cancer world 40

� Klaus Meier: together we can offer the best of both worlds � The TV campaign thatis giving hope to Romania’s leukaemia patients � Managing risk: cancer control in theBRCA era�Compassion goes beyond empathy: the views of a pioneer in supportive care

Klaus Meier

Education & knowledge through people & facts

Number 40, January-February 2011

CancerWorld

40JAN

UARY-F

EBRUARY

2011

CANCER WORLD � JANUARY/FEBRUARY 2011 � 1

Contents

3 EditorialOur role in moulding the image of cancer

4 Cover StoryKlaus Meier: together we can offer the best of both worlds

15 e-Grand RoundManagement of metastatic pancreatic cancer: current strategiesand future directions

24 Cutting EdgePromoting genetic literacy: cancer control in the BRCA era

34 Best Cancer Reporter AwardDesperately seeking a bone marrow match: the media campaignthat made things happen in Romania

40 MasterpieceReal compassion is about moving things forward

48 Impact FactorGemcitabine alone or plus cisplatin for biliary tract cancer?Molecular selection for ‘smart’ study design in lung cancerNewsround

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantCorinne Hall

Editorial AdvisorsJacques BernierFatima CardosoFranco CavalliAlberto CostaVincent T. DeVita

Contributing WritersMarc Beishon, Barbara BurtnessSimon Crompton, Janet FrickerSusan Mayor, Peter McIntyreAmanda Psyrri, Werner ScheithauerAnna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonCorinne Hall

Art EditorJason Harris

ProductionHarrisDPIwww.harrisdpi.com

Printed byGrafiche Porpora

Cover photographTobias Hase

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 ©2011 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

Breaking the taboo on cancer andbringing discussion of the diseaseand the stories of cancer patients

into the public arena has to rank as one of thebig achievements clocked up since Nixondeclared a war on cancer in the early 1970s.Eleven years ago, the live broadcast ofAmer-ican TV presenter KatieCouric undergoing acolonoscopy showed how far society and themedia hadmoved, andwas a good example ofthe inventive use ofmedia to promote aware-ness about prevention and early detectionthat could help save lives. Stories tracking ourgrowing understanding of what cancer is andhowbest to treat it are gradually succeeding insupplanting traditional responses of panic andfear with amore rational approach that helpspatients play an active role in their treatment.Human stories about how cancer affects thelives of patients and their families havehelpedbreak the social isolation of those living withcancer and confront discrimination.

That’s the good news. The bad news isthat,with thebestwill in theworld, cancer canbe a difficult subject to cover well – the massmedia is not at its best when dealingwith sto-ries involvingmany uncertainties, and it oftenstruggles to get across complexpictures of riskand riskmanagement. So though thequantityof coverage has improved, especially with theproliferationofonline information, there is abigquestion about quality.A study by researchersatNorthCarolina StateUniversity has shownthat many online news stories about cancermay actually add to readers’ confusion.

A recent opinion piece in the New York

� Kathy Redmond � EDITOR

Times has highlighted another unsettlingtrend in theway breast cancer, in particular, isbeing ‘marketed’ by campaigns – be theyadvocacy groups or corporations doing their bitfor the cause.Messages are often dominatedby images of young women, with a highlysexualised focus on their breasts, and ‘sassy’upbeat messages that may be designed topromote self-examination, but fail to get a seri-ousmessage across to the right people. Some-where along the line, the reality of breastcancer, which affects primarily olderwomen,and presents real challenges in terms of bodyimage, not tomention the possibility of dyingof the disease, has got lost.

In fact, far fromhelping, these campaignsare probably undermining the cause theyclaim to support.

It is impossible to control the way thatcancer is presented to the public; however, itis possible to challenge irresponsible cam-paigning and journalism, and to promotecritical and helpful media coverage. Oneway ESO has sought to do this is throughour Best Cancer Reporter Award, whichhas now added a new prize, specifically forcampaigning journalism,which this year wasawarded to a Romanian television journalistfor a campaign to set up a stem cell donorregistry (see Desperately seeking a bonemarrowmatch, p34).

You too canplay a role bynominating jour-nalists for the2011Award.Further informationabout theAward and nomination process canbe found by clicking on the media tab atwww.cancerworld.org.

Our role in mouldingthe image of cancer

CoverStory

4 � CANCER WORLD � JANUARY/FEBRUARY 2011

Klaus Meier:together we can offer

the best of both worlds� Marc Beishon

Patientsneeddoctorswhoknoweverythingabout themandtheirdisease,symptomsandcomorbidities.

But doctors cannot also know everything about every drug their patient may need, nor can they

provide regular support and advice to help patients get themost fromoral cancer therapies.A strong

partnershipwithpharmacists is the answer, says the founder ofEurope’s oncologypharmacy society.

Whenwe lookat the idealmultidis-ciplinary team working withpatients throughout their cancerjourney we tend to focus on thefront-linehealthcareprofessionals

–oncologyphysiciansofcourse,pluspathologists, radi-ologists, nurses, psychologists and others vital to pro-viding thebest care. Some, suchas cancernurses, arestill having tobattle tohave the importanceof their rolerecognised, and to gain acceptance as part of thewider team. But there is another major group of pro-fessionals that hashad to fight hard for recognitionoftheir contribution, andwhichsimplydoesnotenter theminds ofmany people. That group is pharmacists.

AsKlausMeier, president of theEuropeanSoci-etyofOncologyPharmacy (ESOP), says, therearebiggains tobemadeby integratingpharmacists into thepatient journey, bybringing their knowledgeof drugsanddrug interactionsdirectly to bear at thebedside,and also forming close relationships with patientswhen they leavehospital, oftenwithprescriptions for

drug regimens that need to be closely adhered to.With the cancer burden expanding across an agingpopulation andmore treatments coming on stream,demand for oncology pharmacy services is expectedto at least double over the next ten years and Meieris keen to outline the very specific perspective theycan bring to the care of cancer patients.

“Pharmacists are primarily scientists and webring evidenceofwhatwill happen in themajority ofcases,whereas doctors aremore interested in learn-ing about each patient from direct experience andespecially about thosewhodon’t respond in a typicalway,” says Meier. “When we work closely togetherwith physicians we get the best of both worlds, oftheory and practical points of view.

“That’s why I’ve tried to replace the term ‘mul-tidisciplinary’ with ‘multiprofessional’ in cancer, toreflect the true coming together of professionsrather than mostly physicians who are in the samediscipline, i.e. medicine.”

This is amessage thatMeier took to theEuropean

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CanCerOrganisation (ECCO)whenhewaselectedas a board member in 2008, a ‘landmark’ event foroncologypharmacists, hebelieves, thatwas achievedrelatively quickly – eight years from the date he andcolleagues set upESOP.

Akeystep forESOPcame in2005when itbecomean umbrella organisation for national oncology phar-macy societies, instead of just a group of individualmembers. “Now our membership has shot up fromaround 300 to about 2200 in 32 countries aroundEurope, and itmay surprise people to see such a largenumber–ESMO[Europe’smedical oncology society]has only about 4000members, sowe represent a sub-stantial number of theEuropeancancer community.”

Given that oncology pharmacy is a relativelyyoung discipline, this presence atECCO level is tes-timony to pioneering work carried out by membersat national level and championed byMeier and col-leagues, withMeier himself playing a leading role inhis homecountry,Germany,where his ‘day job’ is cur-

rently head of clinical pharmacy at a hospital inSoltau, a town in a rural area some 50 km south ofHamburg.

Thereare tensof thousandsofpharmacists aroundEurope, of course, working in hospitals and in com-munity settings suchas independentpharmacies andlargechain stores.But since theexplosion incytotoxicand supportive drugs for cancer, and now the devel-opment of many new agents, including increasingnumbers that can be taken orally, the oncology phar-macy specialism has developed to the point wherequalifications are available in some countries.Along-side are various research programmes that are inves-tigating everything from the economic validations ofdrug costs, to patient information and counselling.

Somepharmacists, suchas those at Stockholm’sKarolinskahospital, also play a leading role in study-ing cytotoxic drugs,workingwith clinicians.Clinicalresearchpriorities for oncology pharmacists includethe stability andcompatibility of drug combinations,

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pharmacokinetics/dynamics in drug dosing, evalua-tion of dose banding, andmedical errors.

Although Meier has himself been a pioneer inoncologypharmacy, notably in settingupcentralisedfacilities for cytotoxic drug delivery, he views hisachievements as not so much scientific but organi-sational, especially in later years with the formationofnotonlyESOP,butalso theDeutscheGesellschaftfür Onkologische Pharmazie (DGOP, the GermanOncology Pharmacy Society) in 1995, the Interna-tional Society of Oncology Pharmacy Practitioners,ISOPP, in 1995, and a growing number of publica-tions,meetings andmasterclasses that are spreadinggood practice and gaining more support for thespeciality.

“I am particularly proud of the book that theGermansocietyproduces forESOP,QuapoS [Qual-ity Standard for the Oncology Pharmacy Service],

which is now in its fourth edition,” saysMeier. “It isthe result of a series of conferences in Luxembourgwe started in 2001 on the standardisation of oncol-ogy pharmacy, and of various workshops. Althoughthe printed book is in English, and despite a lack offunds, we have also made it available on CD and atwww.esop.eu in 22 languages, includingArabic.”

Surprisingly perhaps, given pharmacists’ con-nectionwithdrugs,ESOP is fiercely independent ofindustry, though it has beenwilling to collaborate onspecific projects, including a recent survey done inpartnershipwithNovartis that lookedat the role thatEuropean oncology pharmacists play in dispensingtreatment anddisseminating advice to patientswithchronicmyeloid leukaemia. “If it is a truepartnershipwith industry then that’s OK,” says Meier, “but wedon’twant to sell our souls andour knowledge.”Thispreference to eschew industry sponsorship does,however, make the European and national goals ofESOPand itsmember societiesmore of a challengeto achieve, he admits.

This staunch independence has been a charac-teristic ofMeier throughout his career in pharmacy,where he has been at odds several times with clini-cal colleagues and with hospital management. Hesees winning the arguments as essential to promot-ing the effectiveness of oncology pharmacy, andindeed clinical pharmacy in general.

Meier was a relative latecomer to healthcare.Having startedoutwithamasters in theologyand theaim of becoming a teacher, he later switched topharmacy.Heworked for a spell in communityphar-macies – “I couldhave stayed there and runmyownshop,”hesays, “but Iwasn’tmotivatedby thebusinessside andwanted to support patientsmoredirectly, soI entered the hospital pharmacy system and gaineda postgraduate clinical qualification in 1989.”

That qualification canbe gained in three years inGermany – Meier himself has taught modules inHamburg for some time – and since 2001, clinicalpharmacists can obtain a further qualification inoncology pharmacy, which takes two years. “That’sbeen a success as we now have 300 qualified

“If it is a true partnership with industry then that’s OK,

but we don’t want to sell our souls and our knowledge”

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role of a central pharmacy. ISOPP, theinternational society, finally also issuedguidelines in 2007.

But Meier believes there isstill a long way to gobefore uniformly highstandards of safe prepa-ration are achieved acrossEuropean pharmacies –including eliminating as faras possible exposure to toxiccompounds and medicationerrors, and ensuring infusionsdo not become unstable, whichcanhappen if they aremadeup toofar in advance.

AsaGermancolleague,TorstenHoppe-Tichyin Heidelberg, reports in a paper, ‘Current chal-lenges inEuropeanoncologypractice’(JOncolPharmPract16:9–18), althoughcytotoxic reconstitutionsareunder thecontrol ofpharmacydepartments, inmanyhospitals other types of aseptic reconstitutions forinfusions are still done at ward level, while a surveyof pharmacists conducted by ISOPP and othersshowed best practice was not always followed evenwhen respondentswere awareof a rule.Aspart of itswork raisingawareness about thedangersofhandlingtoxic treatments anddisseminatingknowledgeaboutsafe practices, ESOP has proposed a ‘yellow hand’warning label for handling cytotoxic drugswith care,andwhat to do in the event of an accident.

“Ofcourseweneedsafeconditions–wecouldn’tgo on preparing cytotoxic treatments as we did 20or more years ago, but there is much more thatoncology pharmacists can bring to cancer,” saysMeier. “We have also been able to show hospitalauthorities thatwe can play a pivotal role in improv-ing outcomes for patients, shortening hospital staysand reducing the drugs bill, among other benefits.”

After success inestablishing thecentral oncologypharmacy unit in Hamburg–Harburg in 1987,Meier worked on raising the profile of his andhis colleagues’ expertise within the hospital cancerteam.Ashenotes, oncepharmacistshavedispensingand preparation authority for cancer drugs theyshould also assume responsibility, in partnershipwith theoncologist, for ensuring theyare appropriatefor thepatient, andhe is a strongadvocateof theunitdose system. “This aims to deliver just the right

oncology pharmacists inGermany andwewere theEuropean leader,” he says. “The US has a board-certifiedoncologypharmacist qualification (BCOP),but I feel ours ismore rigorous asweaskpharmaciststo defendcases in front of a panel,whereas it is doneby multiple choice qustions inAmerica.”

TheUK,henotes, isworking on a similar formalaccreditation for oncology pharmacy through theBritish Oncology Pharmacy Association (BOPA),which is also one of Europe’s longest standing suchsocieties.TheUSBCOPprogramme is alsoavailabletopharmacists outsideAmerica–Spain, for example,has adopted it for its oncology pharmacists.

ESOPrunsmasterclasses andworkshops to stim-ulateactivity in smalleror lesswell-organisedcountries,particularly to encourage the take-upof postgraduateprogrammes. “We have also started a journal, theEuropean Journal of Oncology Pharmacy, whichincludes reports from aroundEurope,” he says.

It was while working at the Hamburg–Harburghospital in the 1980s thatMeier took himself out ofthepharmacy to observeworkingpractices of othersand found that cytotoxic chemotherapieswerebeingpreparedbynurseswith little attention to safehand-ling. “I also read a paper about a nurse who had lostherhair, andadvice thatpeople shouldnotworkwithcytotoxic drugs for longer than five years – I thoughtwhynot fouror six years?Looking further, I foundsev-eral articles fromtheUSwhere theyhad startedcen-tral units for preparing oncology drugs, and thoughtwe could do that inGermany.”

Objections to setting up a central service forcytotoxic and cytostatic drugs came not only fromdoctors,whowereconcerned thatpharmacistswouldbecrossing over into their territory for decisionmak-ing, but also from fellow pharmacists, who wereworriedabout takingon the responsibility, saysMeier.“But clearly from a safety perspective alone it hasbecomevital thatdrugs thatcanbe toxic tohealthcareworkers are prepared, transported and delivered assafely as possible, and the role of the pharmacyshould be paramount,” he adds.

The firstquality standardeditionpublishedby theGermansociety (DGOP) in1996 focusedmainly onconditionsneeded tocomplywith thedeliveryofcyto-toxic drugs, notes Meier, and by the next edition in2000DGOPhadstarted tocertifypharmacieson thebasis of the standard. Indeed, the current edition ofQuapoS still majors on drug preparation and the

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Safety first. ESOPis promoting a‘yellow hand’ labelfor cytotoxic drugs,to help ensureeveryone whohandles themis aware of thedangers and knowswhat to do in theevent of a spillage

quantity of drug to the right patient in a way thatminimises thework of nurses,who thenhave less toworry about when administering treatments.”

Meier was one of the early innovators of unitdose systems, which are nowwidespread in hospi-tal pharmacies for all types of drug, not just oncol-ogy, but are far from universal. By the time he hadmovedup to running a central pharmacy system forseveral hospitals inHamburg, he had a service runfrom four locations serving 6000 beds and, in can-cer, 40,000 treatments a year. “Wewere validating,for example, the three drugs in theFOLFOXcoloncancer regime in 20minutes andmaking deliveriesof the first infusion to the hospitals in half an hour.”That was a significant achievement because, as heexplains, preparing a personalised dose has becomemore complex than just calculating thebody surfacearea of a patient, while the logistics of managing alarge patient chemotherapy population is certainlyamajor challenge in itself, as each treatment is usu-

ally prepared on the day of administration andmeans that patient appointments need to be linkedas smoothly as possible with pharmacy resources.

Meier is not keen on the dose banding system,popular in countries such as theUK,which tries tocut costs and patient waiting times. Intravenouscytotoxic drugs are calculated on an individualisedbasis that are within defined ranges, or bands, andare roundedup or down to predetermined standarddoses, which are delivered to the patient usingsyringes or infusions pre-filled to that standarddose. “I’m against dose banding as it should bepossible to run a process that reflects each patient’ssituation,” he says, noting, however, that he’s heardfrom a colleague in Manchester, UK, that a phar-macy there has to cope with very different patientnumbers fromday to day –whichwouldmake unit(individually tailored) dosing very difficult.

A unit dose approach is important, says Meier,because not only is there a very narrow marginbetween adose that is too toxic andone that is insuf-ficiently effective for most chemotherapies, but inthe last decade or so many drug regimens havebecome more complex and much more is nowknown about drug interactionswith treatments forconditions such as diabetes and heart disease, aswell aswith a growing range of supportive therapies.

