople’s lives?Ullrich deflects the question. “Well,there are many stories to be told…” he says, andcontinueswith the tale hehasbegunabout theprob-lemshehadmakingdrug companies understand theconcept of monoclonal antibodies as a targetedcancer therapy. It’s not modesty that makes himchange the subject. Ullrich sticks to an agenda forwhat he wants to talk about.

THE ULLRICH AGENDAThe reason thatUllrich still thinks amagic bullet forcancer might be achievable (and many would dis-agree with him) is that he has already pioneered adifferent direction of cancer treatment fromanyoneelse in the face of reluctance and disbelief. He did


Masterpiece

it, by his own admission, through a dogged refusalto go indirections people toldhim to.Hedoesn’t likebeing toldwhere to go if he believes another way isbetter – whether that be in academia, within thepharma industry or in an interview.

Ullrich knows that very few people operate likethis. He directs my attention to a picture on hisoffice wall of some of the 100 research students atthe Institute under his supervision over the past 20years. “There are a few of them,” he says, “just veryfewwho spotwhat themost important thing is, andgo for it straight away.”

The difference between those few, he explains,and the remainder, is partly that they refuse to be“book-keeper scientists who just add one stone toanother.” Some simply have a creativity of approachthat inevitably puts them at odds with others.

“The essence of creativity is to see connectionswhere other people don’t see them. You can onlymake breakthroughs if you don’t go themost logicalcommon track.”

He provides an example of his counterintuitivecreativity in his current research at theMax PlanckInstitute. Examining gene structures in a cancertumour, one of his students stumbled on an abnor-mal variant in a gene. Was it relevant to why thetumour formed?Research revealed that the aberra-tion was not restricted to the cancer. It was what isknown as a single nucleotide polymorphism (SNP)– a type of variant that also occurs in non-cancerousgenes, and which is responsible for the variety andindividuality of humans. The SNP that the studenthad found, it transpired, was one of themore com-mon of around 10million in the human genome.

A dead-end then.Most colleagues believed so.But Ullrich thought it looked interesting, so con-tinuedwith experiments. They revealed that thoughthe SNPdidn’t cause cancer, it did appear tomakebreast cancer more aggressive. Reports of hisresearch, published in 2002, were met with scep-ticism: the influence of such SNPs was hard toprove, and was likely to bemarginal, he was told.

SoUllrichdevised anewexperiment toprove the

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AXELGRIESCH/M

AXPLANCKINSTITUTEOFBIOCHEMISTRY

“Very few people spot what the most important

thing is, and go for it straight away”

critics wrong, breeding mice with his newlydiscovered SNP with others with a gene variantknown tomakemicemore susceptible tocancer.Thewaycancers developed, progressedandmetastasisedin the mice clearly indicated that the new SNPinfluencedhowaggressive tumourswere.The resultswere published inCancer Research in January.

“Evenmy students said, ‘Why are you continu-ing to look at this?’ Now we are translating theresults back into humans, and are making evenmore exciting discoveries, because the people we

can identify as having a bad prognosis through thisSNP may respond much better to some types oftreatment than those who do not have the allele.”

Sowhat was it thatmade him go on? “I had thisfeeling that there’s something important, and thatmademe fascinatedby thebeauty of this experiment– of changing one single nucleotide in amouse andseeing what the effect was on amajor disease.”

It has been the same story through his career.Ullrich says he’s never had a rational approach to hiswork – he has been led by his ‘inner compass’, hisinstinctive sense that some leads need to be fol-lowed because they are interesting or important.

Hewasborn inLauban,Silesia, in1943.Hispar-ents had fled from theNorthernCzech Republic –formerly knownas theSudetenland–and lost every-thing in the process, so they set up a grocery store tomake a living.Hewas good at biology and chemistryat school, butnoone toldhimhecouldbecomea sci-entist.All he really knewwas that he didn’t want tobe a teacher–which is interesting for amanwhohasspentmuch of his professional life supervising stu-dents. “I hated teachers. I’d seenhow they could setout to destroy the life of a young child.”

With his parents giving him total freedom oncareer choice, hedecided to studybiochemistry at theUniversity of Tübingen, and then went on to earn aPhDinmoleculargeneticsatHeidelberg in1975.Real-ising that if hewas to stay in science, hewouldhave tolearn its international language,English,hedecidedhisnext step shouldbe to go to theUS–preferably some-wherewhere thequality of lifewas good.California forexample. So he applied for a fellowship, and a post-doctoral tenure inbiochemistryat theUniversityofCal-ifornia, San Francisco.He got them.

A FIRST FOR GENE TECHNOLOGYItwas a timewhen the first reports about the poten-tial of gene technologywere beginning to circulate.He decided to see whether he could do anything‘medically relevant’ with the new technology. Inthe mid ’70s, DNA sequencing was still not possi-ble, butUllrich thought insulin looked a promising


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He decided to see whether he could do anything

‘medically relevant’ with the new technology

AXELGRIESCH/MAXPLANCKINSTITUTEOFBIOCHEMISTRY

area for investigation – it was a small polypeptidewith probably a small, manageable gene.

Itwas a long fight to convincecolleagues that thiswas a good route for research, but by 1977 he hadcome up with the molecular cloning process thatcould produce synthetic insulin. The breakthroughoccurred just beforehis fellowshipwasdue to expire,and allowed him to stay on inAmerica toworkwiththe pioneer biotechnology company, Genentech,to develop human insulin, or Humulin – the firsttreatmentdeveloped throughgene-based technology.

“I told the founder of the company, Bob Swan-son, that I wanted to explore my own ideas. I wasprobably a pain in the neck for him, but he let me

do it. It was a great time forGenentech, whichwasa forerunner for semi-academic industrial research,and itwas very, very exciting.Wewere the best clon-ers in the world. And so I got through insulin andinto the field of growth factors – because theywerealso short peptides, and accessible to the technol-ogy that was available at the time.”

THE HERCEPTIN STORYThe interest in growth factorswas to lead tohis great-est breakthroughs in cancer therapy.Ullrich startedinvestigating theway inwhich growth factors – sig-nalling proteins capable of stimulating cell growthor

proliferation – function. He looked inparticular at how they interact withreceptors – molecules that taketheirmessages into cells.He andcolleagues from the UK andIsrael cloned receptors, andfound a new type of receptorfor a growth factor called epi-dermal growth factor (EGF).They called it HER2.Therewas,he says, excitement

– but not at the implications of thediscovery for countering a disease. “It

was the technical challenge,” he says.Itsmajor implications became clearer when they

found its peptide sequenceswere related to an onco-gene. In 1987,Ullrich,working in collaborationwithDennis Slamon and others, discovered that the genefor HER2 was overamplified or overexpressed in atleast 25% of invasive breast cancers. “The end of thestorywasHerceptin– the first targeteddrugagainst theproduct of a gene that was abnormally amplified inabout aquarter of allmammarycarcinomas.Wemadeanantibody thatblocked the functionof thisoncogene.So this was a first, first, first…”

But Ullrich also felt disappointment, espe-cially when initial trials showed that just 15% ofHER2-positive patients responded to Herceptinalone (later trials showed it helped many more in

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“Wemade an antibody that blocked the function

of this oncogene. So this was a first, first, first…”

Then and now, with friend and fellowmolecular geneticist Jürgen Brosius. Whenthe black and white snap was taken, genetechnology was in its infancy; Ullrich spent the restof his career putting it to work to treat disease

combination with other drugs). “As a biologist, ithad to be all or nothing. I had much higher expec-tations, whereas for oncologists who work withthesepatients everyday, itwas ahugebreakthrough.”

Then there were disputes with Genentech,which, he says,was initially reluctant to develop andproduce an antibody as a therapy. In the end, clin-ical development didn’t begin until 1992 andHer-ceptinwas only approved in 1998. “The story ofmylife includes many discoveries that were made tooearly and not understood.” Partly as a result of hisfrustrations with the company, Ullrich took up anoffer to become director of the Department ofMolecular Biology at the Max Planck Institute ofBiochemistry in 1988.

On a personal level, it wasn’t an easy time. Hehad left a house and a wife in California. Eachmonth he spent three weeks inMunich, oneweekin California. “That lasted about five years andended in a divorce.”

But on a research level, things were moving on.Ullrich, who throughout his career has straddledtheacademicandcommercial spheres, convinced theMax Planck Institute that the best way to translatebasic scientificdiscoveries into treatmentswas to linkan academic lab to a company. They allowed him tostart a company to develop the products of research– it was based in theUS and called Sugen.

THE SUTENT STORYItwashere thatSutentwasdeveloped– the firstmul-tikinase inhibitor drug, now a standard for treatingrenal cell carcinoma and gastrointestinal stromaltumours. It came into being after a new receptorcloned by a research student at Max Planck wasfound to be critical to the formation of blood vessels(angiogenesis). Angiogenesis is a key process intumourdevelopment, andUllrich andhis colleaguesbelieved they could develop an angiogenesisinhibitor. Initial trials of a Sugen-developed drugbased on the discovery were disappointing – theyrevealed that it also inhibited other receptors.

But again, Ullrich turned defeat into triumph.

“Sowe rationalised,” he says. “We said, okay,maybethis is good.Maybe other oncogenes are also inhib-ited by the drug, and therefore this drug will beeffective against cancer inmanyways. This is whathappened.” Sutent, it turned out, waswhatUllrichcalls a “broadband antibiotic against cancer” – a newtype ofmulti-targeteddrug.Research continues intopossible new applications.

