Cancer World 35

� Alain Fourquet: taking multidisciplinarity one step further � The EBCC cofounderwho opened the minds of Europe’s cancer doctors� Preoperative breast MRI: the prosand the cons � Patient groups are delivering life-saving messages all over the world

Alain Fourquet

Education & knowledge through people & facts

Number 35, March-April 2010

CancerWorld

35MARCH-APRIL

2010

CANCER WORLD � MARCH/APRIL 2010 � 1

Contents

3 EditorialStop excluding male patients

4 Cover StoryAlain Fourquet: taking multidisciplinarity one step further

15 e-Grand RoundNeutropenia in cancer patients: risk factors and management

26 Cutting EdgeMRI for breast cancer: who benefits, who is harmed?

34 MasterpieceFrom unwanted interference to indispensable partner: the patientadvocate who helped open the minds of Europe’s cancer doctors

42 Impact FactorFuture directions in multimodality therapy for NSCLCSunitinib versus interferon-α in metastatic RCCNewsround

56 Patient VoiceSpreading the word: how patient groups are delivering life-savingmessages to all corners of the globe

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantCorinne Hall

Editorial AdvisorsJacques BernierFatima CardosoFranco CavalliAlberto CostaVincent T. DeVita

Contributing WritersMarc Beishon, Simon CromptonJason Faris, Janet FrickerRoy Herbst, Emma MasonSusan Mayor, Peter McIntyreDror Michaelson, Jack RothAnne Tsao

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonChatrina Melcher

Art EditorJason Harris

ProductionHarrisDPIwww.harrisdpi.co.uk

Printed byGrafiche Porpora

Cover photographFrançois Daburon

Published byEuropean School of Oncology

Direttore responsabileAlberto Costa

Registrazione Tribunale di RomaDecreto n. 436 del 8.11.2004

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

Copyright ©2010 European School of Oncology.All rights reserved

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


Editorial

� Fatima Cardoso � GUEST EDITOR

tors, treatment andoutcomes.Funding isbeingsought to finance a central analysis of the bio-logicalmaterial collected,with a virtual tumourbank being used in themeantime.The intention is toproceed toa randomised

clinical trial of endocrine therapy,whichcouldbe launched as part 3 of this programme. Inviewof the failureofallpreviousattempts to runa clinical trial in this setting, a fully committedinternational effort will be indispensable.Securing funding for such a non-drug

related, purely academic effort has been adauntingprocess,demonstratingonceagain theneed for a central funding body in Europe.While continuing to look for additional sourcesof funding, work on the retrospective analysishas already begun thanks to support from theUSBreast Cancer Research Foundation.This research programme could greatly

enhanceourknowledgeof thebiologyofmalebreast cancer – anessential first step to guidethe development of future therapies. Whilewaiting for the results, a plea is made to allthose involved in the design and implemen-tationof breast cancer trials to stopexcludingmale patients without a good reason. Ifexcludingmalepatients fromendocrine ther-apy trials may be understandable, excludingthem from trials of cytotoxic and biologicalagents is not. Cancer societies and organisa-tions alsoneed toplay their part, by increasingefforts to raiseawarenessandestablishsupportgroups for these patients.

Stop excludingmale patients

Male breast cancer is a raredisease, accounting for lessthan1%ofall breast cancers

worldwide.According to theAmericanCancerSociety, last year it was expected that around1910 men would be diagnosed with breastcancer in the US with around 440 deaths,comparedwith around192,370expectednewcases and 40,170 deaths amongwomen.Male breast cancer patients go through

their difficult fight with very little support,whilehaving to copewith theadditional stigmaof having a ‘female disease’. They also sufferfroma lackof evidenceonhowbest tomanagetheirdisease.Nota single randomisedphase IIItrial has ever been concluded on male breastcancer. As a consequence, management ofmale breast cancer is mainly done by extrapo-lation from its female counterpart.The Breast International Group and the

North American Breast Cancer Groups havenow joined forces to launch a three-part inter-national research programme for male breastcancer, coordinated by the EORTC. It haskicked off with ameta-analysis of clinical dataandacentral pathology reviewof tumour spec-imens from about 1700 male breast cancercases diagnosed in participating institutionsover the last 20 years. Part 2 of the programmewill involvebuilding aprospective internationalregistryofallmalebreastcancercasesdiagnosedat participating institutions over a two-yearperiod, tocollectdataondemographics, risk fac-