ForMeier, thedirection is clear –oncologyphar-macists must also be involved at the bedside toensure thatoverall ‘pharmaceutical care’is optimal foreachpatient.Pharmacists, he says,haveacrucial roleto play in monitoring actual doses of therapeuticdrugsbasedon feedback frombloodplasma readings– which is becoming increasingly used – and inmanaging the other drugs and nutrition of patients.They are also well placed to help with side-effectssuch as pain and fatigue, and to reduce patient anx-iety by explaining how their drug treatment willprogress andchange.Evidence for the importanceofpharmacists in reducing drug-related problems hasbeen reviewed by a team at the University of Bonn,which is also pursuing its own studies on breast and

“We can play a key role in improving patient outcomes,

shortening hospital stays and reducing the drugs bill”

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The first edition of the ESOP publicationQuality Standardfor the Oncology Pharmacy Service focused heavily on safehandling of cytotoxic drugs. The current (fourth) editionreflects the way the role of oncology pharmacists hasdeveloped, with a substantial section on supportivetherapy, including themanagement of nausea and vom-iting, pain management, mucositis and diarrhoea. Italso carries a section on nutritional advice and ther-

apy and unconventional methods of cancer therapy:“The pharmacist should respect the patient’s views regarding alternative

medicines and take his opinions seriously. However, it is also the pharmacist’sresponsibility to stress the importance and safety of evidence-basedmedicineand to inform the patient of the risks involvedwhen using alternativemedicines.”A ‘work in progress’ section on research and development shows the growinginvolvement of oncology pharmacists in research as well as practice.The full document can be downloaded from the ESOP site, www.esop.eu, and isalso available, as a download or on CD, in 22 languages.

SETTING THE STANDARDS

then told–but specificdrugsmaynotbeavailableandthis can take time to sort out. One step is for phar-macists to see patients on admission to review theirmedications, aswedo inmycurrenthospital, andwedraw up a profile of their drug needs and assesspossible interactions with chemotherapy andbiological agents,where itmaybebest to stop takingcertain drugs during the hospital stay.” Interactionswith other prescribedmedicines and themanypop-ular complementary substances areoftenoverlookedby oncologists, adds Meier (see also Cancer WorldJuly–August 2010 formore on interactions).

As patients move around the care system, thereis also a need for hospitals to network much morewithcommunitydoctors tohelp streamline the typesof drugs being taken, adds Meier. “A hospital phar-macist can find, for example, that apatientmaybeon

colorectal cancer, and patients receiving oralchemotherapy (Pharm World Sci 30:161–168).

This is not about treading on the toes ofmedicaloncologists,Meier adds. “They knowa lot about thespecificdrugs theyareusingbut theydonothave theknowledge of a thousand ormore drugs that a phar-macist has and the relationships between groups ofdrugs. If theydid they’dbepharmacists themselves.”Certainly though there is a need for more pharma-cology training for oncologists, as Jaap Verweij, amedical oncologist who studies drug mechanisms,told Cancer World recently (May–June 2010).

The contribution that pharmacists can makestarts early in the patient’s cancer journey, right atadmission to treatment. “In many cases a patientcomes into hospital and someone has to find outabout thedrugs they are taking, and thepharmacy is

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“Medical oncologists do not have the knowledge

of a thousand or more drugs that a pharmacist has”

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siders that giving some formof reimbursement for theeducation and support role of thepharmacist, and thepartnership with physicians, could more than pay foritselfwhenset against theproblemsoftenencounteredwithdrugs thatcancost thousandsofeurosayear–andthat in any case all oncology prescriptions should besigned off jointly by physician andpharmacist in con-sultationwith patients.

“It’s like a study I’ve seen from Liverpool in theUK,wherepatientswithdepressionhadcontinuoussupport from local pharmacists, and 80% were bet-ter after six months. In Germany, we have 80% notbetter in six months.” Expanding the role of com-munity pharmacists, he adds, can also cut thenum-berofpeoplebuyingdrugson the Internet, once theyrealise that cheaper is not always better when thevalue of support becomes apparent.

“We also have to support people who will nevercomplywithanoraldrug regimen,”hesays,noting toothat the many patients who receive conventionalchemotherapy in ambulatory care also need educa-tion and support for issues such as side-effects andhygiene at home. The DGOP, he adds, started anationwide campaign last year to raise awareness ofthe needs of cancer patients among communitypharmacists in Germany, including topics such assupportivecare for fatigueandothereffects, andedu-cational information that can be given to patients.

InitiativesbyESOPincludedrawingupstandardsand protocols in relation to administering prescrip-tions for oral anti-cancer drugs, for which simpleleaflets are being created for each drug giving infor-mation about the three most common interactionsand side-effects. Patients will also be urged to keepmedicationdiaries and to seekcounsellingandadvicefrompharmacists.

“Again,wearenot sayingweare takingworkawayfrom other professionals, particularly hospital andcommunitynurses,whodoplay acrucial part in sup-porting patients. But throughout our lives the onlyprofessionalswho are always close at hand are com-munity pharmacists andweare saying tonurses and

“How can we support people who may take oral

drugs for years or even for life?”

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twodifferent brand-namealphablockers prescribedby his cardiologist and urologist, and not knowhe istaking an overdose,” he says.

Meanwhile, the need to keep costs down isgiving rise to another increasingly important role forpharmacists – providing evidence on the cost-effectivenessof treatments,whenquestionsariseoverwhether to switch to oral anti-emetic drugs, forinstance, or not use certain antagonists for cases ofdelayed vomiting (one study from the US showed a$200,000 saving over one year in a hospital with thelatter approach). Oncology pharmacists are alsolikely tobe increasingly involved in theeconomicval-idation of cancer treatment drugs as the numberexpands and as healthcare systems demand bettercost–benefit analysis.

Meier has himself published on superior out-comes from integratingoncologypharmacy incancercare, noting that not only canhospital stays be short-ened thanks to better drug management and rela-tionshipswithpatients, but “drugcosts canbecutbyup to 20%, with only a small increase of pharmacypersonnel costs of around 3%–5%.”

Particularly challenging, adds Meier, is how tohandle the growth in oral cancer drugs that will betakenmostly in thecommunity. “Howcanwesupportpeoplewhomay take oral drugs for years or even forlife?Yes, doctorsmaybe takinga regularbloodcount,butwhat if thepatient is not taking thedrugproperlyin the weeks between tests? Managing drug adher-ence can really only be done by someone who givesdrugs to patients and can talk to them more oftenabout how they feel, and canmake a call to the doc-tor if necessary. Community pharmacists are theobviouspartners, but as yet inGermany they arenotinvolvedmuch in oncology.”

Other countries, theUK in particular, havemadestrides recently in expanding the role of communitypharmacistswithprogrammessuchas fluvaccinations,health checks and prescribing of some drugs such asthose forerectiledysfunction. In thecomplex insurancesystem in Germany and other countries, Meier con-


weshouldpush formoremultiprofessionalworking,such as joining tumour boardmeetings.”

More disappointing for himhas been the inter-national society, ISOPP, which he founded inHamburg in 1996. “It has far fewermembers thanESOP and hasn’t developed country involvementas well as we have in Europe. I would like to pushthem to bemore active, and I’d like to see thempaycloser attention to the needs of all their membersrather than, for instance, promoting particulardevices at meetings that could cost more than thedrugs themselves.”

Personally, hehas relatively little time to influencesuchmatters nowashe’s four years fromretirement,but with ‘heavyweight’ ESOP colleagues such asvice-presidentAlainAstier inParis and secretaryPerHartvigHonoré inCopenhagenonboard–both sen-ior professors– there’s little fear ofmomentumbeinglost. It’s hard to see him taking a back seat when somuchhe’s started is in train, though,buthiswife andtwo daughtersmay have a say in this.

Acluecomes inacomment aboutESOP’smem-bership – “I’m not satisfied that we only have 2200members” – could he have an eye on overtakingESMO’s 4000?

others that you can count on our speciality in drugeducation and delivery.”

Clinical research is another areawhere oncologypharmacists are important, and Meier says that inGermany their contribution toensuring trials arewellconducted is recognisedby industry. “Althoughwe’renot involved so much in early-phase trials wherepharmacological action is critical, the involvementofpharmacists inphase IIIwork,wherewemanagedoc-umentation andprotocols, has beenabig success aswe help get better quality results. Doctors alone domakemanymistakes in trials.”However, pharmacistsrarely get amention for their role, he adds.

Hewas busy expanding the pharmacy system inHamburg’shospitalsuntil aprivatecompany tookoverand made big changes. “There are problems stillwhen hospital managements see the pharmacy asonly a cheap logistics operation for ordering anddeliveringdrugs, and that’s still the situation inmanyplaces, despite the evidencewe are building up,” hesays. “In Hamburg they called into question ourneed to be close to the bedside.”

Now running a pharmacy for two hospitals and550beds inSoltau, anyone looking for amodel couldusefully track Meier for a few days, observing wardrounds to talk to patients, the way prescriptions forchemotherapy are reviewed and indeed the use of asoftware package that Meier himself developed 20years agocalledCypro,whichhis pharmacists use tocheck the protocol of prescriptions and validate andprepare them(theprogramme isnowavailable com-mercially at www.cypro.eu).

He is certainly pleased that so much work donebyDGOPhasmade itswayonto theEuropean stage.“ESOP now has a board of 14 people from aroundEurope, a growing number of work programmes,our owncongressplanned forBudapest in2012, ourjournal, and targetedworkshops,”he says.Among thepriorities are researching theeffects of chemotherapyon health workers and developing collaborationwithin ECCO. “Now we’re on the ECCO board,whenourmembers run intoconflictswithphysicianswe can tell them that we’re all on the same side and

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“We should push for more multiprofessional

working, such as joining tumour board meetings”

Established in Prague in the year 2000, the Euro-pean Society of Oncology Pharmacy now has2200 members in 32 European countries andcurrently has a seat on the board of ECCO.Its raison d’être is summed up in the Ljubljanadeclaration of 2006:

“The close cooperation between oncology physicians andoncology pharmacists is vital for optimal patient care.The multidisciplinary approach will deliver best practiceto patients within a clinical governance framework.Professional, close and timely collaboration will inparticular ensure economic use of resources andimproved patient safety.”

For further information visit the ESOP website at www.esop.eu

e-GrandRound


Management of metastaticpancreatic cancer:current strategies and future directions

Despite recent progress with combination regimens, pancreatic cancer remains one of theworst

cancer diagnoses.MalcolmMoore reviews the currentmanagement of this disease and considers

where progressmay bemade. Better biological understanding leading tomore tailored treatments

is essential, he argues, which means more phase I/II trials, and greater use of tissue sampling.

Pancreatic cancer is a significantcause of morbidity and mortal-ity throughout the world. In

Ontario, Canada, where I live andwork, there are 1200 new cases anddeaths each year in a population ofabout 12 million people. It is thefourth leading cause of cancer deathin Canada, and is similarly an impor-tant cause of cancer deaths in manyplaces around the world.One of the challenges of treating

pancreatic cancer, particularly in theuse of aggressive chemotherapy, isthe age distribution of those affected.As with many cancers, it has a highprevalence in the elderly. The averageage of development of pancreaticcancer is over 70. Factoring the agedistribution with the fact that thedisease causes significant morbidity,we are dealing with a relatively frailpatient population.About 60% of patients with pan-

creatic cancer have metastatic diseaseat the time of diagnosis. The mediansurvival in these patients is aroundsix months. Approximately 25% ofpatients are diagnosed with disease

TheEuropeanSchool of Oncology presentsweekly e-grandrounds which offer partici-pants the opportunity to discuss a range ofcutting-edge issues with leading Europeanexperts in the field, from controversialareas and the latest scientific develop-ments to challenging clinical cases. One ofthese is selected for publication in eachissue of Cancer World.In this issue, Malcolm Moore, from thePrincess Margaret Hospital, Toronto,Canada, reviews the management ofmetastatic pancreatic cancer, with refer-ence to its epidemiology and biology. Heconsiders the lessons learned so far andlooksat thepotential for targeted therapiesand futuredirections for research. Jean-LucVan Laethem, of the Erasme UniversityHospital, Brussels, Belgium, poses ques-

tions sent in by participants during thelive webcast. The presentation is sum-marised by Susan Mayor.

The recorded version of this and other e-grandrounds is available at www.e-eso.net

that is localised but notresectable; we categorise theseas locally advanced disease.Only about 15% of patientshave resectable cancer. How-ever, even where the cancersare resectable, median survivalis still quite poor, at around 18months, which is shorter thanthat of patients with metastaticcolorectal cancer.Putting all this together,

98% of patients diagnosed withpancreatic cancer will die fromit within five years. To improveon this, we need better sys-temic therapy. Screening strate-gies are currently in very earlystages and it is unlikely theywill have a big impact withinthe next 10 years. We havetherefore focused a lot of efforton effective systemic therapies.

NEW DRUG TARGETS FORPANCREATIC CANCERPancreatic cancer is not like chronicmyeloid leukaemia (CML) or gas-trointestinal stromal tumour (GIST),where a single molecular abnormalitydrives most cases. It is a very compli-cated cancer genetically, with severalgenetic abnormalities. K-RAS isoften considered the ‘signature’mutation in pancreatic cancer,occurring in 75%–90% of cases,but there are abnormalities inmany other pathways, includingHedgehog, aurora kinase,SMAD4 and p16. All of thisfactors into a rather compli-cated malignancy.A very interesting study in

which xenografts were createdfrom 24 resected pancreaticcancers and the genome wassequenced showed the averagenumber of genetic mutationswas 63 (Science 321:1801–

1806). These were clustered into 12core signalling pathways, but therewas marked heterogeneity in the path-ways affected, with each individualshowing a different profile of geneticchanges – including deletions, ampli-fications and mutations – in these keypathways.


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This heterogeneity suggeststhat if we are going to solvepancreatic cancer in the dis-tant future, we are going to belooking at combination therapyand ‘personalised’ therapy basedon individual profiles of thesegenetic changes.

TRIALS AND TRIBULATIONSOF CHEMOTHERAPYA study that I was involved inmore than 10 years ago, inwhich gemcitabine was com-pared with 5-FU in metastaticpancreatic cancer, showedthat, although all patients diedof disease, those treated withgemcitabine had significantlybetter survival.This study led to the

approval of gemcitabine, thefirst drug approved for thetreatment of pancreatic cancer.

It was a relatively small study by cur-rent standards, with only 126 patients.Despite that, the results were clear,with a one-year survival of 18% withgemcitabine versus 2% with 5-FU,despite the fact that there wascrossover.Overall, the results demonstratethat gemcitabine has value inthe treatment of pancreaticcancer. More patients treatedwith gemcitabine had stabledisease and some improve-ments in quality of life and per-formance status. This was notgenerally associated withtumour response, which hasbeen one of the traditional end-points for drug trials.Gemcitabine is now seen

as a foundation for the mod-ern treatment of pancreaticcancer. However, this studyshould not be interpreted assuggesting that 5-FU has no

MORTALITY FROM PANCREATIC CANCER

Age-standardised rates for 2002 in selected countriesSource: IARC. GLOBOCAN 2002. Cancer Incidence, Mortality

and Prevalence Worldwide (2002 estimates)

KEY MOLECULAR ABNORMALITIES

Question: Looking atthe phase III studies,would you recommend acombination of gem-citabine plus a second-ary cytotoxic agent, e.g.nab-paclitaxel, as analternative to gem-citabine alone for treat-ment of pancreaticcancer in patients withgood performance status?Answer: That’s an excel-lent question. Our prac-tice over the last fewyears has been to usegemcitabine + cisplatinas an option for patientswith good performancestatus (PS) who areinterested in a moreaggressive approach to

treatment of their cancer, if we felt theycould tolerate it. We have a community-based practice within a single healthcaresystem in Canada, so we see all of thepatients in our centre. I would say thatit is the minority of patients who couldtolerate these more aggressive regimens.Anecdotally, we have hadsome patients who hadgood responses andseemed to do better.

However, a gem-citabine + cisplatin studypresented at ASCO in2009 (Colucci et al,Abstract 4504 ) was alittle disappointing. Notonly did it fail to show abenefit, but there was noevidence of improvementeven in the PS0-1 (goodperformance) popula-tion. This forces one torethink whether the ideaof giving more aggressivetherapy to good PSpatients is appropriate.

activity. The dose and schedule of5-FU used was probably not optimal,and it may well be that other doseshave some value.A number of relatively large phase

III studies of gemcitabine with a sec-ond cytotoxic agent have been con-ducted in the subsequent 10 years.These include experimental drugs suchas exatecan, and drugs approved forother conditions such as irinotecan,pemetrexed, capecitabine and oxali-platin. While in some cases the phaseII data showed promise, there was noimprovement in survival when a sec-ondary cytotoxic agent was added togemcitabine.These findings led to general pes-

simism about the possibility of achiev-ing much of an improvement fromcombining multiple chemotherapyagents in the treatment of pancreaticcancer. However, analyses of thesestudies have suggested that patientswith good performance status mayobtain some benefit from combinationchemotherapy.