Ullrich,who in2001setuphis thirdbiotechcom-pany, U3 Pharma, continues to work on developingsimilar multikinase inhibitors, which are effectiveagainst a broad range of cancers. His work continu-ally demonstrates the importance of translationalresearch, yet itworrieshimhowslowly the translationfrom bench into clinical practice generally occurs –the result, he says, of simple lack of nerve.

“When I look at how much money and timepharmacompanies say it takes todevelopanewdrug,I think this is not necessary.All this couldbedone inhalf the timequiteeasily.”How?“Byhiringbetterpeo-ple and giving them responsibility. You need peoplewhoarepassionate,whodon’t just see it as a job, andyou need to give them the power to take risks.”

It’s an opinion clearly born of the frictions thathave arisen as his confident approach has beenviewed as too risky. But he’s not a risk-taker in hispersonal life. He lives with his partner, a medicaldoctor, and they enjoy the relatively sedate occu-pations of travelling and cooking.Most of his kicks,he confesses, come fromhiswork, and there are nochildren to distract him.

It isn’t surprising, then, that retirement holds noallure.Ullrichwants to be in the thick of it, pushingforward translational researchandencouraging inter-actionbetweenacademics andmedical scientists, sothat access to biopsies and patient data is easy, andbasic science can be put into practice as quickly aspossible. It’s here, he believes, that the future ofcancer research should lie. Stem cell therapies, heemphasises, are unlikely to lead to novel cancertherapies. Focusing on immunology, he believes, onharnessing thebody’s ownability to fightdisease,pro-vides the best chance of defeating cancer.


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“You need people who don’t just see it as a job,

and you need to give them the power to take risks”

THE MAGIC IMMUNE SYSTEMUllrich believes that immunology holds out thetantalising prospect that, somewhere out there, amagic bullet for cancer still awaits discovery. Eventhough cancer is hundreds of diseases, they allhave a single common denominator. “The biggestproblem is the instability of the genome. It’s notimportant whether you have stem cells or not, butit’s important that the cancer cells that have stemcell characteristics have an unstable genome. Thisis the biggest problem. But you will never defeatcancer without the immune system. It is your ally.Only the immune system is so clever that it cantrack down a cancer cell wherever it is in the body.”

It’s the end of the interview andUllrich, candidbut pragmatic throughout, is just beginning to

reveal some of the passion that he advocates sostrongly in researchers. In a careerwhere hewas ledto investigate cancer by instinct and curiosity ratherthan by a sense of mission, in latter years his workseems to have accumulatedmeaning.He has seenmore andmore people die of cancer –his father andfriends, one of themyoung, and just a fewdays ago.

“I only began to appreciate the incredible com-plexity of cancer after the clinical phase I Her-ceptin results. I’ve felt it as an incredible challenge– you know, to take up the War on Cancer thatRichardNixondeclared in 1971. I have to say, it hasbecome really, a sort of a calling. I sometimes feel alittle depressed that I have to go without havingmade a really strong impact. But it’s a realisation thatcancer is just an incredible, formidable enemy.”

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“Only the immune system is so clever that it can

track down a cancer cell wherever it is in the body”

Speaking at an ESO meeting at the World Conference of Science Journalists. One of most frequentlycited biologists in the world, Ullrich argued that increasing pressures on academic scientists to getcoverage in the wider media can lead to them exaggerating the significance of their findings, whichmay undermine their credibility

JASO

NHARRIS

ImpactFactor

Trials and tribulationsin primary CNS lymphoma

� Stephen Ansell and Vincent Rajkumar

A minority of patients with primary central nervous system lymphoma achieve a complete

response to therapy andmost patients have a poor prognosis.A recent randomised phase II trial

demonstrated that the addition of high-dose cytarabine to high-dosemethotrexate increases the

complete response rate and improves patient outcome.

Primary central nervous systemlymphoma (PCNSL) is anuncommon extranodal B-cell

non-Hodgkin lymphoma confined tothe central nervous system (CNS)that represents approximately 1% ofall non-Hodgkin lymphomas.Although this disease has beenobserved in patients with immunedeficiency, the incidence in immuno-competent patients has increased,particularly among elderly patients.1

Due to the rarity of PCNSL, ran-domised studies have been very diffi-cult to conduct. Patients with thisdisease have not benefitted from theprogress made in systemic B-cell lym-phoma, in that standard treatment

approaches such as cyclophos-phamide, doxorubicin, vincristine andprednisolone (CHOP) chemotherapyhave not been effective in PCNSLbecause of poor drug penetration intothe CNS.2 The use of therapies thatare considered effective – high-dosemethotrexate, autologous stem-celltransplantation and whole-brain radi-ation therapy (WBRT) – has provedchallenging because many patientsare elderly and more susceptible tothe toxic effects associated with thesetreatments.

The initial treatment for patientswith PCNSLwas to useWBRT.WhilePCNSL tumours are very radiosensi-tive, local disease relapses are frequent

and there are virtually no long-term sur-vivors.3 Based on its ability to penetratethe CNS, methotrexate was subse-quently used in clinical trials, and highdoses with folinic acid rescue werefound to improve patient outcome.4

While there is no consensus as to theexact dose that should be used, it isgenerally accepted that ‘high-dose’methotrexate regimens utilise between1 g/m2 to 8 g/m2 administered every twoto three weeks.Other agents, includingcytarabine, procarbazine, temozolomideand rituximab, have sincebeen added tohigh-dose methotrexate and haveproduced higher response rates andpotentially improved progression-freesurvival.5 However, a higher instance of


This article was first published in Nature Reviews Clinical Oncology 2010 vol.7 no.3, and is published withpermission. © 2010 Nature Publishing Group. doi:10.1038/nrclinonc.2010.9, www.nature.com/nrclinonc

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toxic effects have been seen in studiestesting chemotherapy combinations,resulting in higher rates of treatment-related mortality compared with high-dose methotrexate alone.

Inmost of these studies, chemother-apy formed part of a combined modal-ity approach and WBRT was given asconsolidation after induction therapy.Ahigh incidence of neurotoxicity wasseen, particularly in patients older than60 yearswho received combinedmodal-ity treatment.6 Recent studies haveattempted to limit neurotoxicity, eitherby omitting radiation therapy7 and insome studies consolidating the responseto initial therapy using autologous stem-cell transplantation,8 or by use of lowerdoses of radiation therapy.9 In studies inwhich autologous stem-cell transplan-tationwas added and radiation therapyomitted, it was evident that patientswho benefitted most were those whohad a complete response to initialinduction therapy. Similarly, loweringthedose ofWBRT todiminishpotentiallong-term neurotoxicity might only befeasible in patientswhohave a completeresponse to treatment. Therefore, toutilise these approaches we need toidentify treatment regimens that resultin high complete response rates.

High-dose methotrexate hasbecome a standard approach for manygroups treating patients with PCNSL,and doses of up to 8 g/m2 are givenevery two weeks. A recent study byFerreri et al.10 suggests that the addi-tion of high-dose cytarabine to high-dose methotrexate results in asuperior complete response rate andoverall response rate when comparedwith methotrexate alone. In this ran-domised phase II trial, 79 patientswere randomly assigned to receivemethotrexate 3.5 g/m2 alone or incombination with cytarabine 2 g/m2

twice daily on two days for four cyclesas primary therapy for CNS lym-

phoma. The primary endpoint of thestudy was complete response rate. Intotal, 46% of patients receiving bothhigh-dose methotrexate and high-dose cytarabine had a completeresponse to treatment compared with18% of patients receiving high-dosemethotrexate alone. The overallresponse rate and subsequent out-comes of patients were improved withthe addition of high-dose cytarabineto high-dose methotrexate. Althoughsignificant haematological toxiceffects were seen, this was managedwith growth factor administration andadverse effects were felt to be accept-able. These findings suggest thatintensification of induction therapy asdemonstrated by this study mightimprove long-term patient results.

Although the findings are persuasive,certain caveats need to be kept inmind when interpreting these results.First, as in most CNS tumours, radi-ographic assessment of response isnot always easy, and has limitations asa surrogate for clinical benefit. This isfurther exacerbated in non-blindedstudies. Second, although studies ofcombination chemotherapy and com-bined modality therapy in this diseasehave used varying doses of ‘high-dose’methotrexate, the trials that use high-dose methotrexate as a single agenthave employed a dose of 8 mg/m2

every two weeks. This dose results ina high response rate, is well toler-ated, and can be administered repeat-edly until progression in mostpatients. The study by Ferreri et al.10


TREATMENT OF NEWLY DIAGNOSED PCNSL PATIENTS

Transplant-eligible patients receive high-dose chemotherapy followed by an autologous stem-cell transplant, in patients who respond to treatment. Elderly patients are treated with achemotherapy-only approach to avoid neurological toxicity associated with WBRT. Youngerpatients who are not eligible for an autologous stem-cell transplant could be treated with high-dose chemotherapy followed by WBRT (as per the data from the clinical trial of Ferreri et al.10

(highlighted in the figure).

ASCT – autologous stem-cell transplantation; HD AraC – high-dose cytarabine; HDMTX – high-dose methotrexate;MTX – methotrexate; PCNSL – primary central nervous system lymphoma; WBRT – whole-brain radiation therapy

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used a lower dose of methotrexate,3.5 g/m2 delivered every three weeks,which might account for a lowerresponse rate than has been reportedin other studies. Third, the vastmajority of patients (77%) receivedWBRT as consolidation after the ini-tial induction chemotherapy. Manygroups favour consolidation withautologous stem-cell transplantationrather than administering WBRT,because of the increased neurotoxic-ity seen with WBRT. Finally, dosereductions were necessary in 44% ofpatients treated with the combinationapproach (compared with 3% ofpatients treated with methotrexatealone), suggesting that it might beeasier to intensify therapy by increas-ing the dose of methotrexate than byadding a second drug, such as high-dose cytarabine.