Fatima Cardoso is a medical oncologist from the Jules Bordet Institute in Brussels, Belgium, and is the principal investigator of theInternational Male Breast Cancer Programme. e-mail: [email protected]

CoverStory

4 � CANCER WORLD � MARCH/APRIL 2010

Alain Fourquet:taking multidisciplinarity one step further

� Marc Beishon

Alain Fourquetwill break new ground thisMarchwhenhe becomes the first radiation oncologist to

chairEurope’smajor breast cancer conference,EBCC7.Hebelieves progress is beinghamperedby

tunnel-vision drug trials, with protocols that are blind to the effect that the compounds, and the

timing of their delivery, have on the patients’ sensitivity to radiotherapy and the toxicity of the overall

treatment.Delegates can expect to hear a call for radio-oncologists to be involved at an earlier stage.

The importance of a truly multidiscipli-nary approach to cancer care, thoughalmost universally acknowledged, hasyet to be realised in practice outside ofthe top cancer hospitals. Lack of

resources, industry influence, fragmented hospitaldepartments andascendancyof certainpersonalitiesand specialisms – all these play a role in stallingprogress. And all are especially apparent in AlainFourquet’s specialty, radiationoncology,whichdespitebeing one of the three central pillars of cancer treat-ment is often relegated to last place behindmedicaloncology and surgery.

As Fourquet, head of radiation oncology and aspecialist inbreast cancer andbreast conservation atthe Curie Institute in Paris notes, it is not just theshortage in many countries of equipment and spe-cialists suchasmedical physicists and radiographersthat accounts for poor recognitionof the role of radi-ation oncology. “One problem is that people are

understandablyexcitedaboutnewtargeteddrugs,butin some of themajor trials we are seeing treatmentsappliedwithout any real evidence ofwhat order andforhowlongweshouldbedoing things, suchaswhento give adjuvant chemotherapy and radiotherapy andhow to determine efficacy and toxicity. People tendto lackknowledgeandexpertise in treatmentsoutsidetheir own specialism,” he says.

“Another goodexample is the trend to implementpartial breast irradiation in some countries, such asthe US. We don’t know whether it is effective –there is no proper science behind it. The history ofcancer treatment and breast cancer in particular isthat you cannot decide quickly on the effectivenessof new treatments – it can lead to much frustrationandmisleadingconclusions.”And failure to integrateinsight andexpertise across thedisciplines is behindmuchof the rush topremature judgements, headds.

Fourquet speakswith theauthority of virtually anentire career spent in breast radiation oncology, and

CoverStory


with an immense knowledge base on some of theoldest – and tried and tested – techniques. “Weknow that adjuvant radiotherapy cuts the risk ofrecurrenceof breast cancer by70%–75%.There areno drugs that do that,” he says.

Certainly, if there is one place in Europe where asupportive culture of all disciplines, and radiotherapyin particular, is apparent, it is the Curie Institute –foundedbyoneof themost famousscientists, radiationpioneerMarieCurie, andaclinician,ClaudiusRegaud.

“Of course, radiotherapy alongwith surgerywerefor many years the only options for treating cancerbefore we had chemotherapy,” says Fourquet. “ButtheCurie andFranceoverall has aparticularheritage

in using radiation in breast conserving treatment,whichactually goesback to the1950s.When Icamehere it was standard treatment, but unusual else-where. Ithasbeenroutine inFrenchcentres since theearly 1970s – and wasn’t recommended in the USuntil the end of the 1980s.”

Fourquet’s contribution to the field can best bedescribedas steady, if not spectacular, in linewithhisbelief in the importanceof applying researchover thelong term to understand properly the mechanismsinvolved in certain approaches. Implementingradiotherapy techniques in general has also been amajorpreoccupation in recent years.Withcolleaguesat the Curie, he has been patiently building up

FRANCOISDABURON

“Adjuvant radiotherapy cuts the recurrence of breast

cancer by 70%–75%. There are no drugs that do that”

optimal radiation treatment regimens for breast can-cer, and now, as department head for all cancertypes, he has been bringing in the new technologiesthat have radically changed radiotherapy–butdoingsowith caution and a heavy emphasis on training.

In addition to clinical work, Fourquet has beeninstrumental in driving clinical and translationalresearch at the Curie, which is also France’s largestcancer research institute as well as being a compre-hensive cancer centre with its own hospital (in factit has two hospitals now, following a recent mergerwithCentreRenéHuguenin, another cancer centrein Paris). “The future clearly lies in gaining a muchbetter understanding of the biology of breast cancer

andother tumours, and I thinkwehave the toolsnowto identify targets not only for drugs but for radio-therapy too.”