Question: In your experience, are gem-citabine combinations well tolerated bypancreatic cancer patients?Answer: We have a lot of experiencewith this combination, mainly becausewe were involved in a gemcitabine studyin treatment of biliary tract cancer,which is fairly common in our area. Ithink tolerability really depends on thedose and schedule of gemcitabine. Wefound a lower dose, such as the Swissregimen, was very well tolerated.With ahigher dose, patients run into difficultyafter three or four months.

After the gemcitabine + cisplatin studypresented at ASCO in 2009 showeddisappointing results, many peoplebecame convinced that combination oraggressive chemotherapy probably hadlittle role in pancreatic cancer. How-ever, there are some data that suggestthe opposite. The first is a study withgemcitabine + nab-paclitaxel (an albu-min-bound paclitaxel). Paclitaxel, asfar as we know, has very little efficacyagainst pancreatic cancer. However,the efficacy results in a phase II studyconducted by Dan Von Hoff and

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NUMBER OF GENETIC CHANGESIN 24 PANCREATIC CANCERS

The individual biology of pancreatic cancer is very variedSource: S Jones et al. (2008) Science 321:1801–1806, republished with

permission fromAAAS

SURVIVAL IN RANDOMISED PHASE III TRIALS

Attempts to improve outcomes from gemcitabine (Gem) by adding asecond chemotherapy agent have not proved fruitful (figures indicatemedian overall survival, in months)

colleagues look quite encouraging(ASCO 2009, Abstract 4525). Themedian survival was nine months,compared to typically six months inmetastatic disease. The response ratewas 26% (2% complete response plus24% partial response), as opposed to atypical response of 10% with gem-citabine. These are by nomeans defin-itive data, and it may be that thesewere highly selected patients. It iscertainly an interesting enough resultto warrant further studies, and a phaseIII study sponsored by Abraxis is cur-rently ongoing.The next study of interest was pre-

sented atASCO three years ago by theCONKO group. It looked at theeffects of a combination of oxaliplatin,5-FU and leucovorin compared to5-FU plus leucovorin in patients whohad failed on gemcitabine, so this wasa second-line population. The overallsurvival in the oxaliplatin–5-FU armwas 26 weeks, compared to 13 weeksin the 5-FU–leucovorin arm (Pelzer,ASCO 2008 Abstract 4508). Thisgives a significant improvement ofthree months. The study has not yetbeen published, but suggests that anoxaliplatin plus gemcitabine combi-nation was not a wise choice, andcombining oxaliplatin with 5-FUmaybe better.A further study presented at

ASCO (Reiss et al., ASCO 2009,Abstract 4006), randomised patientswith advanced pancreatic cancer tosystemic therapy with or without low-molecular-weight heparin. From ourown experience, 25% of patientsdevelop thromboembolic complica-tions when they have pancreaticcancer, and many of those can becatastrophic. This study showed asignificant reduction in seriousthromboembolic events, but noimprovement in overall survival. Hav-ing said that, the standard procedure

with these patients is to use heparin,because survival tends to be short ifpatients have a thromboembolic prob-lem. I think that this is something toreview in the routine management ofmetastatic pancreatic cancer.

IS FOLFIRINOX THE NEWSTANDARD OF CARE?This question comes out of theACCORD11/0402 trial reported atASCO 2010. The study has a fairlysimple design and compares phase IIIfolfirinox, which is 5-FU, leucovorin,irinotecan and oxaliplatin, with stan-dard gemcitabine as first-line treat-ment for metastatic pancreatic cancer(Conroy et al., ASCO 2010, Abstract4010).The group had previously studied

this regimen in a small group ofpatients (n=35) and had seen inter-esting activity in a good performancestatus population. On the basis of that,they opened a phase II/III study, andmy understanding is that their inten-tion was to go to phase III only if theysaw a strong signal. They saw a 32%response rate to folfirinox and an 11%response to gemcitabine. Based on

this, they continued to accrue patientsinto the study and expanded it as alarger phase III study. The patientswho did well initially were includedin the final analysis.The regimen used was the folfox or

folfiri regimen with the additional drugadded in at full dose (folfox with full-dose irinotecan). This is an intensiveand complex regimen, although we usefolfox and folfiri very commonly in colo-rectal cancer and are very comfortablewith these combinations.As would be expected, the patients

included were a selective population.They were young, with an average ageof 61.All were of performance status 0or 1 (almost 4% PS0 and 60% PS1),which is not the typical population forpancreatic cancer. It is important tonote that the study included only goodperformance status patients, who couldtolerate an intensive regimen.The other unusual factor about

the study population was that fewerthan 40% of the tumours were in thepancreatic head, which is also nottypical, as 60%–70% of cases are typ-ically in the head. This occurredbecause the intention was to include


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FOLFIRINOX VERSUS GEMCITABINE

Folfirinox (as a second-linetreatment) showed a clearsurvival advantage overgemcitabine, but the toxicity ofthe combination regimenmeans it may not be suitablefor all patientsSource: T Conroy et al. (2010)

JCO 28:15s (abstract 4010),

Published with permission

TARGETED THERAPYEven with the recent folfirinox datashowing improved survival, we arenot going to do any better than thatwith more intensive chemotherapy.If we wish to improve survival beyondone year, we need to bring in targetedtherapy.Unfortunately, many of the studies

so far have not been encouraging,including a study of putative RASinhibitors with tipifarnib, a trial of gem-citabine versus the matrix metallo-proteinase inhibitors marimastat andtanomastat, and a trial of EGFR anti-bodies with cetuximab.The use of angiogenesis inhibitors

has also been very disappointing inpancreatic cancer, with at least fournegative phase III studies with differ-ent antivascular therapies includingbevacizumab, axitinib and aflibercept.Sorafenib also has no efficacy. Thismay come back to the biology, as pan-creatic cancer is not a vascular tumour,and I think there is no interest in tak-ing these drugs any further in pancre-atic cancer.A study we did at the Canadian

National Cancer Institute (NCIC)with erlotinib (an oral EGFR inhibitor)gave positive results (JCO 25:1960–1966), and this has now been approvedfor advanced metastatic pancreaticcancer. However, I think we still havesome work to do on the molecularselection of appropriate patients.This study had a simple design,

randomising patients to gemcitabineplus erlotinib or placebo with no priorchemotherapy. The survival curve (seep 20) looks quite different from that forfolfirinox. The median survival for thetwo groups was very similar becausethe curves come together at the end ofthe study. However, the overall hazardratio was 0.81, which means a 23%improvement in average survival. Theone-year survival increased from 17%

patients who had normal bilirubin,because of the drug regimen beingused. Patients who had stents and didnot achieve complete biliary drainagewere not eligible.In terms of adverse events, as

expected there were major differencesin the toxicity of the two arms. Neu-tropenia, febrile neutropenia, fatigue,diarrhoea and neuropathy all occurredmore frequently with folfirinox.Almost half (42.5%) of patients onfolfirinox also received G-CSF.Despite this difference in toxicity,the toxic death rate was low andfairly acceptable for this patientpopulation.The real crux of the study was a

clinically and statistically significantdifference in favour of folfirinox, witha partial response rate of 31% com-pared to 9.4% with gemcitabine, and adisease control rate of 70% versus 50%.Anecdotally, the data that were col-lected for gemcitabine were very typi-cal for a patient population treatedwith this drug.The median progression-free sur-

vival (PFS) values also favour folfiri-nox, with values of 6.4 versus 3.3months (and highly significant P-val-ues). Most importantly, the medianand one-year survival values favourfolfirinox: 11.1 versus 6.8 months formedian survival and 48% versus 21%for one-year survival. The survivalcurves of the two arms demonstrate aclear separation (see opposite). Wehaven’t seen this dramatic differencein survival with any other metastaticpancreatic study. Therefore, this isclearly an important result.The real question and challenge

for the community is: “Are there con-cerns about the trial methodology?” Avery credible cooperative group con-ducted the study, and it is multicentredand randomised. There may be someconcern about the fact that the patients

on folfirinox generally got gemcitabinesecond line, while the patients on gem-citabine did not get folfirinox secondline. Therefore, there is an imbalance.But while these are genuine concerns,the trial is certainly not fundamentallyflawed.Given that we’ve had so many neg-

ative studies of chemotherapy (this isthe first one that is significantly posi-tive), many may ask if we need aconfirmatory trial to be sure it is appro-priate to put patients through this veryintensive regimen. There is no clearanswer, but it is something that peopleare discussing. I think the big chal-lenge that we will all face in our day-to-day clinical practice is that this is nota treatment for everyone. It will bedifficult to distinguish betweenpatients who are eligible for the moreaggressive approach and those moresuited to a palliative regimen such asgemcitabine.The other issue, as a result of the

data showing that oxaliplatin–5-FU isa successful regimen even in second-line patients, is whether it is really nec-essary to have all three drugs in thefirst-line regimen, and whether folfoxwith a second-line regimen would givethe same results. This is, as yet,unknown.At the end of the day, I think this is

indeed a new standard for selectivegood performance status patients.However, most of us have not reallyused folfirinox in this patient popula-tion, so we will need to gain experiencewith it before general use in practice.There have been discussions in NorthAmerica about whether we should doa phase II study of this with folfox,gemcitabine or nab-paclitaxel. Thiswould allow us to get a sense of howpatients improve and how this com-pares to other intensive regimens. Ithink this is going to be of great impor-tance in the future.

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with wild type K-RAS. Wild type K-RAS is not that common in pancreaticcancer, occurring in about 20% ofcases. The hazard ratio for that popu-lation is 0.66, which shows a significantbenefit with erlotinib. In the mutantpopulation this value is 1.07, suggest-ing equivalence. This is an interestingobservation, and further studies arebeing done to see if the benefit is con-fined to the wild type K-RAS popula-tion and is greater in this group.

WHERE DO WE GO FROM HERE?There are lots of interesting new targetsthat we can study in pancreatic cancer:Hedgehog pathway, Notch, heat shockprotein and a number of other sig-nalling pathways including AKT andMEK. There are drugs for most ofthese pathways, apart from K-RAS.I think that it is important thatwecon-

tinue to look long term and realise that itis only bybringing in these types of drugsthatwearegoing tomakeamajor impact.Thechallengeover thenext 10 years is to

efficiently study a lot of different drugsandcombinations todevelopbetter ther-apy. In my opinion, we do need to focusprimarily on the phase I and II arena.We also need tomake sure we have uni-formeligibility criteria.Trials shouldmoveon tophase III onlywhenweget a strongsignal – at least a two-month improve-ment in progression-free survival or sur-vival, or a greater than10% improvementin long-term disease control.The other thing that we have not

done sowell in the past – andneed to dobetter in future – is to incorporate biol-ogy into clinical research. It’s not so badhaving somany negative studies, but theissue is that we didn’t collect tissuesamples. If we had done this, wewouldknow not only that the drugs wereunhelpful, but also the reasons behindthis. Therefore, we should be collectingtissue in all studies as a standard routinesowe can try to understandwhat’s goingon at the biological level.The other thing we have to start to

think about is the heterogeneity of the


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to 24%with erlotinib in this unselectedpatient population.There are a couple of interesting

observations from this study. First,patients who developed a rash witherlotinib had a significantly better out-come than those who did not. Patientswho got a grade 2 rash had a mediansurvival of 10.5 months and a one-yearsurvival of 43%. Those results look verycomparable to what you see with anintensive regimen such as folfirinox.The challenge has been to find out thebiological significance of the data.Does it mean that everyone on thedrug should have the dose escalateduntil they develop a rash in order toachieve a similar outcome?We do notknow, and these studies are ongoing.However, the finding suggests thatthere is a population of patients withinthe overall group who do benefit.We decided to find out whether

there was a molecular method of iden-tifying these patients. EGFR inhibitorswork only in colorectal cancer patients

ERLOTINIB PLUS GEMCITABINE: OVERALL SURVIVAL

Adding the EGFR inhibitor erlotinib to standard therapy increased one-year survivalfrom 17% to 24%; this figure rose to 43% for patients exhibiting a grade 2 rashSource:MJ Moore et al. (2007) JCO 25:1960–1966. Published with permission

ALL PATIENTS ACCORDING TO RASH SEVERITY

disease. Patients with different geneticprofiles will need different approachesand we have to figure out how to incor-porate this into our clinical trials. Pan-creatic cancer is not a single-genedisease, and targeting single-gene path-ways with single drugs is not going to bethe way to make substantial progress.Therefore, we are going to have to workout how to screen multiple combina-tions of drugs in different patient pop-ulations. This is going to involve geneticprofiling at the start of therapy.

CONCLUSIONSIt is easy to be pessimistic aboutmetastatic pancreatic cancer, but wehave made significant progress in sys-temic therapy. Over the past 10–15years, one-year survival has improvedfrom 2% to 25%. The folfirinox datashow that good performance statuspatients can reach one-year survivalrates in the range of 40%–50%. Usingchemotherapy in the adjuvant settinghas also improved survival and long-term disease control.

It is clear that there is a spectrum ofpatients, and ‘one size does not fit all’ interms of treatment. Clinical judgementis important in choosing between thedifferent therapies.However, evenwithnew developments in treatment, pan-creatic cancer is still one of the worstcancers with which to be diagnosed.We have a long way to go and need tofind ways to look efficiently at all theinteresting new compounds at the sametime as developing the biological under-standing of this cancer.

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Jean-Luc Van Laethem, from Erasme University Hospital, Brussels, Belgium,hosted a question and answer session with Malcolm Moore.

Q:Gemcitabine remains a good standardfor the population, but we have to con-sider alternatives and possibly non-gem-citabine-based combinations, such as5-FU–platinum in second line. We alsoneed to find the best way to integratefolfirinox into our practice. One way todo that would be for future studies look-ing at gemcitabine as probably being atargeted therapy, with only about one-third of patients deriving real benefit.In the near future we may be able toselect these patients based on the expres-sion of gemcitabine nuclear transportersin tissue samples. This process is chal-lenging in pancreatic cancer, as it is verydifficult to get tumour samples. What isyour feeling about targeted therapy? Doyou think we should restrict erlotinib toonly 20% of patients and should we relyon the chemo-evaluation? Should wemake some effort to go further with thisevaluation?A: Drawing from data in the NCICstudy and my own experience, my opin-ion is that there is clearly a subset ofpatients that gets significant benefitfrom erlotinib – probably in the range of10%–20%. Scientifically, it is attrac-

tive that this would be the K-RAS wildtype group, because that fits with whatwe have learned in other diseases.However, I think the data that we gen-erated on this in the NCIC trial is lim-ited because we only collected tissue inabout half of patients. At least twoother confirmatory trials are looking atthis specific question.Anecdotally, I have a few patients in mypractice who are still on erlotinib and aredoing very well. We have tested themand they are all in the wild type group.Being able to identify patients whowould benefit from treatment would bemuch more economically efficient.Q:What do you think about the need toovercome the RAS resistance via alter-native pathways e.g. the MEK target?Do you think this process could be effec-tive or should we investigate other path-ways?A: We have never really had a properRAS inhibitor. I think the next bestsolution would be to look at down-stream pathways in RAS and targetthose, e.g. MEK andAKT. It is likely toinvolve more than one drug in order todo that effectively, because there is a lot

of interactionbetween thesepathways. Ifyou turn offthe pathway inone direction,there are otherways that the pathway can flow. There-fore, I think combination therapy isgoing to be the key to this problem.Q: Going back to systemic disease,should we consider adjuvant treatmenteven in resectable disease? The additionof folfirinox in this setting would be agood option to improve efficacy.A: I think that pancreatic cancer isclearly a systemic disease. Even amongpatients with resectable disease, almostall of themwill recur. In many ways, weare probably asking too much of radia-tion therapy and if we had better sys-temic therapies, it is likely that we couldhave a more dramatic impact than withlocal therapy. There is no question thatradiation can have an impact on a localtumour and prevent growth and pro-gression. However, this will only beimportant if the overall disease can becontrolled.

associated with familial adenomatouspolyposis, carriersarealmost100%certaintodevelopcolorectal cancer by the ageof40 unless they act to lower their risk.Other inherited syndromes, however,suchas thehereditarybreast ovariancan-cer syndrome linked toharmfulmutationsin theBRCA1 andBRCA2 genes, have alower penetrance, meaning that carriersare much more likely than the generalpopulation of women to develop breastandovarian (andother) cancers, yet theymay remain free of cancer all their lives.In the twenty years that have passed

since scientists in Berkeley, California,identified theBRCA genes, a number ofother germline mutations have been

� Anna Wagstaff

Thehereditary nature of somecan-cers has been known about formore thanacentury.Familial ade-

nomatous polyposis, which inevitablydevelops into colorectal cancer if leftuntreated, was first described in 1859with the first note of familial associationin 1882.The first recorded operation forpolyposis was performed by Lockhart-Mummery at St Mark’s Hospital inLondon in 1918. By 1927 a registry forfamilieswith this syndromeopenedat thesame hospital, effectively establishingthe first genetic cancer clinic, to keep awatch over those at high risk. By the1940s, management of the conditionmoved towards prevention, as surgeons

began to remove much of the affectedbowel before the onset of cancer.All cancers, by definition, involve

gene mutations, the discovery of whichhas kept cancer researchers busy fordecades, offering a stream of targets forthe development of personalised thera-pies. In thecaseof geneticpredisposition,however, the mutation is not just in thecancerous cells, but in the germline,meaning that it is carried in the DNAwhich forms part of a family’s gene pool,and is passed down the generations.Themutated genemaybe ‘high-pen-

etrance’, in which case carriers are verylikely todevelop theassociatedsyndrome.In the case of the mutated APC gene


CuttingEdge

As more is learned about inherited genetic mutations that

make cancers more likely, there is an acute need to give

those who live with the mutated genes clear information

and accurate advice. But are health professionals equipped to

look for signs of genetic predisposition, and do cancer services have

the skills and expertise to help people manage their cancer risk?