The data presented by Ferreri etal.10 could be particularly relevant inpatients or practices where high-dosetherapy with autologous stem-celltransplantation is not employed. Formany groups, the initial decisionmight be to define which patients areeligible for transplantation. In eligiblepatients, high-dose methotrexate at adose of 8 g/m2 could be consideredwith autologous stem-cell transplan-tation performed in patients whorespond to this therapy.

Nonresponders are commonlymanaged with salvage chemotherapyincluding temozolomide, rituximaband other treatment approaches, oralternatively receive WBRT (see algo-rithm). In patients where an autolo-gous transplant is not considered or atcentres which do not employ thisapproach, the data presented by Fer-reri et al. could be of value. In view ofthe fact that patients aged over 60

years receiving WBRT might have sig-nificant neurotoxicity, these patientscould be managed with chemotherapyalone and could receive methotrex-ate with or without other chemother-apy agents. Alternatively, youngerpatients might benefit from theresults presented by Ferreri et al.10

and these patients could be treatedwith high-dose methotrexate in com-bination with high-dose cytarabineand then receive consolidation treat-ment with WBRT.

Primary CNS lymphoma remainsa challenging disease and furthertrials are needed to provide informa-tion to further optimise the care ofpatients with this devastating illness.The use of drugs that penetrate theblood–brain barrier at increaseddoses seems to be the best approach.Patients responding to this therapymight further benefit from consoli-dation approaches, including autolo-gous stem-cell transplantation orlower dose WBRT.

References

1. JE Olson et al. (2002) The continuing

increase in the incidence of primary central

nervous system non-Hodgkin lymphoma: a

surveillance, epidemiology, and end results

analysis. Cancer 95:1504–1510

2. GM Mead et al. (2000) A medical research

council randomized trial in patients with

primary cerebral non-Hodgkin lymphoma:

cerebral radiotherapy with and without

cyclophosphamide, doxorubicin, vincristine,

and prednisone chemotherapy. Cancer

89:1359–1370

3. DF Nelson et al. (1992) Non-Hodgkin’s

lymphoma of the brain: can high dose, large

volume radiation therapy improve survival?

Report on a prospective trial by the Radiation

Therapy Oncology Group (RTOG): RTOG

8315. Int J Radiat Oncol Biol Phys 23:9–17

4. T Batchelor et al. (2003) Treatment of

primary CNS lymphoma with methotrexate

and deferred radiotherapy: a report of NABTT

96–07. JCO 21:1044–1049

5. GD Shah et al. (2007) Combined

immunochemotherapy with reduced whole-

brain radiotherapy for newly diagnosed

primary CNS lymphoma. JCO 25:4730–4735

6. LE Abrey, LM DeAngelis, J Yahalom (1998)

Long-term survival in primary CNS

lymphoma. JCO 16:859–863

7. IT Gavrilovic, A Hormigo, J Yahalom et al.

(2006) Long-term follow-up of high-dose

methotrexate-based therapy with and without

whole brain irradiation for newly diagnosed

primary CNS lymphoma. JCO 24:4570–4574

8. LE Abrey et al. (2003) Intensive

methotrexate and cytarabine followed by high-

dose chemotherapy with autologous stem-cell

rescue in patients with newly diagnosed

primary CNS lymphoma: an intent-to-treat

analysis. JCO 21:4151–4156

9. B Fisher et al. (2005) Secondary analysis of

Radiation Therapy Oncology Group study

(RTOG) 9310: an intergroup phase II

combined modality treatment of primary

central nervous system lymphoma.

J Neurooncol 74:201–205

10. AJ Ferreri et al. (2009) High-dose

cytarabine plus high-dose methotrexate versus

high-dose methotrexate alone in patients with

primary CNS lymphoma: a randomised phase 2

trial. Lancet 374:1512–1520

Author affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota,USAAcknowledgement: The authors wish to thank PB Johnston and BP O’Neill for their assistance with the manuscript


Practice pointThe use of high-dose cytarabine incombination with high-dose metho-trexate followed by whole-brain radi-ation therapy could be effective inyounger patients with primary cen-tral nervous system lymphoma forwhom autologous stem-cell trans-plantation is not planned.

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Androgen deprivation therapy forprostate cancer: true love or heartbreak?

� Jason Efstathiou, William Shipley, Anthony Zietman and Matthew Smith

The addition of hormonal therapy to radiation therapy improves survival inmenwith unfavourable

risk prostate cancer.Yet,menwith prostate cancer have higher rates of non-cancer death than the

general population and most will die from causes other than their index malignancy. Comorbid

cardiovascular disease is strongly associatedwith cause of death and this raises the possibility that

prostate cancer or its treatment increases cardiovascular disease risk and possibly mortality.

The relationship between andro-gen deprivation therapy (ADT)andcardiovasculardisease isnot a

newstory, although interest has renewedin recent years.Diethylstilbestrol, a non-steroidal oestrogen,washistorically usedin treatingmetastaticprostate cancerbutwas abandoned because of excess car-diovascular and thromboembolic risk.More recently, prospective studies havedemonstrated that gonadotropin-releas-ing-hormone agonists adversely affectsome traditional cardiac risk factors,including lipidprofiles, insulin sensitivityand obesity. In a large population-basedstudy, Keating et al.1 reported that these

agonists are associated with increasedriskof incidentdiabetesmellitus andcar-diovascular disease.

The results of the novel observationsbyKeating et al.1 spawned a host of post-hoc analyses of randomised trials andobservational population-based studiestoevaluate the relationshipbetweenADTand cardiac morbidity and mortality.2–6

To date, the evidence from these studiessuggests that ADT modestly increasesriskof cardiovasculardiseasebutdoesnotnecessarily increase cardiovascularmor-tality.Theabsenceofanapparent increaseincardiovascularmortalitydoesnot,how-ever, exclude the possibility of ADT

increasing non-cancer mortality. Previ-ous reports suggestedhigher non-cancermortality in men treated with long-termversusshort-termadjuvanthormonal ther-apy for advanced disease3 and decreasedoverall survival in those receiving neoad-juvant hormonal therapy before prostatebrachytherapy for early-stage disease.7

Within this framework,Nanda et al.8

attempted to evaluate the relationshipbetween short-term ADT and all-causemortality inmen treatedwithbrachyther-apy for early-stage prostate cancer. Thissingle-institution, retrospective experi-ence included5077menwith localisedorlocally advanced prostate cancer treated


This article was first published in Nature Reviews Clinical Oncology 2010 vol.7 no.3, and is published withpermission. © 2010 Nature Publishing Group. doi:10.1038/nrclinonc.2010.12, www.nature.com/nrclinonc

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with orwithout amedian of fourmonthsof neoadjuvant ADT followed bybrachytherapy.ADTwas linked togreaterall-cause mortality (P=0.04) after amedian follow-up of 5.1 years in a smallsubgroup (n=256) ofmenwith coronaryartery disease- (CAD-) induced conges-tive heart failure or prior myocardialinfarction, but not among themajority ofmenwithout those conditions.

We commend the authors on theirattempt to define a subgroup of patientsinwhomADTispossibly dangerous, andagree that hormonal therapy is not suit-able for everyone. Yet, caution must beexercised in the interpretation of theresults of this study. First, becauseprostate cancer is an indolent disease, itis unclearwhymenwith clinically signif-icant cardiovascular diseasewere treatedwithbrachytherapy rather thanmanagedbyactive surveillance.Second, there isnoestablished survival benefit for ADT incombinationwithbrachytherapy and it isunclearwhy somanymen receivedADTin this setting. Third, there are concernsraised over ascertainment biases in thatthe main conclusion associating ADTwith greater all-cause mortality in menwithCAD-inducedcongestiveheart fail-ureorpriormyocardial infarction isbasedona small subset representingonly5%ofthe entire study population, and a differ-ence of only seven events.

Thechoiceof all-causemortality as anendpoint isparticularly surprisingbecausethe men who received ADT had moreadverse features thanpatientswhodidnotreceive it, including older age, andmore-aggressive cancers. Unfortunately, theauthors did not report cancer-specific ornon-cancer mortality, so it remainsunclear whether the link to greater all-cause mortality was related to prostatecancer, its treatment, or the selection ofpatients at greater risk for death.

Notably, an analysis of a large,multi-centre,prospective randomisedcontrolledtrialwith long follow-up found that, even

within subgroupsofmenwithhigh-riskofcardiac death (that is, age 70 years orolder, prevalent cardiovascular disease ordiabetes) therewasno apparent increaseincardiovascularmortality in those treatedwith adjuvant ADT for locally advancedprostate cancer.2 Similarly, analyses ofanother large randomised trial4 have alsoreported no excess cardiovascular mor-tality inmen receiving short-termADTincombinationwith radiation therapyversusradiation alone.