A case in point is work being carried out by oneof his PhD students on genetic profiling of youngerwomenwith breast cancer –why they have a higherrecurrence rate and the response to radiotherapy.“This is something I’ve had in mind for some time,andwas startedbymystudentwith colleagues at theNational Cancer Institute in Amsterdam, and iscontinuinghere, aswehavea largegenomicplatform.More results will be presented at the EuropeanBreast CancerConference [EBCC].”

Fourquet has a vested interest in publicising the

“I think we have the tools now to identify targets

not only for drugs but for radiotherapy too”

CoverStory


FRANCOISDABURON

and chairman of the entire department by 2006.“I did though spend a year on a fellowship at the

Memorial Sloan-Kettering in New York, workingwithSamuelHellman,whowasoneof the first in theUS to report breast conserving treatment. Iwas veryclose tohim.He is a great physician andadedicatedscientist, andwas anexample formanyofmygener-ation. He encouraged me to build up a long-termresearch programme, whichwe have done.”

But it has not been easy to build up translationalresearch, inparticular. “Itwasn’t verypopularwith thebiologists here at first, but we now have severaltranslational programmes in my field.” The CurieInstitute is now the largest cancer researchcentre inFrance, working to an international level in manyfields. Recent additions include a developmentalbiology and cancer centre, opened in 2008.

TheCurie, he adds, hasbeen rather slow topub-licise its achievements and scale –most in the can-cer community would cite the Gustave RoussyInstitute in the Paris suburb of Villejuif as France’spremier cancer centre. “Theyhavebeenmore activewith their PR – but we will be launching a newwebsite this year with a special breast cancer focusthat will highlight our achievements and facilitiesmuch better,” he says.

Apart from themain research and hospital loca-tion incentralParis, theCuriealsohas labs in thesub-urbofOrsay, andbased there isoneofonly twoprotontherapy machines in France (the other is in Nice).“Thenwith themergerwithCentreRenéHugueninwe will go up to 3000 breast cancer patients a year,from 1700,” says Fourquet, “and we aim to haveone in five patients for all tumours in clinical trials.”

It is a substantial operation, and he also empha-sises that the Curie has not only some of the mostmodern treatment technologies and research plat-forms, but also the databases and experience, inbreast cancer in particular, going back decades,which are proving valuable for research.

One key finding has been fundamental to pro-moting the benefits of radiotherapy. “We have beenable to demonstrate that radiation for breast cancer

EBCC–he is the chair of this year’s event, althoughhe isnotoneofEurope’s greatmeetingattendees.Hetends to pick and choose where he travels, andelected not to go to the SanAntonio breastmeetinglast year, for example. “I agreed to takeon theEBCCfor two reasons. First, it is becoming an importantEuropeanconferenceandweneed tohaveevents likethis here. I don’t see it competingwith theUSand ithas awidermultidisciplinary emphasis.Andsecond,as far as I know, therehasnotbeena radiationoncol-ogist in the chair until now.”

With colleagues, Fourquet has shortened theconference to three and a half days – it was too longbefore, he says – and he is injecting more practicaldebate on clinical cases and controversies, alongwith the traditional coverage of both clinical andresearch topics across the breast cancer spectrum.“Wehavekept the formatofparallel sessionsandcov-erageof organisational andpolitical issues aswell.Ofcourseweneed tobalanceall interests,with thecon-ference being jointly organised by Europa Donna[European Breast Cancer Coalition], EUSOMA[EuropeanSociety ofBreastCancerSpecialists] andthe EORTC (European Organisation for ResearchandTreatment ofCancer].”

As for theprofileof radiationoncologyat this year’sEBCC, it’s no accident that among a good showingfor the field thekeynoteEmmanuel vanderSchuerenlecturewill beon ‘Researchprogress andpriorities inbreast radiotherapy,’ to bedeliveredby JohnYarnold,a clinical oncologist at theRoyalMarsden inLondon.

Fourquet knewhewanted tobeadoctor fromanearly age, andwent tomedical school inParis.But likemany,hischoiceof specialismcamebychance. “Iwasinterested in oncology and haematology, and anopportunity came to work at the Curie, where thedirector was then Robert Calle, one of the pioneersof breast conservation.” He obtained a resident’spost and has never really looked back.