Promoting genetic literacy:cancer control in theBRCA era

CuttingEdge


ILLUSTRATION:FREDVANDEELEN,WWW.ORGANISART.CO.UK

IN BRIEF

� Accounting for around 5%–10% of all breast cancers, harmful mutations in BRCA1 orBRCA2 increase a woman’s chance of developing breast cancer over their lifetimeby approximately five times compared to the normal population.

� Carriers of the harmful BRCA1/2mutations are also approximately 10–30 times morelikely to develop ovarian cancer, with these mutations accounting for around 10% ofall ovarian cancers.

� There is nosingleBRCAmutation, but awide variety ofmutationson these twogenes,manyof which have yet to be recorded. Only some have been demonstrated to be harmful.

� BRCA mutations can also raise the risk of other cancers, including gastric, pancre-atic, colon and prostate cancer, as well as melanoma and male breast cancer.

� Other ‘cancer genes’ include mutated APC genes, responsible for familial adeno-matous polyposis, which lead to colon cancer, and mutatedMLH1, MSH2 MSH6, orPMS2 genes, which are associated with hereditary non-polyposis colon cancer(HNPCC), a syndrome that also raises the risk of endometrial (uterine), stomach, ovar-ian, small bowel (intestinal), urinary tract, liver, and bile duct cancers.

identified that raise the carrier’s risk ofdeveloping particular types of cancer(none as significantly as the BRCAmutations). The implications for theway society deals with cancer and pro-fessionals approach cancer control, areonly now beginning to become clear.

LEARNING TO LIVE WITH BRCAFranciscaBachKolling fromtheNether-landsdescribes herself as oneof the ‘firstgeneration’of identifiedcarriersof aharm-ful BRCA mutation. Diagnosed andtreated forbreast cancer in1990,aged41,it was not for several years that shebecame aware of media reports aboutthediscoveryof a ‘breastcancergene’.Her

later that the implications for their ownlives really dawned on the children.These are the ‘second generation’ –

asymptomatic children, nephews andnieces of the ‘first generation’ – who arenow growing up, forming relationships,starting families, in the knowledge thatthey may have inherited the gene muta-tion. This generation, says Francisca, isfacingdifficulties anddilemmasher gen-eration never had to. While supportingother people with hereditary breast can-cer, shehas learnedabout the friction thatcan build up between siblings when itturnsout that someare luckyandescapedthe gene mutation, while others are notand have a lifelong worry for themselvesand for any children.It is often when this ‘second genera-

tion’ are themselves at thepoint ofhavingchildren that the issueof testingcomes toa head. One young man who knew hemay have inherited a BRCA mutationtold Francisca that he and his partnerhaddecided tohave children “in thenor-mal way”, without being tested. “Theyhope that if thechildrenare girls,medicalresearchwill find someway toavoid themfacing those difficult options of today;that there may be a pill or something tostop you getting cancer.” An optimisticattitude, comments Francisca, who her-self tends to favour double mastectomyformaximumprotection, at least in lateryears – an option she says is very popularamong ‘hard-headed’Dutchwomen.

genetic cancer services. The first is thata hereditary predisposition to canceris something you live with for thewholeof your life. “You get the informationand the counselling to help you decidewhether you want surgery or not, butthey don’t then monitor how you aredoing with it. How are you coping? Doyou need support?”The second is that your own genetic

test result also has profound implicationsfor all your blood relations. This infor-mation could save lives, but could alsogenerate major stress and tension, bur-dening relatives with the knowledge ofrisk factors theywould have preferred tohave remained ignorant about. Fran-cisca feels the onus of deciding who totell what about the familyBRCAmuta-tion was left entirely on her shoulders,and she would have welcomed morehelp and advice from the genetics serv-ices, including practical ideas on how togo about this, advice aboutwhat kind ofreactions to expect, and the chance totalk afterwards about how it went.Her husband was immensely sup-

portive, and together they organised aspecial weekendwith the children, thenaged between 16 and 22, to tell themthe news. Their immediate response,says Francisca, was sympathy for her,but they also seemed quite relieved.“They had been expecting somethingworse – maybe that we were going toget divorced or something!” It was only


CuttingEdge

mother had been diagnosed with breastcancer at the age of 53, so shedecided toget herself tested, despite protestationsfrom herGP that there was no reason tosuspect a genetic predisposition. As itturned out, she did carry a variant of theBRCA1 genemutation–but hermotherdidnot. Itwasher fatherwhohadpassedon themutation–apossibility that is fre-quently overlooked.At her pre-test counselling she

learned that somemutations that raisethe familial risk of breast cancer alsomake ovarian cancer up to 60% morelikely. “That hit me hard. It was likebeing told I had cancer again.”Francisca weighed her options.

Already the mother of three children,she decided to have her ovariesremoved, which greatly reduced herrisk of ovarian cancer (for which thereis no effective surveillance) and some-what lowered her breast cancer risk.She underwent regular breastMRIs tomaximise the chance that any newbreast cancer would be picked up at avery early stage. This strategy paid off asnearly three years later she did developbreast cancer in the opposite breast.She opted for a full mastectomy, andnine years on seems to be in the clear.Francisca has no major complaints

about the quality of counselling shereceived, She does feel, however, thattwo important aspects of hereditarycancer continue to be overlooked by

Hereditary predisposition to cancer is something

you live with for the whole of your life

Young people who start new relationships struggle

with the dilemma: ‘When do I tell him/her?’

Another youngman tested positive, andtoldher of thedilemmahe faced in start-ing a family.Hewas thinking about tryingto get a preconception genetic diagnosis,which involves screening an embryo invitrobefore transferring it to themother’suterus (a procedure available only in afew countries, and only where familyhistory points to an exceptionally highrisk). But heworried aboutwhat itwouldmean for his wife. “I am the carrier, wedon’t want to pass on the genemutationto our children, but I have to ask mywife if she can take the burden, becauseit is quite a heavy procedure medically.”Francisca herself wonders what shewould have decided if she had knownwhat sheknowsnowwhenshewasaboutto start her family.The key, she says, is to find some sort

ofunderstandingandharmonywith thoseyou are living with. But relationships donot always last, in which case he or shemay again face the responsibility ofexplaining about the mutation to a newpartner, and trying to find way of livingwith that burden harmoniously. Fran-cisca says that all young people in thispositionwhostartnewrelationships strug-gle with the dilemma: ‘When do I tellhim/her about my genetic predisposi-tion?’ “We have to givemore attention tothis group,” she says, “because they aregrowing and they think about it quitedif-ferently to us.”Francisca is certainly trying to do her

bit to help, by working with the DutchBreast Cancer Organisation’s advocacygroup forhereditarybreast/ovariancancer,offering support and organising confer-ences. The group also campaigns to stopdiscrimination againstmutation carriers,for instance by life insurance companies– an issue where they have scored somesuccess. However, if you are a self-employed woman in the Netherlands,no-one will insure you against beingunable towork if you know you carry theBRCAmutation.

other genes,while other conditions suchas metabolic syndrome, which raisesandrogen levels, or even a family predis-position to obesity, can also raise therisk of cancer. A point Bonanni likes toemphasise is that the majority of thosewho are referred to hisHighRiskClinicbelong towhat he terms ‘the grey zone’–they have a clear family predisposition tocancer, but the culpable genemutation,or combination ofmutations, will prob-ably never be found.What it all adds up to, he concludes,

is thatwe are all on a spectrumof cancerrisk, influenced by a myriad of genes inthe family gene pool, interacting, ofcourse, with our own particular envi-ronmental and lifestyle risk factors.Understanding the risks, he argues,

opens up new possibilities for refocus-ing cancer control away from treatingestablished disease towards preventionand early detection. Six-monthly breastMRI scans from the age of 25make nomedical or economic sense in the gen-eral population, butmake perfect senseif you can identify women with ademonstrable risk of developing breastcancer at such an early age. The costand side-effects of chemopreventiveagents such as tamoxifen are only out-weighed by the advantageswhenused inwomen at high risk.For this refocusing of cancer services

to become reality, three things need tohappen, says Bonanni.

CuttingEdge


A NEW FIELD INCLINICAL ONCOLOGYWhile the personal and social impact ofgreater knowledge and awareness ofindividual risk has been profound, theimplications for cancer control and caremay be no less radical. BernardoBonanni, head of the division of cancerprevention and genetics at the Euro-pean Institute of Oncology (EIO) inMilan, talks in terms of “a small revolu-tion” that has opened a new field in clin-ical oncology.“We are increasingly looking at risk

assessment as the first thing to do.Wehave many more tools now, includinggenetics, to study the individual risk ofeach patient or cohort of subjects. Wehave risk managers, experts in cancerrisk, and we have to train new expertsin this field.”Hewould like to see cancer services

develop strategies based on modelssimilar to those now widely used toidentify and manage people at risk ofheart attack or stroke.Bonanni is at pains to challenge the

popular misconception that risk levelsare divided into ‘standard’or ‘high’. Thereis in fact no such thing as ‘the BRCAmutation’. Severalmutations have beenrecorded on the BRCA1 and 2 genes,someof themapparently harmless,whilethe harmful ones pose varying degrees ofrisk. Raised risks for various cancers canalso be passed on throughmutations in

RIGHTS AND REGULATIONS ACROSS EUROPE

The possibility of facing discrimination by employers, insurance companies, banks etc. canact as a serious deterrent to being tested for a genetic predisposition to cancer. Rights toprivacy and duties of disclosure vary across the EU countries. The 154 page pamphlet:Patients’ rights, insurance and employment: A survey of regulations in the European Unionwaspublished by the EU in 2002 (http://ec.europa.eu/research/biosociety/pdf/genetic_test-ing_eur20446.pdf), but this is now somewhat dated. A general protocol on genetic testingfor health purposes was adopted by the Council of Europe in 2009 (see Eur J Human Genet17:1374–1377).

� A network of multidisciplinary spe-cialist clinics must be established,building on genetic clinics, butincluding oncologists, prevention-ists, geneticists, genetic counsellors,surgeons and other experts, whoshould discuss as a team the riskmanagement plans for cases referredto them.

� The public, GPs, oncologists andother specialists need to becomemuch more aware, to ensure thatpeople understand their risk, get

good advice on risk management,and are referred to specialist clinicsas appropriate.

� A much greater focus is needed ondeveloping and evaluating effectivepreventive strategies – a cancerequivalent of compounds alreadyused as preventive agents, such asstatins for heart disease.

Bonanni has been promoting all three.He argues for more and better teachingfor oncologists and biologists to under-stand and practice risk assessment and

risk reduction “exactly as cardiologistsand internists do for their fields”. Interms of service provision, he advocatesfor regional hubs of expert multidisci-plinary riskmanagement teams,workingto agreed guidelines. His personal pas-sion, however, is the development ofpreventive agents and strategies.Hehasbeen working for many years as partof a fairly small network of academicresearchers who have swum against atide of scepticism, but whose timemaynow be coming.Bonanni’s outlook is definitely closer

to the youngman hoping for ‘a pill’ thanto Francisca and her generation in theNetherlands, who have largely opted forsurgery. The reality is, however, that theevidence base for prevention is still verymuchwork inprogress, not least becauseproving that an intervention significantlyreduces the risk of developing cancertakesmore time andmoney and a biggerpopulation study thanproving treatmentefficacy. “This is an ongoing field,” saysBonanni. “We always share with peoplevery clearly what is certain and what isuncertain so far.And this honesty iswel-comed by them.”One area of growing certainty, says

Bonanni, is the efficacy of regular breastMRI in picking up tumours in time tostop themspreading (Cancer113:3116–3120; JCO24:5091–5097; J Natl ComprCan Net 8:562–594), so long as this isdone in expert centres, with up-to-dateequipment and expert radiologists. Inpremenopausal patients, he adds, it isimportant that theMRI isdoneduring thesecond week of the menstrual cycle,something radiologistsdon’t alwaysknow.Studies have demonstrated the value


CuttingEdge

Understanding the risks opens up new possibilities

for prevention and early detection

When genetic testing goes badThe importance of accessible expert genetic cancer services in the BRCA era hasbeen highlighted by experience in the US, where private providers stand accusedofmis-selling genetic testing to ill-informedmedical professionals and individuals.Companies likeMyriad, whichwas the first to clone theBRCAmutation, andwhoseclaim to sole rights in the US to diagnose any BRCAmutation were largely invali-dated by a US federal court judge last year, are charged with trying to circumventcancer genetics clinics, pitching instead for referrals directly fromGPs,most ofwhomdo not really understand what they are dealing with. Equally worrying is the directto consumer advertising – oftenwith discounts offered if you can sign up othermem-bers of your family.A recently published study conducted by the Yale Cancer Center (Conn Med74:413–423), reported on a nationalUS series of cases illustratingwhat can happenwhen cancer genetic testing is performedwithout counselling by a qualified provider.Threemajor patterns of bad outcomes emerged: wrong genetic test ordered; genetictest results misinterpreted; inadequate genetic counselling. The results, docu-mented in the report, included:� unnecessary prophylactic surgeries� unnecessary testing� psychosocial distress, and� false reassurance resulting in inappropriate medical management.One family doctor consistently ticked the ‘Jewish’ box on the test form, thinking hewas doing his patients a favour as it is easier to claim the costs for theBRCA test oninsurance if you are Jewish. What he didn’t realise is that there is a particular ‘Jew-ish’BRCAmutation, and thiswas the onlymutation that his patientswere tested for.

risk of breast cancer, and a good trend toreduce risk of ovarian too,” saysBonanni.That evidence will be a lot clearer oncethe results of an ongoing phase III,double-blind placebo-controlled trial inwomen at high risk are known.Bonanni is also enthusiastic about

research into ‘natural compounds’ withcancer prevention properties, such ascarcumin and green tea, and he believesadvice on diet and exercise should be anintegral part of cancer prevention.As for the more radical options of

risk-reducing surgery, Bonanni describeshimself as ‘a moderate’, contrasting theapproachofhis departmentwithwhathe

calls ‘extremists’, who arequick to advise early pro-phylactic surgery “not onlyto gene mutation carri-ers.” Though removingclose to 100% ofbreast tissue hasbeen shown toreduce risk evenbelow the standardrisk for non-mutation

carriers, this canbehard to achieve evenfor experts, and the ideal of a zero risklevel is unattainable, he argues.There is more of a case to be made,

hebelieves, for removal of the ovaries. “Ifyou are still a fertile woman and have arisk of an ER+ cancer, as for exampleBRCA2mutation carriers, removing theovaries very early reduces your risk ofbreast cancer by around 50%. The pri-mary drawback, of course, is that thewoman loses her chance of having chil-dren through natural conception,whichis one reason why Bonanni advocates asequential approach to risk manage-ment, saving more radical options for

of the selective oestrogen receptormod-ulators (SERMs) tamoxifen and ralox-ifene in risk reduction for ER+ breastcancers. The IBIS II study is investigat-ing whether aromatase inhibitors canalso be effective as preventive agents.Anincreasing literature also supports thebeneficial role of the contraceptive pill inBRCAmutation carriers. Bonanni refersto a recent meta-analysis carried out bymembers of his department (EJC46:2275–2284). “It shows the use ofendocrine contraceptives in BRCAmutation carriers does not raise signifi-cantly the risk of breast cancer even iftaken for a long time, but on the otherhand it does decrease the risk ofovarian cancer by 50%.”“Of course SERMs

don’t cover the gapofER-negative carcinogenesis,”adds Bonanni. This iswhy research into othertypes of compound is soimportant.” Such researchincludes everything fromnonsteroidal anti-inflam-matory drugs (NSAIDs) tostatins andvitamins, especially vitaminDand retinoids,which are vitaminAderiv-atives. Much of this work has beenfunded so far by theUSNCI, and led bypioneers like Michael Sporn, who firstcoined the term ‘chemoprevention’ (seeCancer World May–June 2006). ButEurope has also made a contribution,not least Bonanni’s team at the EIO,whichhas spent20yearsworkingonvar-ious potential chemopreventive agents,including fenretinide, a synthetic deriv-ative of vitaminA. “Anumber of publica-tions have found evidence of strongcapability of this compound to reduce

later. “If you are at high risk, you can startsometimes very early in your lifetimewith surveillance, which maybe shouldbe increased over time. At a certainpoint, when the estimate of your riskincreases, youmay opt for a chemopre-vention programme like entering a trial,and when these estimates increase fur-ther, you may need to go for a surgicalprophylactic option.”For individualwomenand theirmed-

ical advisers, adopting such a sequentialapproach in principle is only the firststep. Getting the timing right can betricky, and this is where knowledge ofrisks, risk reduction and counsellingskills are so essential, andwhy Bonanniis advocating for specialist teams.