Herein lies the true lesson of theNanda study.ADT as an adjunct to radi-ation was adopted in the 1990s foradvanced disease on good evidence. Infact, it is firmlyestablished thathormonaltherapy decreases cancer-specific and,in somecases, all-causemortality formenwith locally advanced or high-gradelocalisedprostatecancer.Regrettably, thisevidenceof improvedsurvivalhas, inpart,led to the increase in theuseofhormonaltherapyacross theentire spectrumofdis-ease even among men with lower-riskprostate cancer and older men with sig-nificant competing causes of mortality.9

This over-exuberant expansion in theindications for hormonal therapy mightreflectboth theoptimismandgood inten-tions of treatingphysicians; however, theissueof financial reimbursementcouldbeinvolved as well.10

The results of theRadiationTherapyOncology Group (RTOG) 94-08 study(presented as a late-breaking abstract atASTRO annual meeting 2009) are ofparamount importance to informingproper patterns of practice. This land-mark trial demonstrated that short-termADT before and during radiation ther-apy modestly improved overall survival(P=0.03) in patients with early-stagelocalised prostate cancer andnotably didnot increase the risk of intercurrentdeath. The actuarial 10-year death ratefrom intercurrent disease (excludingdeaths fromprostate cancer)was 35% intheADTplus radiation therapy arm and

37% in the radiation alone arm(P=0.49). The results of the risk groupanalysis revealed that the intermediate-risk subgroup experienced the greatestbenefit from short-termADT, althoughit is debatable whether this remainsvalid in the era of dose-escalated radia-tion therapy (which is being addressedin an ongoing RTOG trial). Results ofthis risk group analysis, however,demonstrate that there is no role forhormone therapy in low-risk disease.Secondary analyses from this impor-tant randomised trial will help shed fur-ther light on the unintended adverseeffects of hormonal therapy in early-stage disease, including those with sig-nificant cardiac comorbidity.

Westrongly recommend limitinguseof adjunctive ADT to settings with anestablished survival benefit. These evi-dence-based indications include menreceivingexternal-beamradiation therapyfor intermediate and high-risk disease.The absence of an established survivalbenefit should be sufficient reason toavoid ADT in other settings, includingmenreceivingbrachytherapyand/orexter-nal-beam radiation therapy for low-riskdisease. The increased understanding ofpotential adverseeffects ofADTserves toreinforce careful selectionof appropriatecandidates for treatment.

Clinicians shouldnotnecessarilywith-hold ADT from men who might benefitfrom it in terms of cancer-specific sur-vival despite a history of cardiac comor-bidity after careful consideration of therisks and benefits. Good general medicalcaredictates thatpatientswithunderlyingcardiacdisease receive secondarypreven-tive measures, including lipid-lowering,antihypertensive, glucose lowering, andantiplatelet therapy as appropriate. Thereis no evidence to recommend additionalcardiac testing or coronary interventionin patients with cardiovascular diseasebefore initiation of ADT. In lieu of arandomised controlled trial directly


Learning can be fun

e-grandroundJoin us every Thursday from

18:15 to 19:00 hours CEST (Central European Summer Time)

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addressing the question of the effect ofADToncardiachealth,webelieve futuretrials ofADTaswell asnovel formsofhor-mone therapy shouldprospectively assesscardiovascular risk factors and stratifypatients according to their comorbidities.

The questions raised by the rela-tionship between ADT and cardiachealth in prostate cancer patients arecomplicated. The initial excitement sur-rounding hormonal therapy could nowbe over, as the relationship finds a newbalance based on evidence.

References

1. NL Keating, AJ O’Malley and MR Smith (2006)

Diabetes and cardiovascular disease during

androgen deprivation therapy for prostate cancer.

JCO 24:4448–4456

2. JA Efstathiou et al. (2009) Cardiovascular

mortality after androgen deprivation therapy for

locally advanced prostate cancer: RTOG 85–31.

JCO 27:92–99

3. JA Efstathiou et al. (2008) Cardiovascular

mortality and duration of androgen deprivation for

locally advanced prostate cancer: analysis of RTOG

92–02. Eur Urol 54:816–823

4. M Roach et al. (2008) Short-term neoadjuvant

androgen deprivation therapy and external-beam

radiotherapy for locally advanced prostate cancer:

long-term results of RTOG 8610. JCO 26:585–591

5. AV D’Amico et al. (2007) The influence of

androgen suppression therapy for prostate cancer

on the timing of a fatal myocardial infarction. JCO

25:2420–2425

6. SM Alibhai et al. (2009) Impact of androgen

deprivation therapy on cardiovascular disease and

diabetes. JCO 27:3452–3458

7. DC Beyer, T McKeough and T Thomas. (2005)

Impact of short course hormonal therapy on overall

and cancer specific survival after permanent

prostate brachytherapy. Int J Radiat Oncol Biol Phys

61:1299–1305

8. A Nanda, MH Chen, MH Braccioforte et al.

(2009) Hormonal therapy use for prostate cancer

and mortality in men with coronary artery disease-

induced congestive heart failure or myocardial

infarction. JAMA 302:866–873

9. MJ Barry, MA Delorenzo, ES Walker-Corkery et

al. (2006) The rising prevalence of androgen

deprivation among older American men since the

advent of prostate-specific antigen testing: a

population-based cohort study. BJU Int 9:973–978

10. JM McKoy et al. (2005) Caveat medicus:

consequences of federal investigations of marketing

activities of pharmaceutical suppliers of prostate

cancer drugs. JCO 23:8894–8905


Author affiliations: Department of Radiation Oncology (Jason Efstathiou, William Shipley, Anthony Zietman) and Division of Hematology and Oncology (Matthew Smith),Massachusetts General Hospital, Boston, Massachusetts, USA

Practice pointAndrogendeprivation therapy is asso-ciated with many adverse effects,including cardiovascular disease. Itsuse as an adjunct to local therapy,such as radiation, in the treatment ofprostate cancer should be limited tosettings with proven survival benefit.

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N E W S R O U N DSelec ted repo r t s ed i t ed by Jane t F r i cke r

Cetuximab rash isa good sign in headand neck cancer� Lancet Oncology

For patients with locoregionally advancedsquamous-cell carcinoma of the head and

neck (SCCHN), the latest five-year overallsurvival data confirm that radiotherapy pluscetuximab is better than radiotherapy alone.Furthermore, the US investigators found thatcetuximab-treated patients with a prominentcetuximab-induced rash (grade 2 or above) hadmore than 2.5 times longer overall survivalthan patients exhibiting no rash or mild rash.

In 1998, JamesBonner and colleagues fromthe University of Alabama (Birmingham,Alabama) designed a randomised trial investi-gating the value of adding cetuximab to radio-therapy in 424 patients with locally advancedSCCHN. Results at three years showed that sur-vival was 55% among those randomised tocetuximab and radiation compared to 45% forthose randomised to radiotherapy alone. Ofparticular interest to the investigators wereseveral studies acrossmultiple cancers (includ-ing colorectal, non-small-cell lung cancer andpancreatic cancer) suggesting a correlationbetween overall survival and presence of acetuximab-induced acne-like rash.

In the current paper, Bonner and colleaguesreport the five-year survival data and investigate

ther support for considering the combinationofcetuximab and radiotherapy as a standardoption in the treatment of locally advancedSCCHN,” write the authors, adding that theirprevious report provided the impetus for theinclusion of cetuximab and radiotherapy as atreatment option for locally advancedSCCHN inthe 2007National Comprehensive CancerNet-work (NCCN) guidelines.

It is possible, add the authors, that theacneiform rash is a biomarker of an immuno-logical response conducive to optimal out-comes. “In the future, the presence or absenceof a cetuximab-induced rash [might be used]to identify patients who benefit from moreprolonged treatment with cetuximab or treat-ment with other agents,” write the authors,adding that further work will be necessary todetermine themechanistic significance of theacneiform rash.

In an accompanying editorial, Kevin Har-rington, from the Institute of Cancer Research(London, England), writes, “The relatively rapidonset of skin reactions (>75% exhibited therash within two weeks) seems to offer theprospect of making decisions to continue orstop cetuximab after the first few weeks oftreatment.”

He adds that the National Cancer InstituteCommon Toxicity Criteria were used to definethe boundary between mild rash (grade 1)and prominent rash (grade 2). “This discrimi-nation rests on the absence (grade 1) or

the relationship between cetuximab-inducedrash and survival. Patientswith locally advancedSCCHN of the oropharynx, hypopharynx orlarynxwithmeasurable diseasewere randomlyallocated in a 1:1 ratio to receive either com-prehensive head and neck radiotherapy alonefor six to seven weeks (n=211) or radiotherapyplusweekly doses of cetuximab (400mg/m2 ini-tial dose, followed by seven weekly doses at250mg/m2, n=213).

Results show thatmedianoverall survival atfive yearswas 36.4% in the radiotherapy-alonegroup versus 45.6% in the cetuximab/radio-therapy arm (HR 0.73, 95%CI 0.56–0.95;P=0.018). The median overall survival in theradiotherapy-alone group was 29.3 months(95%CI 20.6–41.4) comparedwith 49.0months(32.8–69.5) in the cetuximab group.

As expected, patients randomised tocetuximab experienced a greater number ofgrade 3 and 4 infusion reactions than thosewho received radiotherapy alone. Of thepatients who received cetuximab, thosewith aprominent cetuximab-induced acneiform rash(grade 2–4) had a 68.8-monthmedian overallsurvival comparedwith 25.6months (HR 0.49,95% CI 0.34-0.72, P=0.002) in those whodeveloped mild or no rash (grade 0–1). Thesmall number of patients in the radiother-apy-alone group who developed acneiformrashes showed no survival difference com-pared with patients not exhibiting rash.

“These updated survival results provide fur-

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presence (grade 2) of symptoms, rather than anobjective measure of the rash. Therefore, thereliability of this measure must be confirmedin future studies.”