Althoughsomeother cancer sites formedparts ofhis earlywork, suchas lymphomasandHodgkin’sdis-ease, hemoved rapidly intobreast, becomingheadofthe radiationoncologybreast cancer serviceby1991,

CoverStory


“I don’t see EBCC competing with the US,

and it has a wider multidisciplinary emphasis”

notonlyhasan impacton local control andhelpspre-serve the breast in good condition, but also has animpact on survival, independent of other treatments,which has come recently from statistical overviewssuchas thatby theOxfordGroupunderRichardPeto.Properly doing our radiation treatment has a sec-ondary impact on distantmetastases and cuts long-termmortality.”

As he adds, “Wewere not able to show this for along time, because the way radiotherapy was deliv-ered20 to30years ago introducedsequelaeand long-term complications, and even radiation-relatedmortality. That’s not the case anymore – we canspare the toxicity and see the long-term impact.Here, we now offer radiotherapy to 85% of womenoperated on for breast cancer, which is not the caseeverywhere, although that’s partly due to lack ofaccess to facilities.”

That radiotherapy technology has moved onrecently is anunderstatement.AsFourquetnotes, thekey linear accelerator (linac)machineshavenot onlybecomemuchsmaller andmore reliable,butalso rad-ically improved with techniques such as IMRT(intensity-modulated radiotherapy) and integrationwith sophisticated imaging. “The machines we usenow can provide different photon energies for vary-ing the dose, and the combination of imaging andIMRTmeans that rather thangiving ahomogeneousdose to one region we can adapt to the anatomy orshape of a tumour. The first big stepwas 3Dconfor-mational targetingandalsobeingable tomeasure theactual dose in a [tumour] volume and organs at risk,whichwe couldn’t do before.”

TheCurie,headds,wasoneof the first inEuropeto install a tomotherapy machine, which has a CTscanner and linac built into a circular head andallowsmodulateddoses tobedelivered at any angle,with the patient on a moving table. “We can reallyfocus treatment on complicated volumes with this,such as being able to spare salivary glands almostcompletelywhen treatingheadandneckcancer– it’sbetter thanwhat is now conventional IMRT.”

Hestresses, though, that the aim is tohave a ‘one

stop shop’ for all radiotherapy options – simplemachines are fine for some treatments, such as skincancer–andwith theproton facility anda largenum-ber of differentmachines at themain institute (thereare seven linac suites alone), he feels this aimwill beachievedwith thedelivery of anewprotonmachine,expected this April, which will replace an outdatedunit. “In patientswithmelanoma of the eye, we canachieveabout95% local controlwithprotons.Weareaiming especially to treatmore childrenwith protontherapy, which will help to cut the long-term risk ofcontracting other cancers later in life.”

Amajorproblemis thesheercomplexityof thenewtechnologies. “It has been like moving from a single-seaterplane toanAirbus–wehavemanymorecontrolsand verification systems, as sources of error are noweverywhere. It’s verydemanding in termsof trainingandawareness andwe have to be extremely cautious.”

Fourquet has a small army of physicists,dosimetrists, radiographers and so on in his largedepartment – the simulation and set-up involved inpreparing and delivering treatment is very labourintensive and requires extensive knowledge, despitethe fact that it is all doneoncomputers.He ismind-ful that France, like most countries, has had disas-trous failureswith radiotherapy—as recently as2007therewas amajor scandal when it was revealed thatahospital inEpinal, northeastFrance,hadoverdosedmany patients, some of whomdied.

“That was a good example of many things youshould not do,” says Fourquet. “The second Frenchcancer plan, which was issued recently, addressesquality in radiotherapy with more radiation oncolo-gists andmedical physicists, and a minimum num-ber of patients that a centremust see. It also focusesmuchmore onmultidisciplinaryworking and trans-lational research. Tomymind it ismuchbetter thanthe first plan, although that did generate investmentinmoremodern facilities across the country.”

The new criteria for radiotherapy units include aminimumof600patients a year,with twomachines inoperation to increase ‘up time’. “Youcannothaveacen-trewithonly onemachineanymore,whichmaycause

“We aim to treat more children with proton therapy,

which will cut the risk of other cancers later in life”

CoverStory


that DCIS was radio-resistant so the whole breastshould be removed. We started a prospective data-base, which now has 30,000 files, and by 1989 wewereable to showthat treatmentwithconserving sur-gery and radiationhas a similar rate of recurrence aswith invasive cancer.This triggereda lot of studies tounderstandDCIS.”