A SERVICE FOR THE BRCA ERAEurope now faces the challenge oforganising services that translate ournew-found insight about genetic cancerrisk and riskmanagement strategies intoeffective prevention. The UK has beenahead of the game, setting up regionalgenetics services in the 1990s, many ofwhich developed distinct cancer genet-ics services. Rachel Iredale, who worksas a research fellow with the CancerGenetics Service forWales, stresses theunique nature of the genetics servicesmodel in healthcare.The unit of care is the family rather

than the individual, and the service doesprovide the sort of support Franciscalacked in discussing how to raise theissueof a geneticpredisposition tocancerwith other family members. They caneven help, “for instance bywriting to theGPsof familymembers to say that some-body in the familyhas abowel cancer anditmight beworth screening people.”

CuttingEdge


Bonanni advocates a sequential approach to risk

management, saving more radical options for later

Another key aspect addresses Fran-cisca’s concern over long-term follow-up. “Once you are referred into theservice you are with us for life,” saysIredale. “We get a lot of 18-year-oldwomenwhohave seen theirmothers dieof cancer, or their sisters or their auntshave got it, and they want to do some-thing quite quickly. They can come forcounselling, and they can re-access theservice at any stage. As they get to par-ticular milestones in their lives, whentheywant to getmarried or are thinkingof having children, fears about canceroften re-emerge, so they can re-contactthe service at any time.”Iredale has also been working with

high-risk families to produce a series ofaround 50 digital stories (www.cancer-geneticsstorybank.co.uk) to help peo-ple in similar situations, answeringquestions like: “What is it like to have agenetic counselling appointment?”“What feelings will I have if I go forgenetic testing?” “Howwill I tellmy kidsthat cancer is running in our family?”Raising awareness among GPs,

oncologists and other health profes-sionals about the need to look for afamily history of cancer is also part ofthe genetics services remit. “We havetwo questions that we give that arevery sensible and a six-year-old couldunderstand:� Are there two or more close rela-tives with cancer on the same sideof the family?

� Has any relative beenunder 45whendiagnosed with cancer?

What the service doesn’t do, for themoment, is the sort of ‘directive’ publichealthwork that is becomingcommon in

theUS,whichencouragespeople to takeresponsibility for their ownhealthby find-ing out about their family history of can-cer and taking appropriate action. Onesuggestion fromtheUSSurgeonGeneralhasbeen forpeople todiscuss these issueswhen they gather at family occasionssuchasThanksgiving– theso-called ‘turkeytalk’. Theadvocacy groupFORCE–Fac-ing Our Risk of Cancer Empowered –also aims to help people find out abouttheir risk level anduse that information tohelp them stay healthy.Iredale is convinced that this is the

wayEuropeneeds to start thinking in theBRCAera. “Becausewe knowmore andmore about the genetic components ofcommon conditions, like heart disease,diabetes, asthma, there is a shift within

certainly the academic and clinical com-munities to try to get people to use thisinformation for health promotion andpromoting good public health.We call itacquiring a genetic literacy.”She would like to see this public

education start at primary school age,and haswritten a research proposal thatcould be the first step inmoving towardsthe more proactive US ‘empowerment’model. “Children need to know whatrole genetics plays in their family. Andthey need to learn that genetics isn’t ascaryword, cancer isn’t a scaryword, andthey can have a lot of it in their families.They need to use that information in away that helps them and encouragesthem to make good diet, lifestyle andreproductive decisions.”


CuttingEdge

In the US people are encouraged to find out about their

family history of cancer and take appropriate action

The turkey talk. Finding out about the conditions and diseases that run in your family is a stepeveryone can take towards managing risks to their own health

Desperately seekinga bone marrow match

The media campaign that made things happen in Romania

WhenTV journalist PaulaHerlo travelledabroad to research a story on advancedtreatments for patients with blood dis-

eases, she discovered something about her owncountry that shocked her.While looking at transplantation treatments

for leukaemia at La Fundació Josep Carreras in

Spain,Herlo was shown theEuropean network forregistries of bone marrow and T-cell transplantdonors.One researcher offered to help her localiseher story for her Romania Pro TV viewers. “Sheaskedme ‘Do youwant to know howmany donorsRomania has on the registry?’When I said yes, shetried to find it on her computer. Then she told


BestReporter

Apowerfulmedia campaign that is set to transform theprospects ofRomanianpatients in need of

transplant treatmentswonTV journalistPaula Herlo anESOBestCancer Reporter award. The

€5000 prize is the first in a newCampaigner category. She talked toCancer World about howher

Pro TVbroadcastsmobilised public opinion behind the call for a national stem cell donor registry.

� Peter McIntyre

CRISTINANICHITUS

enthusiastically agreed to supportthem. In March 2009 Herlobegan a series of interviewswith families and patientsthat grabbed the attentionof the public.She highlighted cases

like that of 18-year-oldDragos Croitoru, whowaited threemonthswhilethe health bureaucracyin Romania consideredwhether to send him abroadfor treatment.Approval arrived

on the day that doctors told hismother that he had only a week to

live. “I don’t even know if I have the strengthto get out of bed anymore,” he told Pro TV. “I feelthat it’s all over. I don’t evenhave the strength to pickup a glass of water and drink.”Herlo’s reports detailed unbearable foot drag-

ging – including the five days it took the BucharestPublicHealthDirectorate to find a driver to deliverDragos’papers to theMinistry for approval. She toldher audience: “Dragos’ story is illustrative of aflawed system that puts people’s fate in the handsof bureaucrats for whom the lives of these patientsdon’t mean anything. They are just files.”Dragos got to Israel for treatmentwhere sadly he

died. For him, the treatment had come too late.

A SUSTAINED CAMPAIGNOver thenext twomonths,Herlo andProTV ran25stories highlighting the need for a national registryunder a slogan “Avem viata in sange” – “there is lifein our blood”. “We showed how patients are dying– abroad the survival rate is 80%, and inRomania itis 20%.”Out of the many tragic stories, it was the first

that causedHerlomost heartache. Caludiu Voicu,an eight-year-old boy fromSlatina, hadwaited a yearfor approval to be sent abroad for treatment, at a cost

BestReporter


me ‘I can’t do it; you don’thave a registry.’”Without an approved

registry, neither theRoman-ian health system nor thepatients waiting for treatmentcould link to the EuropeanMarrow Donor Information System(EMDIS), an international computer net-work of registries that covers more than 85% ofstemcells donorsworldwide.Andwithoutbeingpartof the global network, the only chance thatRoman-ianpatientshadof finding abonemarrowmatchwasfrom close relatives.When Herlo returned home she found that

about 150 leukaemia patients a yearwerewaiting inRomania for transplants,withoutmuchhope.Therewere also 3500 people withHodgkin’s disease and3700 Romanian children with thalassemia major,many of whom could be treated with T-cells frombone marrow. Meanwhile, the three centres inRomania that carry out bone marrow transplantscould only do so if they found donors within thepatient’s family.“I realised at that moment that I must do a

campaign, because in our country, if a patient hasleukaemia and does not have a donor in his family,they are condemned, unless theyhave themoney fortreatment inFrance or elsewhere.” To get treatmentabroad costs anything from €75,000 to €150,000–out of thequestion formost families, given that thewage for a teacher is about €350 amonth.Herlo’s team at Pro TV agreed to launch a

campaign, and haematologists in the country

“Dragos’ story is illustrative of a flawed system

that puts people’s fate in the hands of bureaucrats”

Result. Former Health Minister IoanBazac (opposite) and Paula Herlo(right ) were the first to be testedto be registered donors, underan approving media spotlightat the Ministry of Health,September 2009

The campaign was taken up by newspapers and blogs,

and 36,000 people said they were prepared to be donors

BestReporter


of about €100,000.As a result of the campaign, hemade it to Hungary, but his leukaemia was too faradvanced. “He passed away last year – it was veryhard. I helped his family get him treatment, but itwas too late for him.”The campaign was taken up by newspapers

and blogs, and 36,000 people signed up on the ProTV website saying that they were prepared tobecomedonors.After twomonths, the thenHealthMinister Ioan Bazac announced that Romaniawould set up a registry thatwouldmeet internationalcriteria. In September 2009, live on TV,Herlo andthe Minister became the first two people to beentered on registry as potential donors.“It was a big surprise when they responded. It

was like a dream. But when I had spoken to theMinister I told him that we would continue thiscampaign for a year or two years if necessary.”One of those who had beenwatching the cam-

paign was Olga Cridland, president of the PAVELAssociationAgainstChildhoodCancer inRomania.She says that scarcely aweek goes bywhen shedoesnot hear of a new patient who needs to be sentabroad for treatment. The campaign got patients andfamilies talking and they became active supporters.Hugely impressed, Olga nominated Herlo for theBest Cancer ReporterAward.“I think that themedia has a big power in influ-

encing things, depending onwho is doing the cam-paign. If it is made in a really good and, how can Isay, stubborn way, I think this can change manythings regarding health, and changes in the laws.Our attitude as organisations is to try to worktogether with the media. When we heard Herlo’scampaign I thought it was a very goodway to do it.”

ETHICAL PITFALLSHerlo recognises the potential ethical pitfalls in run-ning a campaign based on highlighting tragedy andhope in people’s lives, and stresses the importanceof having a good team to take decisions. “My col-leagues are very receptive to my ideas and support

me very much – my boss is a great woman. Ofcourse, there were discussions about ethics and Itreated every case very carefully. But I admit thatalong the campaign there were very emotionalmoments, when families who lost their loved onesspoke about their drama and the chance that everyRomanian patient should have.”Herlo says shewould prefer to avoid these sorts

of highly emotive, dramatic stories, “but experi-ence showed me that the Romanian authoritiesreact only to pressure from public opinion and themass media. Sometimes we have to call things bytheir names and show that people suffer, so that theones who can change their destinies react.”Media campaigns, she adds, can get things

done, because the public becomes a partner. “Theycan ask the authorities to change things. I stronglybelieve that amedia campaign can change laws andevenmentalities.”Herlo, who has won awards for her reports on

economic and social issues before she turned tohealth, is now running a series on the crisis in theRomanianhealth system, campaigning for a changein laws and funding. “Romania has an under-financed health system. The funds are going intoblack holes, without anyone paying for it. The hos-pitals are going bankrupt one by one, and thepatients are paying for treatment although theyalready pay the health insurance.”The implications for anyone diagnosed with

cancer can be dire. “Cancer patients are somehowcondemned in Romania. For example, once apatient is diagnosedhemustwait formonths some-times for the treatment to be approved by HealthInsurance Office.”Olga Cridland says that organisations like hers

are learning to work more effectively with themedia, inviting reporters to come and speak topatients directly. PAVEL has formed a partnershipwith the health channel Sanatatea TV and is alsoworkingwithAdevarul newspaper (“TheTruth”) tohighlight the need for early referral of childrenwith


cancer, backed by theUICC ‘MyChildMatters’ campaign.PAVEL also appreciates the

part of Herlo’s latest health cam-paign that is pressing for govern-ment action to ensure thatcommon cancer drugs are avail-able on the Romanian market.Because thenumber of patients isrelatively small, lower-cost drugssuch as Cosmegen (dactino-mycin) used in the treatment ofHodgkin’s lymphoma, cannot bebought in Romania. “Unfortu-nately,wehave abig economic cri-sis nowaffecting the entire healthsystem,” saysCridland. “Many people are sufferingand we have tried to alert the authorities but it hasnot changed the situation. It is a tragedy becausepeople have to travel abroad to buy this or that drug.”These are issues, she says,where a campaigning

media canwakepeopleup. “Not allmedia are good,”she says. “I want to make a distinction. But if youspeak to aproper journalist, sometimes theyhelp youto express clearlywhat youwant to say. I don’t knowabout other countries, but I have a good impressionabout media in our country. When reporting onchildren, mostly the journalists are very sensitive.”While she campaigns on these broader health

issues,Herlo has not givenup the bonemarrow reg-istry. Of the 36,000 people who volunteered tosign up, so far only about half have actually done so.The registry is due to be linked to other internationalregisters in February 2011, when it will finallybecome a resource for hope and treatment – andHerlo is not ready to let thematter drop. “This cam-paignwill continue next yearwith a series about theimportance of becoming a donor. I will prepareanother campaign to sustain this register.”Given her record so far, Romanian patients in

need of a transplantation treatmentwill soonbe fac-ing a much brighter future.

BestReporter

“Patients are paying for treatment although they already

pay the health insurance”

“Sometimes we have to show that people suffer,

so that the ones who can change their destinies react”

Inspiration. Paula Herlo with RamonaIlian, a little leukaemia patient she meton her visit to Barcelona’s Vall D’Hebronhospital while researching her story on

blood transplantation treatments

DALILADULGHERIU

Real compassion is aboutmoving things forward

� Simon Crompton

The decision to focus on infections associated with cancer treatments, back in the early ’70s, put

Jean Klasterskyon apath thatwould lead to himpioneering the field of supportive care in cancer.

His researchhashelpedestablish the value of goodcommunication, yet hewarns that compassion

in a doctormeansmore than empathy, and getting too emotionally involved can lead to burnout.

Professor JeanKlastersky is quite clear abouthisachievements, and what drove him towardsthem. Itwasn’t a personal commitment tohelp

people with cancer. It was an early aspiration to con-tribute to scientific progress– tobeaGreatPhysician:a Freud, a Babinski, anOsler.It’s not that compassionhasn’t been intrinsic tohis

ground-breakingworkon infectionandcancer, and thedevelopment of supportive care. “But I always toldmyself that real compassion inaphysician,”he sumsupsuccinctly, “is tokeep thingsmoving, tomakeprogress.”And that’swhathe’s doneover40years.Fromcar-

rying out early and influential trials on sepsis in neu-tropenia, through putting both supportive care andinfection in cancerpatients on the internationalmap,towritinghighly influentialworks on lungcancer anddoctor burnout, Klastersky has pushed the canceragenda forward.In theearly 1970s,whenhewas setting out onhis

work investigating infections related to cancer treat-ments, patientswithacute leukaemiawere (inhisownwords) still “dying like flies” before they reached

remission. “I think that our concepts and researchchanged that a lot. Actually the improved care forpatients with infection was the first example of sup-portive care in cancermedicine,” he says.Trimandstill energetic inhis 71st year, I’mspeak-

ing tohimat the Institut JulesBordet, a specialist can-cer hospital and research unit in Brussels, where hewasheadof theDepartment ofMedicine for 27 yearsuntil his official retirement in 2005. The institute ispart of the Free University of Brussels, where hestarted his career and where he has remained fornearly its entirety.Without a trace of vanity, he says that he would

probably have succeeded in any area of medicine,acknowledging that ambition and occasional oppor-tunism have moulded his career. He comes from anoldCzech family “of low-rate nobility”, which can betracedback to the16thcentury.His family leftPraguewhenhewas six, at theendofWorldWar II,whenhisfathercametoworkat theCzechembassy inBrussels.Butwhen theCommunistParty tookover in1948,hisfamily stayed in Brussels as political refugees, and


Masterpiece

theprinciple that the laboratory and theclinic shouldgo together, and you should go from one to the other.I was very, very impressed by the concept.” It was acrossover that ended up defining his career.Training in internalmedicineasan internand then

a resident at theFreeUniversity of Brussels between1962 and 1965, he came under the influence ofHenri Tagnon,whowas trying to reshape the InstitutJulesBordet into oneof thebest cancer centres in theworld.Hesuggested that the youngKlastersky shouldstart specialising in infectious diseases – particularlysince the institute currently had to rely on externalmicrobiology services. A Fullbright fellowship gothim toHarvardMedical Schoolwherehe spent threeyears as a chief resident and then research fellow.

ONE FOOT IN THE CLINIC ONE IN THE LABHereturnedwitha solid training in infectiousdis-ease, and in1971became the youngest associateof the Faculty of Medicine at the university.Tagnon gave him the responsibility of setting upa newmicrobiology lab on completely newprin-ciples. “I applied theprinciples that I discoveredin theStates– that the infectiousdiseaseconcepthas one foot in the clinic, and one foot in the lab.Thewhole servicebetween the twowasall directedby one person – that was me. It was a completelyrevolutionary concept.”Embodying the strong link between the lab and

thepatient,Klasterskyhadanopportunity to researchand trial innovative treatments. He focused onresearch that would significantly improve survivalrates in patients whose immune systems were com-promised by chemotherapy, and developed the con-cept of synergistic antibiotics (effective combinationsof different antibiotics) forneutropenicpatients (whohave low levels of neutrophil blood cells). He alsodeveloped theconcept of endotracheal treatments forpatientswithgram-negativepneumonia (whichare fed

through the trachea).As his work progressed, helooked on as Tagnon estab-lished, and then led (aspresident) the Euro-pean OrganisationforResearchandTreatmentof Cancer(EORTC).