He comments too on the implications ofrecent studies showing important survival dif-ferences between SCCHNs that were associ-ated with the human papillomavirus (HPV)and those thatwere not.While the importanceof ensuring balance in human papillomavirus(HPV) status between the treatment groupscould not have been anticipated when thestudy was conceived, writes Harrington, thebetter prognosis of patients with HPV-positivelocally advanced SCCHN means that HPVstatus must be included as a stratificationfactor in future studies.

� A Bonner, P M Harari, J Giralt et al.

Radiotherapy plus cetuximab for locoregionally

advanced head and neck cancer: 5-year survival

data from a phase 3 randomised trial, and relation

between cetuximab-induced rash and survival.

Lancet Oncol January 2010, 11:21–28

� KJ Harrington. Rash conclusions from a phase

3 study of cetuximab [editorial]. ibid pp 2–3

Abbreviatedradiotherapy effectivefor breast cancer� New England Journal of Medicine

Anintense three-week course of radiationtherapy was found to be just as effective

as the standard five-week regimen for womenwith early-stage breast cancer, report Cana-dian researchers.

Inwomenwith breast cancerwhoundergobreast-conserving surgery,whole-breast irradi-ation reduces the risk of local recurrence andcan prevent the need for mastectomy. Radio-biologic models have suggested that a largerdaily dose of radiation (hypofraction), givenover a shorter time (accelerated therapy)mightprove just as effective as standard treatment,consisting of 50.0 Gy of radiation given in

25 fractions over a period of fiveweeks in dailyfractions. Such an abbreviated regimen wouldoffer the advantage of being both more con-venient for patients and less resource intensivethan standard schedules.

In 2002 Tim Whelan, from the Michael GDeGrooteSchool ofMedicine atMcMasterUni-versity,Hamilton,Ontario, reported the five-yearresults of a randomised clinical trial comparingabbreviated radiation with the standardapproach. At the time, local recurrence rateswere the same (3%) for both groups, and cos-meticoutcomes (reflecting the radiation-relatedmorbidity) were also similar. “Nevertheless,because radiation-relatedmicrovasculardamageincreases over time, therewas concern that latetoxic effects of radiation associated with thehypofractionated regimencoulddevelop,”writethe authors, who in the current study reporttheir findings at amedian follow-upof12years.

Between 1993 and 1996 the investigatorsrecruited women with invasive breast cancerwhohadundergone breast-conserving surgerywith negative axillary lymph nodes who wererandomised to either standard whole-breastirradiation (50 Gy given in 25 fractions over aperiod of 35 days, n=612) or acceleratedhypofractionated irradiation (42.5 Gy given in16 fractions over a period of 22 days, n=622).

Results at 10 years showed that the risk forlocal recurrence was 6.7% among the stan-dard-treatment groupand6.2%amongwomenin the hypofractionated-treatment group(absolute difference, 0.5 percentage points;95% CI –2.5 to 3.5).

There were 126 deaths in the standard-treatment group and 122 in the hypofraction-ated-treatment group (P=0.79).

At 10 years, 71.3% of the women in thestandard-treatment group and 69.8% in thehypofractionated-treatment grouphadgoodorexcellent cosmetic outcomes (absolute differ-ence, 1.5 percentagepoints; 95%CI –6.9 to 9.8).

Although there was a worsening of thecosmetic outcome over time, say the authors,which coincided with the increase in toxiceffects of irradiation of the skin and subcuta-neous tissue, there was no increase in toxiceffects in women who received accelerated

hypofractionated radiation therapy as com-pared to those who received standard therapy.

“Our long-term results provide support fortheuseof accelerated, hypofractionated,whole-breast irradiation in selectedwomenwithnode-negative breast cancer after breast conservingsurgery,”write the authors, adding that such anapproach was both more convenient and lesscostly than standard treatment. “Its availabilityas a treatment option may lead to an increasein the number of women who receive breastirradiation after breast conserving surgery.”

Potential limitations, write the authors,were that the trial was restricted to womenwho had node-negative, invasive breast can-cer. For this reason the results are not applica-ble to patients for whom nodal irradiation isplanned. Furthermore, women with largebreasts were not included, and few womenreceived adjuvant chemotherapy – a treat-ment thatmay place them at increased risk foradverse cosmetic outcome with standardradiotherapy. “So it is unclear whetherhypofractionation would lead to an outcomethat would be any worse than that with stan-dard treatment,” write the authors.

� T Whelan, J P Pignol, M Levine et al. Long-

term results of hypofractionated radiation therapy

for breast cancer. NEJM 11 February 2010,

362:513–520

Adding MRI to breastcancer assessment doesnot cut reoperations� The Lancet

The addition of MRI scans to conventionaltriple assessment techniques for the diag-

nosis of breast cancer has no effect on thereoperation rate, reports the UK COMICE trial.

The COmparative effectiveness of Mag-netic resonance Imaging in breast CancEr(COMICE) trial was the first randomised trial toassess whether contrast-enhanced MRI inwomen with primary breast cancer scheduled

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forwide local excisions decreased their need forreoperations. The COMICE trial was inspired byobservational studies showing greater accu-racy for MRI than for X-ray mammography orultrasound (JCO 17:110–119). It is known thataround 20% of women return to surgery for‘reoperation’ because their tumour has notbeen completely removed. The COMICE inves-tigators hoped that by better delineating theextent of the tumours the ‘reoperation’ ratewould beminimised.

Lindsay Turnball and colleagues, from theCentre forMagnetic Resonance InvestigationsatHull Royal Infirmary (Hull, England), recruited1623 women aged 18 years or older withbiopsy-proven breast cancer from45 centres intheUK. In addition to receiving triple assessment(defined as clinical examination, imaging ofthebreast byX-raymammographyand/or ultra-sound, and pathological assessment of thelumpby fine-needle aspiration cytology or corebiopsy) women were randomised to receiveMRI (n=816) or no further imaging (n=807). Theprimary endpoint of the studywas the propor-tion of patients undergoing a repeat operationor further mastectomy within six months ofrandomisation, or a pathologically avoidablemastectomy at initial operation.

Results show that 19%ofwomen (n=153)needed reoperation in the group that receivedMRI in addition to conventional tripleassessment, compared with 19% (n=156)in the group that did not receiveMRI (OR 0.96,95%CI 0.75–1.24; P=0.77).

The researchers also found no differencesin health-related quality of life between thegroups 12months after initial surgery, and nosignificant difference in costs ($8877.36 perMRI patient vs $8402.10 per non-MRI patient;P=0.075).

“However, in terms of total costs, resultssuggested a difference between the two trialgroups, with theMRI group costingmore thanthe non-MRI group, although the differencewas not statistically significant,” write theauthors. “In view of the similar clinical andhealth related quality-of-life outcomes ofpatients in both groups, we conclude that theaddition of MRI to the conventional triple

immunotherapy regimen associated with thehighest response rates has been the combina-tion of interferon-α2a, interleukin-2 and fluo-rouracil, with response rates as high as 39%being reported by Atzpodien and colleagues(Br J Cancer 85:1130–1136). Not all groups,however, have been able to reproduce suchhigh response rates. TheMRCand EORTC there-fore decided tomount a large-scale randomisedtrial comparing interferon-α2a alone, the thenstandard of care in Europe, with combinedinterferon-α2a, interleukin-2 and fluorouracil.

Between April 2001 and August 2006, theRE04/30012 trial, undertaken in 50 centresacross the UK, the Netherlands, Slovakia,Germany, Belgium and Denmark, randomlyallocated 1066 patients with metastatic renalcancer to treatmentwith interferon-α2a alone(n=502) or treatmentwith interferon-α2a plusinterleukin-2 plus fluorouracil (n=504). Treat-ment was not masked.

Results show that themedian overall sur-vival was 18.8 months for patients receivinginterferon-α2a versus 18.8 months for com-bination therapy (HR 1.05, 95%CI 0.90–1.21;P=0.55). The absolute difference in overallsurvival was 0.3% at one year and 2.7%at three years, favouring single-agent inter-feron-α2a.

The best overall response, however, wassignificantly higher in patients receiving com-bined therapy, at 23%, comparedwith 16% forpatients receiving interferon-α2a alone(P=0.0045), though this was not nearly as highas that reported by Atzpodien and colleagues.

Not surprisingly, grade 3/4 toxicity wasmore common among patients receiving thecombined therapy (53% vs 36%, P<0.0001).

On the basis of these findings, the authorsconclude that, “Although combination ther-apy does not improve overall or progression-free survival compared with interferon-α2aalone, immunotherapy might still have a rolebecause it can produce remissions that are ofclinically relevant length in somepatients. Iden-tification of patients who will benefit fromimmunotherapy is crucial.”

They note that dose modifications andbreaks occurred with both regimens, but that

assessmentmight result in extrauseof resourcesat the initial surgery period,with fewor noben-efits to saving resources or health outcomes,and the additional burdenonpatients to attendextra hospital visits.”

In an accompanying commentary, Eliza-bethMorris, fromSloan-Kettering Cancer Cen-ter and Weill Cornell Medical College (NewYork), said that the COMICE study does notfully answer the question of whether preoper-ative breast MRI adds benefit, because recur-rence andoverall survivalwerenot examined. “Itis too early to completely dispensewith preop-erative breast MRI. Importantly, COMICE hasshown that preoperative breastMRImight notbe for all womenand that routine breastMRI inthe evaluation of early breast cancer, as man-aged by those participating in this study, doesnot decrease reoperation rates.”