Masterpiece


Klastersky has been based in Belgium ever since,raising his own family there.It was the high-quality science teaching at a Bel-

gianpublic school that gavehimacommitment to gointo medicine in his early teens. He was particularlyinspired by a small book by the great French physiol-ogistClaudeBernard, entitledAn Introduction to theStudy of Experimental Medicine. “Bernard defined

“I saw this concept of European organisations andthought,why shouldn’twedo that for infection in can-cer patients?” So in 1973, with collaborators from theUK,US andAustralia, he founded theEORTC inter-national antimicrobial therapycooperative group.Over20years it published20pivotalpaperson infectiousdis-ease in immunocompromisedpatients.The first, in theJournal of InfectiousDisease in1976, reportedon the firstever large randomised comparative study on theman-agement of sepsis in neutropenic patients. It gaveinternational relevance to the innovative activity inBrussels and itmadeKlastersky’s name.When Tagnon retired in 1977, Klastersky, at just

37, was chosen as his successor. But there was aproblem: it would be unusual for theHead ofMedi-cine at aworld renownedoncology centre tobe a spe-cialist in infection rather thancancer. So straight afterhis appointment, Klastersky took a sabbatical of sev-eralmonths inAmerica to trainas anoncologist. Itwasa logical conclusion for him, further forging the linksbetween oncology andmicrobiology.

At the institute, he made a point of seeing patientswith all types of cancers and having as broad a per-spective on medical oncology as possible. Hebecame professor ofmedicine, professor ofmedicaloncology, and professor of physical diagnosis, and theteaching his department provided attracted fellowsfrom all over Europe. Under his stewardship, med-ical oncology beds expanded from 40 to 100, newhaematology, intensive care, supportive care and psy-cho-oncology units were established, the researchfacility was expanded, the number of physiciansincreased from 15 to 60 and the research budgetwent up to€3 million.

THE CONCEPT OF SUPPORTIVE CAREItwashis broad insight into the factors that affect thewelfare of patientswith cancer apart from the canceritself that gave rise to the concept of supportive care,for whichKlastersky is arguablymost famous. Thou-sands of oncologists around the world have read hishandbook Supportive Care in Cancer.


Masterpiece

A new type of treatment. Klastersky with palliative care specialists Gary Morrow (US) and Andreas Du Bois (Germany) discussing howto define ‘supportive care’ at one of the first meetings of the newly founded Multinational Association for Supportive Care in Cancer

He focused on improving survival in patients whose

immune systems were compromised by chemotherapy

Klastersky iskeenlyaware thatdefinitionsof supportivecare differ from country to country and are hotlydebatedbyhealthprofessionals.But in1992,whenheandHans-JörgSennof theStGallenTumourDetec-tionandPreventionCentre inSwitzerlandcreated theMultinational Association for Supportive Care inCancer (MASCC), things were clear.“Somethingwas definitely going on at that time,”

he says. “We felt that supportive carewas really a fifthmodality in cancer treatment and should be to someextent separate fromothermodalities.”Thedefinitionthey cameupwithwas simple. “Itwas all the care youprovide to cancerpatients outside specific anticancertherapy. Itmeansyouarepreventingcomplicationsnotonly related to the cancerous disease itself, but alsorelated to the therapy. Supportive care startswith thediagnosis of cancer, and goes through thewhole evo-lution, encompassing psychological support, end oflife, pain, antiemetics, antibiotics and so on. Besidesanti-cancer therapy, everything is supportive care.”The concept worked well, says Klastersky. There

was aneed for specific research in thearea, dedicatedmeetings, and medical oncologists with a particularinterest. It is a mark of how well the important prin-ciples of supportive care are now understood thattheyhavebecome integrated intocancer care, andareno longer seen separately, he believes.“I thinkmedical oncologistsnowunderstand that it

is a questionof quality of life, aswell as quantity of life.Thepatient alsounderstands this, and requires thisper-spective.Attention toquality of life necessitates all thesupportive caremethodsbeing integrated intomedicaloncology, and this happens at the good centres. They

need tobe seen tohave a supportive careprogramme.”Good communication between clinician and

patient is an intrinsicpart of good supportivecare, andthis is another areawhere Klasterskymade hismark.The institute’s onco-psychiatry unit trains Belgianphysicians ingoodcommunication techniques, and itssupportive careunit provides intensive support – andplenty of talking time – for patients with chronicproblems related to their illness, such as pain. Hisresearch has indicated the value of good communi-cation to patients and clinicians alike.Hereagain things are improvingonan international

level.Lawsandregulations in someEuropeancountriesnow compel clinicians to tell patients the truth, andmakeclearwhat they knowandwhat theydon’t know.And multidisciplinary working has made treatmentdecisions better discussed andmore democratic.“I think that doctors coming along and telling peo-

plewhat to dohas almost completely disappeared,” hesays. “I think thatpatientsarealsobecomingmoreawarethat things aren’t always black and white, and thatdecisionsmight be complicated andneeddiscussing.”It’s an optimistic viewpoint. In fact Klastersky is

generally extremely positive about the way cancerservices are progressing internationally. “I often thinkof the picture on the front of Scientific American in1971, with President Nixon signing the NationalCancer Act, and declaring war on cancer. Well, ofcourse, cancer is still here, but since then so muchenergyhasbeendevoted to fighting it that40years laterwe can see a tremendous difference – particularlytechnological achievements that aremaking cancer atype of chronic disease.”

WHO SEES THE PATIENT AS A WHOLE?Buthedoeshaveworries. Ifhisowncareerhasbeentes-timony to the benefits of acquiring as wide a perspec-tive on cancer as possible, it is not surprising that hismainconcernabout the futureofmedicine ishow lim-ited the field of visionofmanyphysicians is becoming.“My fear is that the training of the oncologist will

becomemoreandmorenarrow. I can see that youcan

Masterpiece


Focus on febrile neutropenia. With Canadian specialists RonFeld of the Princess Margaret Cancer Center, in Toronto (right),and Andy Padmos, then head of medical oncology at KingFaisal’s Hospital, Saudi Arabia, at an early international meetingon preventing and treating one of the most serious side-effectsassociated with some chemotherapy regimens

havebreast cancerpeoplewhodonot go into the treat-ment of colorectal cancer, and that you might havepeoplewithinbreast cancerwhoaremore specialisedin hormonal therapy, for example. But it worries methat, at somepoint, toomanymedical oncologistswillhave very sophisticated medical skills but will fail toreally see thepatient as awhole. I thinkwe shouldbevery attentive thatmedical oncology remainsabroadertypeof activity.”He rememberswitnessingat onehos-pital six different specialists attending a patient –none of themwas taking overall responsibility for thepatient. If something went wrong, would they allblame someone else, hewondered.“I come from general internal medicine, and I

know it’s toughnowadaysnot all to specialise in smallareas.But I think there’s a potential dangerwhen youdon’thaveonepersonwhocanclearlyput together thewhole picture of a patient under one head.”Fascinatingly, another worry surrounds doctor–

patient communication: not lack of it, but toomuch.For all his research showing thebenefits of goodcom-munication, Klastersky has also demonstrated that itcan be counterproductive if physicians become tooemotionally involved with patients. In a paper onphysicianburnout published in the Journal of CancerEducation last year (March 2010) his team ofresearchers found thatheavyclinicalworkloadand theoveruseof facilitativecommunication skillswereasso-ciatedwith cancer physician burnout.

“I think that sometimes, if communication becomestoo detailed, amutual emotional involvement beginswhich can be very difficult for some physicians – it’sclosely related to theirpersonalities.Wehadaverynicemedical oncologist here, who burnt out completely.Her problem was that she spent hours discussingissueswithonepatient, andshewasno longer thesolu-tion, shewas part of the problem.”“It’s very difficult to regulate, and every person-

ality is different, but youneed tomaintain emotionaldetachment.” That’s why he believes the physi-cian’s role transcends relationships. It’s aboutmak-ing progress.If there’s one small hint of regret fromKlastersky

during our conversations, it centres onhis specialismin lung cancer.Not long after hebecameHeadof theDepartment of Medicine at the Institut in 1977, hedecided tomake lung cancer a specialty –mainly, heacknowledges, because “[I] had to make myselfknown” in the field of oncology, andmost areas apartfrom lung cancer already seemed to be well-servedwith experts at the institute.He created the EORTC Lung Cancer Working

Party, andwaspresidentbetween1978and2003.Thegroup’s first study demonstrated that cisplatin wasactive innon-small-cell lungcancer. Its seconddemon-strated that the combination of cisplatin plus VP16wasactive.Aseries of influential studies followedoverthe next 10 years.Yet concentrating increasingly on supportive care

in the 1990s distracted him from achieving more inthis area, he believes. “I think it was amistake formewhenIdecidednot tobemore super-active in the fieldof lungcancer,” he says. “I couldhavebeenmore suc-cessful in that field.”


Masterpiece

“Every personality is different, but you need to maintain

emotional detachment... It’s about making progress”

A transatlantic supportive alliance. Stephen Schimpff, head ofthe University of Maryland Cancer Center in Baltimore, Maryland(left), organised the first symposium on supportive care in1987, and is pictured here in Brussels for the secondsymposium held a year later. Also pictured is Klastersky’s wifeMarie-Thérèse Klastersky-Genot, an oral surgeon specialised intreating patients with severe oral mucositis

A WINNING FORMULAKlastersky isconsciousofhisdeepdesire toachieve.Heanalysed it and broke it down last yearwhen asked bytheMDAndersonCancer Center inHouston to talkto fellows about the recipe for a successful medicalcareer. “First, you need the person to be driven by aninternal passion – the need to be a physician orwhat-ever. Then you need values, so you know what to dowith yourpassion– tomakemoney, or leave amessagefor posterity and so on. Then you need to be able toevaluate your skills, to be aware of your strengths andweaknesses.And for all yourpassion andvalues, if youdon’t know your weaknesses – for example being tooempatheticwith apatient – youmaynot succeed.Youmay burn out.”A “relativelypeaceful life”, headds, is an important

factor for success inanyprofessional career, “and Iwaslucky enough to have anunderstanding and support-ivewife to share the good and less good aspects of it.”Theacclaimhe’s received throughouthis career –

he’s won the Guy R Odom Award in 1990 for out-standing achievements in infectiousdisease research,the LucienCoxAward in 1997, the Louise BiernauxFoundation Award in 2001 and the Hoyez-VanCutsemAward in2003– testifies that the formulahasworked pretty well for him.Still seeing patients as a consultant at the Institut

Jules Bordet, he’s now co-ordinating a programme ofcollaborationbetweennineBrussels cancerhospitalscalled the ‘programmedes soins oncologiques’. Look-ing back, he says, it’s the teaching aspect of his role –thepassingonof knowledgeandexperience toothers,that he has foundperhapsmost satisfying.As profes-sor ofmedicine at the faculty ofmedicine, FreeUni-versity of Brussels, he spent 30 years teaching until2005. He is still attending professor at CharlesUniversity in Prague, where he goes every threemonths to give a series of lectures (inCzech).Aside from the enjoyment it gives him, teach-

ing gives Klastersky a sense that he’s filled in thepicture of a great physician that he started draw-ing in his schooldays.

“For all your passion and values, if you don’t know

your weaknesses, you may not succeed”

Masterpiece


Passing on the baton. In 2005 Klastersky ceded leadership of the JulesBordet Department of Medicine to Martine Piccart, after 27 years in the post

“I always thought that this idea of the great physiciancarriedwith it theneed to transmit importantmessages– by communication, but also by example. That’sbeen important to me, and has taken a substantialamount ofmy time.”“Again, you have to knowwhat your values are. It

has often been said to me that I didn’t achieve all Icould have on the political side – making a career inEORTC, for example, and becoming President. Butyou cannot do everything at the same time, and youhave to make your choices according to your values.Myvalues aremore todogood international research,good teaching.”And are there any particular ways in which he

would likehis students to followhis example? “As longas oncologistsmake efforts to keep themselves com-petent andcontinue to see thepatient rather than thetumour, there is no better recipe than that.”

ImpactFactor

Gemcitabine alone or plus cisplatinfor biliary tract cancer?

�Werner Scheithauer

A randomised phase III trial comparing cisplatin plus gemcitabine with gemcitabine alone for

patients with advanced biliary tract cancer has provided evidence for a new standard treatment

option for these patients. The therapeutic outcome (overall survival, disease-free survival and

diseasecontrol rate)was significantlybetter in thecombinationarm,withno increase in toxic effects.

Advanced biliary tract carcinoma(ABTC) is a heterogeneousmalignant disorder of the diges-

tive tract that has a poor prognosis and israre in theWesternworld.Very few treat-ment options are available for ABTC,owing to a paucity of definitive studiesassessing chemotherapy regimens. Therationale for the use of chemotherapywas justified by a study published in1996 by Glimelius et al.1, which sug-gested a survival and a quality of lifeadvantage for patients treated withchemotherapy comparedwith thosewhoreceived best supportive care alone.

Numerous small nonrandomisedstudies of various anticancer chemother-

apeutic drugs and combinations of suchdrugs for ABTC have been published.A pooled analysis of 104 palliativechemotherapy trials inABTC (a total of112 trial arms and 2810 patients)reported a tumour response rate of22.6%, a disease control rate of 57.3%, amedian time to progression of 4.1months, and a pooled overall survival of8.1 months.2 Single-agent antimetabo-lites (5-fluorouracil or gemcitabine)seemed to be more active than othersingle agents (such as anthracyclines,taxanes and topoisomerase I inhibitors).Furthermore, combined treatments ofantimetaboliteswith platinumsalts (cis-platin, oxaliplatin or paraplatin) were

superior to other agents and drugcombinations.2 On thebasis of these find-ings, UK investigators initiated a ran-domised phase II study to comparecisplatin plus gemcitabine with gem-citabine alone, which was subsequentlyextended to aphase III trial.3 The studybyValle and colleagues is a pragmatic, well-conducted trial, appreciating theneed formultidisciplinary patient management.This trial incorporated biliary stenting in45%ofall patients inboth treatment arms.Maintenanceof biliary drainage is criticalinpatientswithadvancedbiliary tract can-cer.Aside from theessential quality of lifebenefit, biliarydrainage is aprerequisite forchemotherapeutic drug administration


This article was first published in Nature Reviews Clinical Oncology 2010 vol.7 no.10, and is published withpermission. © 2010 Nature Publishing Group. doi:10.1038/nrclinonc.2010.130, www.nature.com/nrclinonc

ImpactFactor

and counteracts potentially life-threaten-ing biliary sepsis.

Valle and co-workers recruited a totalof 410 patients with locally advanced ormetastatic cholangiocarcinoma, gall-bladder or ampullary cancer. Thesepatients were randomly assigned to anoutpatient chemotherapy regimenwitheither cisplatin (25 mg/m2) plus gem-citabine (1000 mg/m2) on days 1 and 8every threeweeks, or gemcitabine alone(1000mg/m2) on days 1, 8, and 15 everyfour weeks for up to 24 weeks in botharms.3 The primary endpoint – a signif-icant improvement in median overallsurvivalwith combination chemotherapycomparedwith gemcitabine alone –wasclearlymet (11.7months vs 8.1months;HR0.64;P<0.001). Similarly, significantincreases in the median progression-free survival (8 months vs 5 months;P<0.001) and the rate of tumour control(complete or partial response or stabledisease, 81.4%vs 71.8%;P=0.049)wereobserved in the experimental arm,importantly with no increase in toxiceffects relative to gemcitabine alone.On thebasis of these results, the authorsconclude that cisplatin plus gemcitabineis an appropriate option for the treatmentof patients withABTC.3

These data are consistent with theknown preclinical4 and clinical syner-gies5,6 of cisplatin and gemcitabine inothermalignancies, such as lung cancerand head and neck cancer, and previousphase I andphase II trials inABTC.2 Thefindings are also supported by the resultsof a randomised trial involving 83 Japan-ese patientswithABTC, treatedwith thesame regimens,whichwere presented atthe 2009ASCOAnnual Meeting. Thattrial reported amedian overall survival of11.2 months in the cisplatin plus gem-citabine group compared with 7.7months in the gemcitabine-only group.7

The study byValle et al.3 provides an out-

standing contribution to the field as it isthe very first randomised trial sufficientlypowered to define an active treatmentregimen inABTC.Owing to the smallernumber of patients and heterogeneouspatient population in ABTC as com-pared with other common malignan-cies, phase III trials have been achallenge to conduct. The authors havesuccessfully overcome this inherentproblem, assisted by an effective co-ordination of national clinical researchefforts. This UK study has not onlydefined a new standard of care, but alsodemonstrated that it is feasible to per-form large-scale studies inABTC. Fur-thermore, despite inherent difficulties inassessing objective response in this dis-ease entity, the authors have succeededto do so using RECIST criteria. Theseobjective response datawere obtainablein at least 74% of their patients whopresented with measurable disease (anon-prerequisite for study entry). Thefindings of this trial also go against pre-vious beliefs that gallbladder cancer andcholangiocellular cancer subgroups varyin the rate of chemotherapeutic respon-siveness. For example, Eckel et al.2

reported a greater likelihood of objectiveresponse (36% vs 18%) but inferioroverall survival time (7.2 months vs9.3 months) in patients with advancedgallbladder cancer relative to thosewithcholangiocarcinoma. The Valle et al.3

study is in contrast to the rather contra-dictory findings of this retrospectivepooled analysis of previous palliativechemotherapy trials inABTC.