� L Turnbull, S Brown, I Harvey et al.

Comparative effectiveness of MRI in breast cancer

(COMICE) trial: a randomised controlled trial.

The Lancet 13 February 2010, 375:563–571

� EMorris. Should we dispense with preoperative

breast MRI? ibid pp 528–530

Combination chemo-therapy no advantagein kidney cancer� The Lancet

Combined treatment with interferon-α2a,interleukin-2, and fluorouracil did not

improve overall or progression-free survivalcompared with single therapy using inter-feron-α2a alone, found a joint MRC (BritishMedical Research Council) and EORTC (Euro-peanOrganisation for Research and Treatmentof Cancer) study. However, the investigators, ledby Martin Gore from the Royal Marsden NHSTrust (London, England), concluded the com-bined regimen may still have a role to playbecause it produced remissions of clinicallyrelevant length in some patients.

In metastatic renal cell carcinoma the

ImpactFactor


breaksweremore frequent for patients receiv-ing combined therapy than for those receivinginterferon-α2a,with three-quarters of patientsgiven interferon-α2a alone receiving 80% ormore of their expected dose.

The high degree of dose reduction withcombined therapymight provide anexplanationfor the absence of benefit with this regimen,write the authors. “However,webelieve that thisfinding is representative of the feasibility ofthis treatment, and no difference existedbetween the treatments according to size orexperience of the treating centre.”

The study, they add, might be criticised forlimiting the cycles of combination immunother-apy to two, although this decision was takenafterwide consultationwithmajor cancer cen-tres where cytokine therapies were used.

In an accompanying editorial, BernardEscudier from the Gustave Roussy (Villejuif,France) congratulated the MRC RE04/EORTCGU 30012 investigators on undertaking thelargest ever trial in mRCC. “They have clearlyanswered the initial question: the triple regi-men was definitively not superior to inter-feron-α2a andwasmore toxic. Thus, althoughthe response rate is higher than with inter-feron, chemoimmunotherapy should no longerbe used in mRCC.”

The study, he added, emphasises that inter-feron remains an acceptable option in patientswith good-risk features, and that the safety ofinterferon appears to be better when used bydoctors who havewide experience of the drugcomparedwith thosewhodonot. For example,grade 3–4 fatigue occurred in 18% of patientsin RE04/30012 study, run in UK and EORTCcentres, comparedwith 30% of patients in theCALGB study in the US.

� ME Gore, CL Griffin, B Hancock. Interferon

alpha-2a versus combination therapy with

interferon alpha-2a, interleukin-2, and fluorouracil

in patients with untreated metastatic renal

cell carcinoma (MRC RE04/EORTC GU 30012):

an open-label randomised trial. The Lancet

20 February 2010, 375:641–648

� B Escudier. Chemo-immunotherapy in RCC:

the end of a story [editorial]. ibid pp 613–614

Molecular profilingpredicts Hodgkin’slymphoma outcomes� New England Journal of Medicine

Increased numbers of tumour-associatedmacrophages are strongly associated with

shortened survival for Hodgkin’s lymphomapatients, a Canadian study has reported. Theselatest findings offer a new biomarker for riskstratification, allowing clinicians to predictwhich patients can be cured with standardtreatments andwhich aremore likely to relapse.

Currently most patients receive at leastfour cycles of polychemotherapy and, if indi-cated, radiotherapy. Autologoushaematopoieticstem-cell transplantation can rescue about50% of patients in whom primary therapy hasfailed. Despite advances in treatments forHodgkin’s lymphoma, around 20% of patientsstill die from progressive disease. None of theprognostic-factor scoring systems currentlyavailable are able to identify those patients inwhom treatment is likely to fail.

Randy Gascoyne and colleagues, from theBritish Columbia Cancer Agency (Vancouver,Canada), set out to build “a robust discrimina-tivemodel” predictive of treatment failure, thatmight be used to identify a small set of genesthat could be used to separate patients into thedifferent outcomegroups. The studywasunder-taken in two stages.

The first stage of the study involvedanalysing 130 frozen samples obtained frompatientswith classic Hodgkin’s lymphomadur-ing diagnostic lymph-node biopsy for geneexpressionprofiling todeterminewhich cellularsignatures correlatedwith treatment outcome.Primary treatmentwasdefinedas a failure if thelymphoma had progressed at any time afterthe initiation of treatment, while treatmentsuccesswas defined as the absence of progres-sion or relapse. The second stage involved vali-dating the findings in an independent cohort ofpatients with immunohistochemical analysis.

Results of the first stage of the studyshowed that gene-expression profiling identi-

fied a gene signature of tumour-associatedmacrophages thatwas significantly associatedwith primary treatment failure (P=0.02).

Of the potential markers identified in thefirst part, the researchers further analysedCD68+macrophages, CD20+Bcells, andmatrixmetalloproteinase-11 (MMP11) by immunohis-tochemical staining of samples from an inde-pendent cohort of 166 patients. CD68, theydiscovered, “stood out because of its significantcorrelation” with survival. On a scale of 1 to 3,a score of 3 (representing the highest concen-tration of CD68+ macrophages) was associ-ated with lower 10-year disease-specificprogression-free survival of 59.6%, compared to88.6% for a score of 1 (P=0.003), as well as anincreased likelihood of relapse after stem-celltransplantation (P=0.008).

In patients with limited-stage disease, aCD68 score of 1 was associated with 100%10-year disease-specific survival (P=0.04).

“Our study showed the value of enumerat-ing CD68+macrophages in diagnostic lymph-node samples for prediction of the outcomeafter primary treatment and secondary treat-ment (in particular, autologous stem-cell trans-plantation),” write the authors. “The absence ofan increased number of CD68+ cells in patientswith limited-stage disease defines a subgroupof patients for whom the rate of long-termdisease-specific survival is 100%with theuse ofavailable treatments.”

Inanaccompanyingeditorial, VincentDeVitaand JoséCosta, fromtheYaleSchoolofMedicine(NewHaven, Connecticut),wrote that the tech-nology should enable “the selection of patientswith a particularly poor prognosis (regardless ofstage) for aggressive treatment,which canbringmore logic to the treatment of this curable can-cer.” Most patients, they add, could be spared acombination of therapies or radiotherapy withattendant long-term toxic effects.

� C Steidl, T Lee, S Shah. Tumor-associated

macrophages and survival in classic Hodgkin’s

lymphoma. NEJM 11 March 2010, 362:875–885

� V DeVita, J Costa. Towards a personalised

treatment of Hodgkin’s disease [editorial].

ibid pp 942–943


Should you respecta dying wish?

� Anna Wagstaff

Some terminally ill cancer patients, seeing only suffering and indignity ahead, want to die at

a time and in a manner of their own choosing. But how does legal backing for assisted dying

impact on efforts to strengthen palliative care?And is helping patients to die compatible with

the duty of doctors, nurses and carers to save life and protect the vulnerable?

ForGeorge andHannah, thedecision to end their lives ata time and in a manner oftheir choosingwas not diffi-cult. Both were dying from

cancer.After 50 happy years of marriedlife, they saw their lives spiralling down-hill out of control.

Hannah (names have been changedfor reasons of privacy) had pulledthrough aweek shewas not expected tosurvive. Blockages caused by advancedGIST (gastrointestinal stromal tumour)had triggered colonitis and peritonitis.Dosed with large amounts of diamor-phine, shewas troubled by nightmarishhallucinations – though fully conscious,she had beenunable tomove or tell any-one what she was going through.

Her husband, suffering late-stagecolon cancer that had spread to the liver,hadbeen througha similar acutecrisis and

badexperienceswithhis painmedication.They were unable to get about or to

eat or drink properly and they knew thattheir pain and discomfort would onlygetworse. In addition,Hannahcouldnotstray far fromabathroomandwas effec-tively housebound.

Despite expert and dedicated carefrom doctors and nurses, both facedthe prospect of progressively losing con-trol over their bodies while remainingmentally active and alert. “Having seenwhat their end would be like, they veryquickly made their decision,” saiddaughter Diana.

If deciding what they wanted waseasy, achieving their aim was not. Theironcologist, GP and palliative carework-ers at the hospice were all deeply sym-pathetic and helpful. But this was theUK,where therewas no lawfulway theycould intervene to help end a life. Like

others before them, disabled andunwellas theywere,George andHannah founda way to make the trip to Switzerland,togetherwith their children, where theyended their own lives on their own termsat a Dignitas clinic.

Initially very hostile to the idea,Diana changed her mind as she sawwhat a tremendous relief her parentsfelt at taking back control. “Seeingsomebody frightened of the way theyare dying is a horrible thing,” she says,“Not having any control over your bodyor how you are looked after; knowingthen that all you have to do is have adrink and go to sleep. The peace thatthey reached – certainly in my parents’case – was extraordinary. I think it isabsolutely inhuman that we should beleft to the last weeks of harrowing dete-rioration, pain, not being able to eat,drink, walk…”

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Why should anyone be able to tellsomeone in this position that theycan’t just slip away, she asks?

Diana is careful to be very specificabout thequestion sheposes. This is notabout doctors or anyone elsedeciding that a person is suf-fering too much or their life isno longerworth living.Nor is itabout a right to die that appliesto everyone at any time regard-less of their circumstances. It isabout the right of people whoare dying andwho are sufferingto be able to get assistance inending their lives with dignity,without having to travel abroadand be reviewed by doctorsthey have never met. “You arenot choosing to die – fate hasdetermined that. You arechoosing the method of yourdeath and that is the funda-mental thing,” she says.

PUBLIC SYMPATHYThe stories of George andHannah are far from unique.All over Europe public sym-pathy is growing for peoplewho find themselves in thisunenviable situation. Pressureis building for legal changesthat would allow people who are suffer-ing with a terminal illness to die in themanner theywish– as is alreadypossiblein a handful of countries including theNetherlands, Belgium and Switzerland.

Opposition to such legislative changecomes from various quarters. There arethose who, often for religious reasons,believe that taking a life – even your ownlife –under any circumstances ismorallywrong and must always be a crime. Butthere are also those whose oppositiontakes amore pragmatic form. If laws arechanged tohelp people in genuineneed,like Hannah and George, the argumentgoes, a linewouldbecrossed.We’dbeon

a slippery slope, ending a life wouldbecome socially acceptable, and vulner-able people would be at risk.

The extreme example often cited isthe Nazi programme of killing ‘lifeunworthy of life’ – people deemed use-less to society because they were oldand infirm, disabled or had learning dif-ficulties. This is the spectre raised byBaroness Campbell, who has musculardystrophy and spearheadedopposition in

the House of Lords to a British bill onassisted dying, which would havegranted immunity from prosecution topeople helping friends or relativesmakethe trip to Switzerland to die. Shedescribed listening to doctors discussingwhether or not she was worth resusci-tatingwhen shewashospitalisedwith anacute chest infection. “‘You wouldn’t


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want to be resuscitated,’ they said, caus-ingme to even doubtmyself.Whywerethey saying this? What did they knowthat I didn’t? It could have been a deathsentence, one that Iwas too ill to resist.”

Given that the proposed legislationwas about terminally ill people whoexpressed a consistent and independentwish to end their own lives, the argumentmay say more about the emotive andoften muddled nature of public andpolitical debate on this issue than aboutthe real dangers inherent in legalisingassisted dying. Yet evidence from theNetherlands does seem to indicate that

A QUESTION OF CONTROLLars Johan Materstvedt is a professorof philosophy who specialises in thisarea. Based in Trondheim University,Norway, where he conducts research onmedical ethics, he was lead author of

the position paper drawn upby an Ethics Task Force ofthe EuropeanAssociation forPalliative Care (EACP) in2003. He says that while theDutch euthanasia regulationwas drawn up to address sit-uations where medicine wasunable to deal with ‘medical’problems, today it is increas-ingly being used to deal withissues of ‘personal control’.“In those situations ofextreme physical symptoms– pain, dyspnoea and so on –they are usingmore andmorepalliative care and palliative(terminal) sedation. Themainreasons people want assistedsuicide or euthanasia is notpain, shortness of breath orvomiting. It ismore andmorea psychological and psy-chosocial thing.”

The legislation specifiesthat doctors can only consideragreeing to a request by a

patient to end their life by drugs wherethere is ‘unbearable’ suffering with ‘noprospect of improvement’, and wheredoctor and patient agree that there is no‘reasonable’ (palliative) alternative inlight of the patient’s situation. Wantingto die on one’s own terms rather thanslowly collapsing into incontinence anddependence, losing thewill ormotivationto fight on, arenot strictlymedical needs.Yet these sorts of issues prompt anincreasing proportion of requests to die,saysMaterstvedt. “Research has shownthat in many cases, doctors think thereare good alternatives, but the patientsays ‘no, this is intolerable, I don’t want

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changing the law to relieve the sufferingof people like Hannah andGeorgemayresult in the law gradually being appliedto awider group of people than originallyintended. In the Netherlands, since2002 doctors have lawfully been able toend a patient’s life at his or her request –they use the term ‘euthanasia’. C

OURTESY

OFCORRIEREDELLASERA,THEGUARDIAN,LIBÉRATION,TROUWANDDIEWELT


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further treatment, I want an injectioninstead.’Doctors cannot force thepatientto undergo treatment, so this puts themin a very difficult position. Sometimesthey give in.”

Today, there is debate in theNether-lands over whether being ‘tired of life’should be sufficient reason to have theright to assisted dying. This seems

unlikely to happen any time soon, andwould presumably require a shift awayfrom the currentDutch system, inwhichdoctors are the sole arbiters, to some-thing more akin to the Swiss model,where much of the process of assisteddying is in the hands of civic society, inthe form of lay volunteers working in‘Right to Die’ societies like Dignitas.

As a palliative care specialist who prac-tised for 25 years in the Netherlands,Ben Zylicz (now based in the UK) isuncomfortable with the Dutch legisla-tion. He resents the way many patientsnow feel they can visit a doctor anddemand their ‘right’ to die. “My view isthat everybody has his own autonomy,within this he may wish to die. Auton-omy of the patient alsomeans autonomyof the doctor and of society. My view isthat they should look together for some-where halfway between. The patientmay ask, but not demand, that the doc-tor kill him. The doctor may never say,‘Sorry, I’m not at home’ because you areasking for this. They should look for acompromise. A kind of compromise ispalliative care.”

Heworries that the attitude that seesassisted dying as a right is leading todoctors agreeing to perform euthanasiaas a ‘first resort’, without making suffi-cient efforts to persuade thepatient to tryalternative options.

“Most patients who are requestingassisted dying are not aware ofwhat pal-liative care can do. Many hundreds ofpatients I cameacrosswhowanted todieearlier were first of all very afraid theywouldhave terriblepain. Itwasnot actualpain, but fear of complications of verybad, poor dying.Manyof themhadexpe-rience of their parents or grandparentsdying like this. They justwanted to avoidthis. These are the patients who, whenthey seek our help,we canhelp in nearly100% of cases. That’s our daily bread.”

Zylicz classifies patients asking foreuthanasia into five categories –A toE–based on a study of 200 patients he didaround 15 years ago.

“In many cases, doctors think there are good

alternatives, but the patient says ‘no, this is intolerable’ ”

TERMS OF DEBATE

The term ‘euthanasia’ comes from the Greek words eu- “good” + thanatos “death”. Its firstrecorded use in English was in 1869, signifying “legally sanctioned mercy killing”.Misuse of the term to provide cover either for a state policy of killing people deemed of novalue to society or for paternalistic doctors taking it upon themselves to decidewhich patientsshould be ‘put out of their misery’ and which ‘had lives worth living’, led to the adoption ofthe term ‘voluntary euthanasia’ to refer to situations where the patient has made his orher own request to die. Many now reject this term, arguing that all euthanasia is voluntaryby definition – helping a patient to die without their explicit request is ‘murder’.In the Netherlands, Belgium and Luxembourg, legal sanction for helping patients to die restsonly with doctors and is reserved for patients who have requested help to die, who aremen-tally and psychologically competent tomake that request (this does not necessarily excludepeople suffering mental illness), who are suffering unbearably and for whom there is noprospect of improvement in their situation. These countries use the term ‘euthanasia’.In Switzerland, ‘euthanasia’ – as in a doctor administering a lethal drug – is illegal. However,clause 115 in the penal code states that assisting someone to commit suicide is punish-able ‘if done for selfishmotives’, which effectivelymakes it lawful for any citizen to help some-one end their life so long as they can show it was done for altruistic reasons and that theydo not administer the drug themselves. The law was originally conceived as a way to enable‘honour suicide’ in the days when bankers who reduced their clients to destitution mightchoose to ‘fall on their swords’. Today this is the law that allows Right to Die societies likeDignitas to help people die through ‘assisted suicide’. Only a doctor, however, can prescribethe drug (usually natrium pentobarbital) and there are strict rules of professional ethics –similar to those that apply in the Netherlands – that govern the circumstances under whichthis can be done.Though understandable given its historical context, the term ‘assisted suicide’ is con-sidered by many as inappropriate and demeaning when applied to people who are ter-minally ill. Debates about both ‘euthanasia’ and ‘assisted suicide’ now often use the term‘assisted dying’.

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A stands for Afraid. Patients who needreassurance about what palliative carecan do for them.

B stands for Burn out. Very often inthe past these patients were very effec-tively treated for their disease, and theirdisease is halted or absent, says Zylicz,but they are sodamaged that they cannotlive. “They are exhausted by their lives.For these patients it is very difficult tohelp them, and the only thing is to pre-vent these cases from happening.” Hismessage to oncologists is, “Be very care-ful of heroic operations, of overtreat-ment of the disease, because sometimeswe can create this kind of exhaustedpatients who are very difficult to treat.”

C stands forControl freak. “Peoplewhoare notmedically ill, but they think thatthey can just come to a doctor and thedoctorwill just take out a syringe and killthem. They want to be in control. Andthink everybody around has a duty tosupport them in this,” says Zylicz. “Thisis a very difficult group for us, and pal-liative care is not a very good approachfor them.”

D stands for Depression. Researchhas consistently found a significant linkbetween depression and requests foreuthanasia, and is a factor in about one-third of all euthanasia requests that areturned down by Dutch doctors. “Withthese patients, recognition and treat-

ment of depression can change enor-mously their wish to live.”

E stands for Extreme. These arepatients who do not respond to treat-ment or cannot tolerate the side-effects– only 3%–4% of patients requestingeuthanasia fall into this category, saysZylicz. “Thesepatients are really not to behelped by medical means. You maysometimes look for the last resort ofterminal sedation, providing they areterminally ill and dying.”

There seems tobea fair consensusonthe general outlines of this classificationamongprofessionals involved in this area,though many show a bit more under-standing for the wishes of the ‘controlfreaks’ – presumably the people Mater-stvedt talks about, who for ‘psychosocial’reasonsdon’twant to lose control of theirbodies and become dependent.