The biology of biliary tract cancersseems to be in the spectrum ofgastrointestinal epithelial cancers withsimilar oncogenicmutations.8,9 Keyonco-genic mutations in biliary tract cancersinclude KRAS, EGFR, and BRAF,potentially offering a genetic basis fortailored first-line regimenswith targeted

agents as has beendemonstrated in colo-rectal cancer.10 In view of the urgentneed for further improvements in theeffectiveness of anticancer treatment inABTC, anti-angiogenic drugs, EGFRinhibitors, inhibitors of BRAF or thedownstreamMAPK/MEKpathway andother promisingnovel biologicalswarrantinvestigation. Such testing should bedone through well-conducted prospec-tive clinical trials with companion bio-logical exploration to better understandtheoptimal placeof suchdrugs inABTC.The study by Valle et al.3 has been animportant contribution for such futuretrials. The study has firmly established anewclassic cytotoxic regimenas standardof care and demonstrated the need andfeasibility of coordinated national andinternational clinical research efforts,which are of paramount importance tocontinued progress in this field andimproved outcomes for our patients.

Details of the references cited in this article can be

accessed at www.cancerworld.org


Practice points� The combination of cisplatin plus

gemcitabine is aneffectivepalliativetreatment option in patients withlocally advanced or metastaticcholangiocarcinoma, gallbladder orampullary cancer.

� The demonstration from a ran-domisedphase III trial that cisplatinplus gemcitabine significantlyimproves disease control rate, pro-gression-free survival and overallsurvival, with no increased toxiceffects comparedwith gemcitabinealone, confirms this regimen asthe new standard treatment foradvanced biliary tract carcinoma.

Author affiliations: Department of Internal Medicine and Cancer Center, Medical University of Vienna, Vienna, Austria

ImpactFactor

Molecular selection for‘smart’ study design in lung cancer

� Amanda Psyrri and Barbara Burtness

The ZODIAC trial reported that the addition of vandetanib to docetaxel in second-line

treatment of unselected patients with metastatic non-small-cell lung cancer resulted in a

statistically significant improvement in progression-free survival compared with docetaxel

alone. Identification of biomarkers to assist in molecular selection of patients for targeted

therapy is a tool for ‘smart’ clinical trial design.

Patientswith advancedormetasta-tic non-small-cell lung cancer(NSCLC)haveadismaloutcome.

Platinum-based chemotherapy is thestandard first-line treatment; however,this approachyieldsdisappointingmediansurvival rates that donot exceedoneyear.Molecularly targeted agents that blockpivotal pathways in cancer progressionand can reverse chemoresistance seempromising. EGFR inhibitors and anti-angiogenic compounds have demon-strated marginal benefit in unselectedcohorts of patients with advancedNSCLC. However, the superiority ofgefitinib over chemotherapywasdemon-strated in amolecularly selectedpopula-tion of patients bearing a sensitisingEGFRmutation.1 Novelmolecular ther-apies such as those targeting the insulin-like growth factor 1 receptor or the

EML4–ALK fusion protein have shownpromising results in preliminary studies.Other targeted therapies acting onRAS/RAF/MEK, PI3K/AKT/mTOR orMETkinase arebeing studied in clinicaltrials, especially in resistant patients.

Patients with advanced NSCLC willeventually relapse or develop resistanceto first-line treatment. Several chemother-apy agents, such as docetaxel and peme-trexed, have shownactivity andhavebeenapprovedby theFDAfor second-line treat-ment of advanced ormetastaticNSCLC.Docetaxel is associatedwith response ratesbetween 15% and 20%, overall survival of8.3 months and one-year survival rates ofup to37%.2Ameta-analysis that evaluatedthe benefit of two-drug combinationsversus single-agent chemotherapy in thesecond-line setting and demonstratedimprovements in response rateswith two-

drug combinations did not translate intoimprovements inprogression-free survival(PFS) or overall survival.3 In addition, thetwo-drug combinations were associatedwith substantial toxic effects.

A rational approach to improve activ-ity in the second-line settingmight be thecombination of a targeted agent withconventional single-agent chemotherapy.Several targeted therapies have beentested in the second-line setting. Erlotinibis an EGFR tyrosine kinase inhibitor(TKI) approved for second-line therapy inNSCLC.A randomised study comparingerlotinib with placebo showed improve-ment in median overall survival (6.7months vs 4.7 months) and quality oflife across all patient subgroups withinthe erlotinib arm.4 Gefitinib, anotherEGFRTKIwith a different pharmacoki-netic profile to erlotinib, failed to yield a


This article was first published in Nature Reviews Clinical Oncology 2010 vol.7 no.11, and is published withpermission. © 2010 Nature Publishing Group. doi:10.1038/nrclinonc.2010.156, www.nature.com/nrclinonc

ImpactFactor

survival advantage in a phase III trial.5

A new study has reported promisingresults using vandetanib in combinationwith docetaxel to treat patients withadvancedNSCLC.6 Vandetanib is an oralinhibitor of EGFR and VEGF signallingpathways. The agent also targets therearrangedduring transfection (RET) tyro-sine kinase, an important growth factor inthyroid and other cancers. Vandetanibreverses primary or acquired resistance toEGFRTKIs in xenograftmodels ofhumanNSCLC,particularly in resistant tumourswithhigh tumour-derivedandhost-derivedVEGF levels.7 In a randomised phase IIItrial of second-line therapy for NSCLC,vandetanib single-agent therapy demon-stratedequivalent efficacy to erlotinib, butwith additional toxic effects (such as diar-rhoea, hypertension and asymptomaticQTcprolongation).8 Vandetanib improvedPFS in combinationwith docetaxel, com-pared with docetaxel alone, in a ran-domised phase II trial.9 An interestingsubset analysis suggested the benefit wasgreatest for women.9

Herbst et al.6 havenowreported resultsfromarandomised,double-blind,phase IIIstudy (the ZODIAC trial) to confirm thePFSbenefit of addingvandetanib (100mg)to docetaxel in advanced NSCLC. Thestudy included 1391 patients randomlyassigned to receive vandetanib 100mgdaily plus docetaxel or placebo plusdocetaxel. Docetaxel could be given forup to six 75mg/m2 doses (or 60mg/m2 forpatients treated in Japan) on a three-weekschedule. The primary objective was a20% improvement inPFS. The outcomesin women were also analysed independ-ently to thewhole study population.

The ZODIAC study demonstrated averymodestbut significant gain inmedianPFS of 0.6 months (4 months with van-detanib vs 3.2 months with placebo,P<0.0001) and a similar PFS gain inwomen(from4.2months to4.6months inthe placebo and vandetanib groups,respectively). Herbst and colleagues

observed no improvement in overall sur-vival, and only a 6%difference in the pro-portion of patients who had diseaseprogressionby sixmonths after treatment.This small improvement inPFSoccurredat a cost of substantial toxic effects;grade 3 and 4 adverse events includingrash, leukopenia, neutropenia, and neu-tropenic fever weremore common in thevandetanib group than in the placebogroup, and QTc prolongation requiringdose interruption was noted in nearly 2%of patients.A longer time to deteriorationof lungcancer symptomswasalso reportedin patients receiving vandetanib. Inter-estingly, themedianexposure todocetaxelwas only four cycles (or approximately12 weeks) in each arm, and importantly,monotherapy with vandetanib continuedin the experimental arm, while no activetherapywasused in theplacebo armafterdiscontinuation of docetaxel.Aweaknessof thestudy, as theauthorspointout, is thatdespite PFS being the primary endpointtherewasno independent blinded reviewof radiological evaluations.

Aphase III comparisonofpemetrexedplus vandetanib versus pemetrexed aloneinpreviously treatedpatientswithNSCLC(theZEAL trial) didnotmeet theprimaryendpoint of statistically significant PFSprolongation.10 Similar to the ZODIACtrial, theZEALstudydemonstrated a sig-nificantly higher overall response rate andsymptomcontrol in the vandetanib groupcomparedwith pemetrexed alone.

The increase in PFS of borderlineclinical significance with an increase intoxic effects andno improvement in over-all survival, reported in the ZODIACtrial, taken in the context of the negativeZEAL trial, are unlikely to impact the cur-rent standard of care in patients receivingsecond-line treatment. For good respon-ders to first-line chemotherapy, single-agent chemotherapy such as docetaxel orpemetrexed constitutes a rational choicewith fewer toxic effects. EGFR TKI ispreferred in patients with poor response

or tolerance to first-line chemotherapy.The results reported by Herbst et al.6

underscore the vital importance of incor-poration of molecular selection into thefuture design of clinical trials that use tar-geted therapies.Forexample,EGFRmuta-tions are consideredpredictivebiomarkersof high clinical benefit with EGFR TKItherapy, especially for first-line treatment.Herbst and co-workers did not present asubgroup analysis of tumour and circulat-ingbiomarkerdata includingEGFRmuta-tion status, as the analysis is still ongoing.Inhibition of VEGF and RET signalingmay have also contributed to the anti-tumour efficacy of vandetanib.

A personalised approach to treatmentselection is the future of lung cancerman-agement in all lines of therapy. Such anapproach may require tumour re-biopsybefore administration of second-linetherapy to identify, for example, knownbiomarkers of resistance to EGFR TKI.Noninvasiveapproaches, suchasbiomarkeranalysis on circulating tumour cells andblood biomarkers predictive of responseor resistance, hold promise for treatmentselection.Unfortunately, formost targetedtherapies, clinically validated biomarkershave not been identified, and this remainsa critical focus of research in the field.


Practice points� Thecombinationof achemotherapy

drug andamolecular-targetedagentappears to be a rational approachfor previously treated patients withadvancedNSCLC;however, clinicaltrials in un-selected patient cohortsoften fail to demonstrate substantialsurvival benefit.

� Identification and validation of bio-markers for response or resistancewill assist in thedevelopmentofper-sonalised targeted strategies inadvancedNSCLC.

� Are trials being stopped too early?� Are patient groups skewing

the research agenda?� Are you getting the career

breaks you need?� Which is better? Medical

oncologist or organ specialist,robot or surgeon?

The new, redesigned CancerWorldwebsite invites you to contribute tocurrent debates by using its commentfacility. You can also suggest topics forcoverage and find links to related sites.Get online and take a look

Cancerworld It’s your world. Get online and have your say

www.cancerworld.org

ImpactFactor

References

1. TS Mok et al. (2009) Gefitinib or

carboplatin–paclitaxel in pulmonary

adenocarcinoma. NEJM 361:947–957

2. N Hanna et al. (2004) Randomized phase

III trial of pemetrexed versus docetaxel in

patients with non-small-cell lung cancer

previously treated with chemotherapy. JCO

22:1589–1597

3. M Di Maio et al. (2010) Clinical

assessment of patients with advanced non-

small-cell lung cancer eligible for second-line

chemotherapy: a prognostic score from

individual data of nine randomised trials. Eur

J Cancer 46:735–743

4. FA Shepherd et al. (2005) Erlotinib in

previously treated non-small-cell lung cancer.

NEJM 353:123–132

5. N Thatcher et al. (2005) Gefitinib plus best

supportive care in previously treated patients

with refractory advanced non-small-cell lung

cancer: results from a randomised, placebo-

controlled, multicentre study (Iressa Survival

Evaluation in Lung Cancer). Lancet

366:1527–1537

6. RS Herbst et al. (2010) Vandetanib plus

docetaxel versus docetaxel as second-line

treatment for patients with advanced non-

small-cell lung cancer (ZODIAC): a double-

blind, randomised, phase 3 trial. Lancet Oncol

11:619–626

7. GN Naumov et al. (2009) Combined

vascular endothelial growth factor receptor

and epidermal growth factor receptor (EGFR)

blockade inhibits tumor growth in xenograft

models of EGFR inhibitor resistance. Clin

Cancer Res 15:3484–3494

8. RB Natale et al. (2009) Vandetanib versus

erlotinib in patients with advanced non-small

cell lung cancer (NSCLC) after failure of at

least one prior cytotoxic chemotherapy: a

randomized double-blind phase III trial

(ZEST) [abstract]. JCO 27 [Suppl. 15]:8009

9. JV Heymach et al. (2007) Randomized,

placebo-controlled phase II study of

vandetanib plus docetaxel in previously

treated non small-cell lung cancer. JCO

25:4270–4277

10. R De Boer et al. (2009) Vandetanib plus

pemetrexed versus pemetrexed as second-line

therapy in patients with advanced non-small

cell lung cancer (NSCLC): a randomized,

double-blind phase III trial (ZEAL) [abstract].

JCO 27 [Suppl. 15]:8010

Author affiliations: Second Department of Internal Medicine, Propedeutic, University of Athens Medical School, Attikon University Hospital, Athens, Greece (Amanda Psyrri);Department of Medical Oncology, Division of Medical Sciences, Fox Chase Cancer Center, Philadelphia, USA (Barbara Burtness)


ImpactFactor


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

Functional limitationsfollowing breast cancertreatment influence mortality� JNCI

Physical limitations following breast cancertreatment, defined as reported difficulties

in the completion of tasks of everyday living, canhave far-reaching effects on how long womenlive, a US study has found. Older breast cancerpatients in particular, and those who are over-weight, are more likely to experience functionalimpairments for at least 18 months after treat-ment. The research indicates that the health ofbreast cancer survivors couldbegreatly improvedwith simple modifications in habits, such asbecoming more physically active.

Breast cancer survivorship is increasing dueto improvements in early detection and adjuvanttherapy. Since overall survival is considered themost therapeutically relevant outcome for can-cer patients, little attention has been paid to thephysical limitations and other health problemsaffectingwomenwhohavehadbreastcancer.Butthe recentUS InstituteofMedicine reportempha-sised the need to identify high-risk breast cancerpopulations who could be targeted with inter-ventions to promote quality and length of life.

To determine how physical limitations fol-lowing initial breast cancer treatment affectmorbidity and mortality among women whohave had breast cancer, Dejana Braithwaite andcolleagues from the University of California, SanFrancisco, studied 2202 women diagnosed withstage I, II or III breast cancer between 1997 and2000. The women were followed for up to 11years after diagnosis.

Baseline questionnaires, completed on aver-

Limitations of the study include the fact thatinformation on physical impairments was avail-ableonlyafter initial treatment so that functionallimitations prior to cancer diagnosis could not beevaluated. The lack of a control group also meantthat theeffectofphysical limitationsonmortalitycould not be compared between women withand without breast cancer.

In an accompanying commentary, HarveyJay Cohen from Duke University Medical Center(Durham, North Carolina), writes that the study’sconclusions could be incorporated into a cancersurvivorship plan, especially for elderly survivors.“Such an evaluation could guide therapy regard-ing underlying co-morbidities and otherreasons for functionaldecline, suchasobesityanddecreased physical activity.”

� D Braithwaite, WA Satariano, B Sternfeld et al.

Long-term prognostic role of functional limitations

among women with breast cancer. JNCI 6 October

2010, 102:1468–1477

� HJ Cohen. Functional assessment and the

cancer survivor: something old, something new. ibid,

pp 1450–1451

Reduced-intensity treatmentdelivers similar benefits tostandard therapy in earlyHodgkin’s lymphoma� New England Journal of Medicine

Patientswithearly-stageHodgkin’s lymphomashowed similar rates of disease control

regardless of whether they were treated withstandard or reduced-intensity chemotherapyand radiation, a study from the German Hodgkin

age21monthsafterdiagnosis, askedparticipantsabout endurance, strength, muscular range ofmotion and small muscle dexterity followinginitial treatments such as chemotherapy, radia-tion therapy or hormone therapy. The study thenexplored theextent towhich the impact of func-tional limitations on survival differed as a func-tion of age, body mass index (BMI), tumour stageand other lifestyle characteristics.

Results showthatat leastonefunctional lim-itation was present in 39% of study participants.The authors found that functional limitationsincreased with age - 39.3% of women with oneor more functional limitation were aged 65 to 79versus 23.8% of those without any functionallimitation (P<0.001). Women with limitationswere also more likely to be overweight or obese– 35.7% of women with one or more functionallimitations had a BMI of at least 30, versus 21.4%of women without limitations (P<0.001).

More women with functional limitationsdied from causes other than breast cancer –8.9% of women with versus 2.7% without limi-tations (P<0.001). In contrast, similar propor-tions of patients with and without functionallimitations died of breast cancer (P=0.99)

“A new finding from this analysis amonglonger-term breast cancer survivors is thatfunctional limitations following initial adjuvanttreatment primarily affect overall and compet-ing-cause survival, but not breast cancer-specificsurvival,” write the authors. The study, they add,underscores the need to track long-term effectsand explore whether they are amenable to inter-ventions. “...functional statusmaybean importantaddition to clinical screening among breast can-cerpatients to identifygroups thatareathighriskof poor prognosis, allowing the targeting offunctionally impaired patients to improve qual-ity and length of life.”

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Study Group (GHSG) has concluded.The integration of the chemotherapy regi-

men consisting of doxorubicin, bleomycin, vin-blastine and dacarbazine (ABVD) with radiationtherapy resulted in greater efficacy and allowedthe radiation field and dose to be reduced, lead-ing to widespread use of the combinedapproachinpatientswithearly-stageHodgkin’s lymphomaand a favourable prognosis. Four cycles of ABVDfollowed by 30 Gy of involved-field radiationtherapy is now regarded as the standard of careby many groups.

In1998theGHSG initiated theHD10 study toinvestigate whether fewer cycles of chemo-therapyand lowerdosesof radiotherapycouldbedelivered while maintaining high rates of diseasecontrol in patients with early-stage Hodgkin’slymphoma and a favourable prognosis.

Between May 1998 and January 2003,GHSG investigators, led by Andreas Engert,from the University Hospital of Cologne (Ger-many) randomly assigned 1370 patients withnewly diagnosed Hodgkin’s lymphoma and afavourable prognosis in a 1:1:1:1 ratio to oneof four treatment groups – four cycles ofABVD followed by 30 Gy radiation (group 1,n=346), four cycles of ABVD followed by 20 Gyradiation (group 2, n=340), two cycles of ABVDfollowed by 30 Gy radiation (group 3, n=341),or two cycles of ABVD followed by 20 Gy ofradiation therapy (group 4, n=343). Patientswere recruited and treated at 329 hospitals andoutpatient practices in Germany, Switzerland,the Netherlands, the Czech Republic and Aus-tria. The primary outcome was freedom fromtreatment failure, with secondary endpointsincluding progression-free survival, completeresponse and treatment toxicity.

Results show that, at five years, rates offreedom from treatment failure were 93.0% forthe four-cycle ABVD regimen versus 91.1% forthe two-cycle regimen (P=0.39).AmongpatientsrandomisedtofourcyclesofABVD, five-year ratesof freedom from treatment failure were 92.8%with 20 Gy compared with 93.1% with 30 Gy.Patients treated with two cycles of chemother-apy had 90.9% freedom from treatment failurewith 30 Gy and 91.2% with 20 Gy. The intentiontotreatanalysis showednosignificantdifferences

between the two chemotherapy groups for thesecondary endpoints of overall survival (P=0.93)and progression-free survival (P=0.28).

Grade 3 to 4 adverse events occurred in51.7% of patients treated with four cycles ofABVD versus 33.2% receiving two cycles(P<0.001). Additionally, grade 3 to 4 adverseeventsoccurred in8.7%ofpatientswhoreceived30Gyversus2.9%whoreceived20Gy (P<0.001).

“In summary, the HD10 trial showed that inpatients with early-stage Hodgkin’s lymphomaand a favourable prognosis, treatment with twocycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and lesstoxic than, four cycles of ABVD followed by30 Gy of involved-field radiation therapy,” writethe authors.

The overall survival rate of 94.8% at eightyears for all patients in the study, add the authors,may suggest that some patients are still beingovertreated. The introductionofpositron-emissiontomography, theyadd,mighthelp identifypatientswho can be cured with even less treatment.

� A Engert, A Putsches, HT Each et al. Reduced

treatment intensity in patients with early-stage

Hodgkin’s lymphoma. NEJM 12 August 2010,

363:640–652

Ovarian cancer strategiesdemonstrate similar survival� New England Journal of Medicine

Neoadjuvant chemotherapy followed byinterval debulking surgery was shown to be

non-inferior to primary debulking surgery fol-lowed by chemotherapy in patients with bulkystage IIIC or IV ovarian cancer, a collaborativestudy by researchers from the EORTC Gynaeco-logicalCancerGroupandtheClinical TrialsGroupof the Canadian NCI has reported.

Primary debulking surgery followed by adju-vant chemotherapy is the standard of care forpatients with advancedovarian cancer.However,in several prospective studies investigatorshave evaluated outcomes with neoadjuvantchemotherapybeforecytoreductive surgeryasan

alternative approach. One meta-analysis of suchtrials showed worse outcomes for those receiv-ing neoadjuvant chemotherapy compared withthose undergoing primary surgery.

Between September 1998 and December2006, 632 patients from 59 centres in eight coun-tries with stage IIIc or IV epithelial ovarian carci-noma, fallopian tube carcinoma or primaryperitoneal carcinomawere randomised toprimarydebulking surgery followed by platinum-basedchemotherapy (n=336) or to neoadjuvant plat-inum-basedchemotherapy followedbydebulkingsurgery (n=334). The primary endpoint was over-all survival with the trial statistically powered toevaluate non-inferiority of the neoadjuvantchemotherapy versus primary surgery.

After a median follow-up of 4.7 years,results show that patients with neoadjuvantchemotherapyhadamedianoverall survivalof30months versus 29 months for patients receivingprimary surgery. Subgroup analysis failed toidentify any patient or tumour characteristicsthat were associated with better outcomes withone treatment than the other.

For both treatment groups the strongestpredictor of overall survival was complete resec-tion of all macroscopic disease. For the primarysurgery group, median overall survival was 45months for patients who had no residualtumours, 32 months for patients with residualtumoursmeasuring1–10mm,and26months forpatients with residual tumours greater than10 mm. For the group receiving neoadjuvanttherapy, the corresponding figures were 38, 27and 25 months respectively.

“In conclusion, among patients withadvanced (stage IIICor IV)ovarian, fallopian-tube,or peritoneal ovarian carcinoma, survival afterneo adjuvant chemotherapy followed by intervaldebulking surgery is similar to survival after pri-mary debulking surgery followed by chemother-apy,” write the authors, led by Ignace Vergotefrom Leuven University Hospitals (Belgium).

Given these findings and the results of otherstudies, the authors suggest that the goal oftherapy should be the elimination of all macro-scopic residual disease, rather than the elimina-tion of lesions larger than 1 cm in diameter.“A potential drawback of neo adjuvant

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chemotherapy followed by debulking surgery isthat the occurrence of fibrosis after chemother-apy may make complete resection of macro-scopic disease more difficult,” write the authors.

The standard of care for women with stageIIIB or earlier-stage epithelial ovarian cancer (agroup with a better prognosis) remains primarycytoreductive surgery, say the authors, addingthat it is also important to rule out primarytumours of gastrointestinal origin when select-ing patients for neoadjuvant chemotherapy.

� I Vergote, CG Tropé, F Amant et al. Neo

adjuvant chemotherapy or primary surgery in stage

IIIC or IV ovarian cancer. NEJM 2 September

2010, 363:943–953

Less-invasive lymph nodesurgery is safe inbreast cancer� Lancet Oncology

Breast cancer patients with biopsies detect-ing no cancer cells in the sentinel lymph

nodes who avoided axillary lymph node dissec-tion (ALND) showed the same overall survival ateight years as women who underwent ALND,reports the largest ever randomised trial ofbreast cancer surgery.

Sentinel lymph node (SLN) surgery wasdesigned to minimise the side-effects of lymphnode surgery but still offer equivalent outcomesto ALND. The National Surgical Adjuvant Breastand Bowel Project (NSABP) B-32 trial, led byDavid Krag from the University of Vermont(Burlington, Vermont), set out to establishwhetherSLNresectionachieves thesamesurvivaland regional control as ALND.

Between May 1999 and February 2004, thephase III trial enrolled 5611 women with inva-sive breast cancer and randomly assigned themin a 1:1 ratio to either group 1 (n=2807), whoreceived SLN biopsy plus ALND, or to group 2(n=2804) who received SLN biopsy alone (withALND only if the SLNs were positive). Thewomen were operated on by more than 200

axillary disease might arguably be clinically rele-vant if it translates intooverall survivaldifferenceswith longer-term follow-up,” he writes.

� DN Krag, SJ Anderson, TB Julian et al. Sentinel-

lymph-node resection compared with conventional

axillary-lymph-node dissection in clinically node-

negative patients with breast cancer: overall survival

findings from the NSABP B-32 randomised phase

3 trial. Lancet OncolOctober 2010, 11:927-933

� JR BensonAn alternative to initial axillary-lymph-

node dissection. ibid pp 908–909

Study helps definemetastatic breast cancerpatients benefittingfrom phase I trials� British Journal of Cancer

Around one-fifth of patients with metasta-tic breast cancer (MBC) entered for phase

I clinical trials show a measurable benefitafter four months, a single-institution UKstudy has reported.

Despite recent advances in drug develop-ment, most women with MBC have a limitedmedian survival time of approximately 18–24months, with only around 20% alive five yearsafter diagnosis of metastatic disease. Patientswho remain sufficiently well may be offeredearly experimental phase I trials, but appropriateadvice for patients remains uncertain due tolimited studies documenting outcomes. A recentretrospective analysis reviewing outcomes forpatients with MBC participating in phase I clin-ical trials at MD Anderson Cancer Center (Hous-ton, Texas) found patients had a median overallsurvival of 6.7 months. In the current study,Charles Swanton and colleagues performed asimilar retrospective analysis on MBC patients atthe Royal Marsden Hospital (Sutton, UK) enter-ing phase I clinical trials, to further characterisethis cohort of patients.

In the study, outcomes for 70 patients withMBCtreatedbetweenOctober2002andOctober2009 in30phase I trials in theDrugDevelopment

surgeons from 80 centres in Canada and the US.Outcomes analyses were undertaken in patientswho were assessed as having pathologicallynegative sentinel nodes and for whom follow-up data were available.

Altogether 3989 of participants in the studyhad pathologically negative sentinel nodes.Results show that the eight-year Kaplan–Meier estimates for overall survival were 91.8%(95% CI 90.4%–93.3%) in group 1 and 90.3%(95% CI 88.8%–91.8%) in group 2.

Eight-year Kaplan–Meier estimates fordisease-free survivalwere82.4%(95%CI80.5%–84.4%) in group 1 and 81.5% (95% CI 79.6%–83.4%) in group 2.

Additional results showthat therewereeightregional node recurrences as first events in group1 and 14 in group 2 (P=0.22). The most commonadverse events were allergic reactions, mostlyrelated to the administration of the blue dye.

“Our trial shows thatoverall survival, disease-free survival, and regional control were all sta-tistically equivalent in SLN-negative patientswho had an ALND (group1) or SLN surgery alone(group2),” conclude the authors, adding thatresults published earlier from the trial havealready shown that patient-reported outcomesand morbidity related to range of motion,oedema, pain and sensory defects were lower forthe SLN group than the ALND group.

“NSABP B-32 results suggest that when theSLN is negative, SLN surgery alone with no fur-ther ALND is an appropriate, safe, and effectivetherapy for patients with breast cancer,” theauthors conclude.

Inanaccompanyingcommentary, JohnBen-son fromtheUniversityofCambridge (UK)wrote,“The paper from Krag and colleagues consti-tutes a seminal publication on the primary end-points of loco regional recurrence and overallsurvival for the largest randomised trial of SLNbiopsy. It vindicatescontemporarypracticeofSLNbiopsy and provides support for a reduction inextent of axillary surgery for most patients withbreast cancer.”

However, Benson cautioned that longer fol-low-up is required, and highlighted the fact thatthere were almost twice as many regional recur-rences in theSLNbiopsyonlygroup. “Lowvolume

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Unit at the Royal Marsden Hospital wereanalysed. For those women who had partici-pated in more than one trial, only the first trialentry was considered for the analysis.

Results show that the median overall survivalwas 8.7 months and the median time to progres-sion was 7.0 weeks. In all, eight women (11.4%)obtained a partial response, 12 (17.1%) had sta-bledisease, and50 (71.4%)hadprogressivediseaseat first radiological assessment. The overall clini-cal benefit rate (defined as partial response plusstable disease) at four months was 20%.

Patients with triple-negative breast cancershowed greatest clinical benefit rate, at 30.7%,while HER2-positive patients showed a clinicalbenefit rate of 19% and oestrogen receptor (ER)-positive/HER2-negative patients showed a clin-ical benefit rate of 8.7%.

In a multivariate analysis, abnormal lactatedehydrogenase levels, serum albumin less than35mg per 100 ml, more than five previous treat-ment lines, liver metastases and ECOG (EasternCooperative Group) performance status greaterthan 2 at study entry were significantly associ-ated with poor overall survival. In addition, themultivariate analysis showed that patientstreated in trials based on a PARP inhibitor had asignificantly longer time to disease progression(Cox regression HR 0.45, 95% CI 0.23–0.86;P=0.015). No patients discontinued the trialsdue to treatment-related toxicities.

“Early patient referral in selected tumourtypes and chemo-refractory disease may aug-ment the chance of benefit to experimentaltherapies. In addition, selection of patients basedonprognostic tools canassistgo-no-godecisionson trial participation for those least likely tobenefit,” write the authors.

The shorter median overall survival found inthe MD Andersen patients, add the authors,probably results from patient heterogeneity andthe inclusion of greater numbers of poor prog-nostic patients.

� AT Brunetto, D Sarker, D Papadatos-Pastos, et

al. A retrospective analysis of clinical outcome of

patients with chemo-refractory metastatic breast

cancer treated in a single institution phase 1 unit.

Br J Cancer 24 August 2010, 103 607–612

Advanced GIST patientsshould remain on imatinib� Lancet Oncology

Interrupting imatinib (Glivec) after three yearsin responders with advanced gastrointestinal

stromal tumours (GIST) leads to a high risk ofrapid progression, the BRF14 trial by the FrenchSarcoma Group has reported.

Imatinib mesylate – a small-moleculeinhibitor targeting mutations of the KIT orPDGFRAgenes thatencodetyrosinekinase recep-tors–hasgreatly improvedoutcomes forpatientswith advanced GIST, increasing survival from25% in the era before imatinib to 75% after itsintroduction. Resistance to imatinib, however,begins to occur after 20– 24 months, due largelyto the acquisition of additional mutations.

Since the effect of imatinib discontinuationon progression-free survival and overall survivalin long-lasting responders with advanced GISTwas unknown, Axel Le Cesne and colleagues,from the Institut Gustave Roussy (Villejuif,France), undertook the current study.

For the open-label, multicentre phase IIItrial, the investigators identified 50 patients withnon-progressive GIST (according to RECIST cri-teria) who had been taking imatinib 400 mg/dayfor three years, and randomised them to eithercontinue (n=25) or stop taking the drug (n=25).

Results show that after a median follow-up of 35 months, two-year progression-free sur-vival was 80% in the continuation group versus16% in the interruption group (P<0.0001). Themedian time to progression was nine monthsafter randomisation in the treatment interruptiongroup, and had not been reached among thegroup that remained on imatinib (P<0.0001).

All but three patients in the discontinuationgroup relapsed, most (68%) within a year ofstopping therapy. Of the three patients who didnot relapse, one had refused to stop imatinib andthe other two had their tumours resected.

Among21patients in the interruption groupwith progressive disease, 20 resumed treatmentwith imatinib at the time of progression. Tumourcontrol (complete response, partial response orstable disease according to RECIST) was obtained

in all cases three months after the imatinib re-challenge. Re-introduction of imatinib upontumourprogression in20patientswasassociatedwith 100% tumour control after three monthsaccording to RECIST criteria.

One important issue to be explored waswhether imatinib interruption affects the emer-genceof resistance.Results showednodifferencein mutations between the two groups (P=0.826).

“Our findingsshowthat imatinib interruptionin the setting of advanced disease results inrapid progression in most patients,” write theauthors, addingthat the timetosecondary resist-ance was similar in the two groups. “[This] showsthat imatinib interruption neither prevents norpromotes the emergence of imatinib resistancein GIST,” theyconclude. Theabsenceof anyeffectof imatinib interruption on overall survival, writetheauthors, couldallow imatinib-free intervals incases of prolonged and uncomfortable side-effects related to the drug.

They note that similar findings have beenreported in chronic myeloid leukaemia (CML),where a pilot phase II trial showed that ima-tinib interruption resulted in a rapid molecu-lar relapse in 50% of patients judged to be incomplete response.

In an accompanying commentary, MichaelHeinrich from Portland VA Medical Center (Port-land, Oregon), wrote that these findings supportthe need for continuous treatment with tyrosinekinase inhibitors in GIST, CML and by extension inother cancers responsive to such drugs. “Thesefindings also suggest that current efforts toimprove thepotencyof TKIsagainst theactivatedoncogenes in CML and GIST might improve theduration of disease control, but will not be suf-ficient to achieve a cure,” writes Heinrich, addingthat therapieswith theability toeradicate the ini-tiating stem cells are needed for a cure.

� A Le Cesne, I Ray-Coquard, B N Bui, et al.

Discontinuation of imatinib in patients with

advanced gastrointestinal stromal tumours after 3

years of treatment: an open-label multicentre

randomised phase 3 trial. Lancet Oncol October

2010, 11:942–949

� MC Heinrich. Imatinib treatment of metastatic

GIST: don’t stop (believing). ibid pp 910–911

cancer world 40

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