THE ROLE OF PALLIATIVE CARERSLike many palliative care specialists,Zylicz defines his job as helping peoplelive the best lives they can, and seeseuthanasia as incompatible with thisaim. He talks about the need to go theextra mile to win patients’ trust, to givethem the confidence that there willalways be someone there for them, evenat 6.00 am onNewYear’s Day. He talkstoo about fears among many of the eld-erly people he cares for at the DoveHouse hospice in Hull, England, thatthe doctors will take it upon themselvesto end their lives prematurely, undercover of administering pain-relievingmedication. And he feels very stronglythat palliative care specialists should notbe expected to end lives – “If we had aduty to complywith patients’requests foreuthanasia, I think thatwouldbe the end

“Most patients who are requesting assisted

dying are not aware of what palliative care can do”

“A huge step towards a more compassionate law”. Last July, multiple sclerosis sufferer Debbie Purdywon a landmark ruling that effectively gives the green light for her husband to accompany her toSwitzerland to die. Though assisting a suicide remains a crime in England and Wales, punishable by upto 14 years in prison, the legal authorities have now been forced to spell out the circumstances underwhich those accompanying people like Debbie to clinics abroad will – or won’t – face prosecution

BENSTANSALL/AFP/GETTYIMAGES


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of palliative care” – and nor should theytake on the task voluntarily – “I cannot doeuthanasia for one patient and givemor-phine to relieve the pain of anotherpatient. I need a clear description ofmyjob, for both our sakes, but particularlyfor the patient.”

That said, he concedes that in thecase of the Netherlands, the quality ofpalliative care accessible to the averagepatients has jumped from a very lowlevel 15 years ago to a standard compa-rable to what is available today in theUK, where the palliative care and hos-pice movement started 50 years ago.Part of that, says Zylicz, is thanks topressure on the Dutch Minister ofHealth, who was criticised, at the timethe euthanasia bill was being debated,for failing to invest in the country’s pal-liative care services. Equally important,though, was the impetus the new lawgave for doctors to train up in palliativecare techniques. “Many GPs and con-sultants realised that if they do nothave the knowledge to deal with theseproblems they would maybe feel theyhad to comply with these requestswhen they did not want to. This processis still continuing; there is an enormousinterest in Holland in palliative careamong GPs.”

Eight years on, Zylicz believes thattheway euthanasia requests are handledin the Netherlands is now improving.“This was a problem in theNetherlandsfor a long time that doctors were doingthis without exploring alternatives.That’s dangerous. I think this process isnow reversing in theNetherlands. Doc-tors have more choices and patientshave more choices.”

A good result, surely. Yet questions

remain over whether greater choicewillalways be the outcome of introducingrights to assisted dying.AsMaterstvedtcomments, “If we look 10, 20, 30 yearsahead, there is this tsunami of old peo-ple who are going to need palliativecare, and the costs are going to be enor-mous. Do you have the money for allthat treatment as people live longer andget diseases like cancer? There is aneconomic issue.”

Thedanger that legalisationofassisteddying couldbe seenas a cheaper alterna-tive to developing palliative care servicesis amajor concern, particularly for pallia-tive care organisations, which are stillfighting to become part of mainstreammedical practice inmuch of Europe.

But some believe these fears aremisplaced – includingGeorg Bosshard,a GP and medical ethicist who wasinvolved in the medico-legal investiga-tion of early assisted suicide cases inSwitzerland, and has been following theissue closely ever since. “There is no evi-dence that, once you have open legisla-tion on assisted suicide, palliative carewill have less support than before. Ithink the truth is the opposite. If youlook at places like theNetherlands, Bel-gium, Oregon, you see that discussionon assisted suicide has always forceddiscussion on palliative care. I cannotsee an opposition of these two worlds.The goals are different.”

This is a view strongly shared byFrancoCavalli, medical oncologist anddirector of the Southern SwitzerlandInstitute ofOncology (IOSI) in Lugano,who is currently trying tomake it easierto help the small minority of hospi-talised cancer patients who want assis-tance in dying.

PATIENT CHOICEWith very few exceptions, hospitals andnursing homes in Switzerland do notpermit assisted dying to be carried outon the premises, and most people, ofcourse, want to end their lives at home.However, there are occasions when forvarious reasons this is not feasible.While IOSI has long provided palliativecare as an integrated part of individualcare plans, Cavalli believes that beingable to offer assistance in dying givespatients an added option and is part andparcel of patient choice.While he sym-pathises with the battle palliative carespecialists are still having to establishthemselves in many parts of Switzer-land, and agrees that lack of access topalliative care is still a significant prob-lem, blaming this on the legal avail-ability of assisted dying, he says, issimply incorrect. As he points out,countries with the strongest oppositionto assisted dying are often also themostrestrictive when it comes to givingpatients in acute pain access to opioidmedication – still a major issue in partsof Europe.

“To be able to help someone at theend to die increases the autonomy ofthe patient, and if you try to do this youalso will try to give them the best pal-liative care you can offer. And patientsin general are very much in favour ofmore palliative care. So you cannot saythat at the end you can decide moreabout your death but not about whichtype of palliative care you are going toget. I am personally convinced that,even if we were to becomemore liberalin assisted suicide and euthanasia, thatwould not impact negatively on pallia-tive care. It would even impact posi-

“Every country must find a way

that fits its culture and institutions”

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tively in the sense that it is recognisingthe autonomy of the patient and thatthe patient can decide.”

There is, however, a caveat here.“Switzerland is Switzerland, theNether-lands is the Netherlands and the UK isthe UK,” as Bosshard puts it. “Everycountrymust find away that fits its cul-ture and institutions, and there is nogold standard on how to approach thisissue.”TheNetherlands andSwitzerlandare two of the most liberal states inEurope, with populations that getinvolved in civic issues. The right toeuthanasia or assisted dying only cameabout after decades of debate andpublic pressure, andwas part and parcelof a concerted move away from a tradi-tional culture of healthcare based onpaternalism to one that put patientsmuchmore in the driving seat.

It’s a moot point whether the samecould be said about Belgium and Lux-embourg, both of which introducedeuthanasia provisions very similar to theDutch system shortly after it was intro-duced in the Netherlands, promptingcriticism from some quarters that therehad been insufficient public debatewithin their own countries.

Certainly lively discussions havebeen underway for many years incountries like Scotland, where anassisted dying bill is currently beingdebated in Parliament, France, wherea similar bill is being sponsored by theSocialist Party, and England, whichhas reached an uncomfortable com-promise on the rights of friends andfamily accompanying someone toSwitzerland to die. Even in Germany,where awareness of past crimes hasmade any talk of assisted dying com-plete taboo within the medical estab-lishment, public debate is growing,and there are calls to open up debateon this issue within the German gen-eral medical council.

The real concerns are, perhaps,

about countries where palliative careservices are rudimentary and the con-cept of patient autonomy is not welldeveloped. “People tend to ask whatwould happen if euthanasia wereallowed in Italy or Greece or Spain,”says Cavalli, “but that is a theoreticalquestion, as there is no immediateprospect of these countries becomingvery liberal as regards euthanasiabecause of ideological reasons.”

The same does not apply tomany ofthe former eastern bloc states, wherehealthcare retains much of the pater-nalistic culture of former communistdays, adds Cavalli. “I’m afraid that, inthe current situation of financial crisisand very poor healthcare systems, if youdo not really specify in the law thatassisted suicide and euthanasia is pos-

sible only with the absolute consent ofthe patient and you have measures toenforce that, youmight even have somekind of ‘social euthanasia’, because doc-tors in geriatric homeswill say these arepeople of no value any longer and arejust a burden to society.”

This does not mean, says Cavalli,that debate on the issue should beavoided or suppressed. “I think publicdebate can only improve the situation.Because you cannot talk about auton-omy of the patient for the last hour oftheir life and not talk about the rest oftheir life. If you start to recognise theautonomy of the patient and the rightof the patient to decide, not the doctoror the state or the Pope, in the endyour whole approach to the patientwill change.”

Views from the frontlinePrimary care physicians in theNetherlands havemixed feelings about their role per-forming euthanasia according to a study byHarm vanMarwijk and colleagues pub-lished in the journal Palliative Care (2007, 21:609). No study has yet been done toinvestigate views on assisted dying among oncology professionals.� “I can say ‘no’now,withmyacquiredpalliative knowledge,without leaving patients

in the cold. Iwant to be skilled in palliative care and also able to performeuthana-sia well. I want to feel good about this.”

� “I now say clearly to everyone: I don’t perform euthanasia anymore. Tomy sur-prise a number of people say: ‘Doctor, you are so right, I understand completely.’Then I thought tomyself: howdeep do these requests really go? I found that dis-concerting to notice.”

� “I wish theywould no longer askme, but I’m scared to say so. Perhaps Iwill havethe courage to say so in a few years time. I feel very close to people, but I also feelangry: ‘what do you think you can ask of me?”

� “I found it [performing euthanasia] very hard and lonely the first time, but I feltI’d done a good thing.”

� “What has struckmemost is the commitment of the family [to the patient’s cir-cumstances], they all sympathized. I found that unique, and stood therewith tearsin my eyes.”

� “I need to care deeply for someone to be able to perform euthanasia. I have onlyperformed euthanasia for people for whom I cared and whom I knewwell.”

� “Wewere crazy to do it, looking back.Who am I to do this? Euthanasia was putonmyplate. It’s a rotten job…Iwish theywould no longer askme, but I’m scaredto say so.”

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