Then there is ongoingworkonyoungerwomenathigh risk of cancer through the genetic BRCA1/2mutations. It had been thought that mastectomy isnecessary because conserving surgery followed byradiation would be detrimental because of a lack ofDNA repair genes, and cancer may be induced.“But we have been able to show, with others, thatthere arenomore recurrences than in thosewithoutthe mutations. The explanation seems to be that,although these aggressive tumours lack the ability to

usproblemswithcapacity.Wealsohavebigdiscussionshereaboutwhetherweshouldmove topublishingout-comes of hospitals as well, as theUK is doing.”

The application of radiotherapy in breast cancerhas meant applying evidence-based research tocounter dogmaover the years, saysFourquet, so anynew research focus inFrance’s cancerplan is only tothe good. The demonstration of a mortality impactafter controlling for factors suchas cardiacmortalityhas itself helpeddispel thedogma that camewith thechemotherapy era– that breast cancerwasmetasta-tic and local treatment could have no impact. “Thequality of local treatment actually then declineduntil we could show its survival impact,” he notes.

“Wealsopublishedoneof the first papersoncon-serving treatment forDCIS [ductal carcinoma in situ– non-invasive cancer]. Back then therewas dogma

CoverStory


“It has been like moving from a single-seater plane

to anAirbus... sources of error are now everywhere”FRANCOISDABURON

therapy toolderwomenhere, asweknowwecanalsospare theheart and lung, andwehaveparticular reg-imens for frail patients.”

Some oncologists are suggesting now that olderwomen do not need radiotherapy, but as Fourquetpoints out, “With the benefit of cutting the risk ofrecurrence by 70%–75%, what threshold do youdecide this is useless for any group?Yes, there couldbeapatient forwhomyouestimate the risk is1%over10 years, so I agree, a drop to 0.3% or so is tiny. Butthat is notmost patients – theonly group I can thinkof arewomenwhohave surgery andendocrine treat-ment – and then the question is: Which is better, afewcourses ofnon-toxic radiotherapyor five ormoreyears of endocrinedrugswithpotential side-effects?”

A trendhe isparticularly concernedaboutnow ispartial breast irradiation. “The idea of treating onlypartof thebreastwith radiationcameabout for agoodreason instates suchasLouisianaandTexas in theUSwhere access to health facilities can be poor andwomen often cannot afford to travel long dis-tances for several radiation cycles. Ratherthan carrying out mastectomies, oncolo-gists wondered if they could preserve thebreast and cut the number of radia-tion cycles.” The first studies withtechniques such as brachytherapy(implanted radiation sources) wereinteresting, he says, and industrythen stepped in with many moreapproaches. InEurope, countrieswithoverstretched radiotherapy units alsobecame interested, in particular theUK, Italy andHungary.“Butwedon’t know if it is effective–

there is no real sciencebehind the ideaofirradiating a smaller volume. There aretrials runningnowthatwill eventually give an

answer, but not after five years, asmost recur-rences by then are in the initial site. By ten years

and beyond we will see if there are differences.Whatweknowfromtrials suchas that carriedoutby

“You could make a small gain by adding a chemo cycle

and lose it by delaying radiotherapy,”

CoverStory


repair the DNA mutations, they are actually moresensitive to radiation.This is ongoing researchandweneed more data, but we have good clues now.”Anothermajor study, carriedoutbyFourquet andcol-leagues in the EORTC, has shown the benefit of ahigher ‘boost’ radiation dose for younger women,and is also the subject of more ongoing trials inFrance and theNetherlands.

At the other end of the age spectrum, he isequally sure that olderwomendeserve the opportu-nity to have a full range of treatment, includingradiotherapy and chemotherapy, provided healthassessments showtheycan tolerate it. “WhentheUK,for example,decidednot to treatwomen justbecausethey were old back in the 1970s and 80s, the out-comes were terrible. We nearly always offer radio-

therapy raises concerns about long-term harm, butthis was not tested in any trial.

“This is a typical example with new agents –angiogenesis inhibitors suchasbevacizumab[Avastin]can be similarly toxic with radiotherapy.Weneed tobe involved to test new compounds for both toxicityandefficacybycoordinating trial designwithmedicaloncologists and industry. It’s too late when the trialsare running.”

With breast cancer 10-year survival rates up to85%, and local recurrence at 6%over the same time, itis of course the groupswhohavehigh recurrence ratesthat most concern Fourquet and colleagues, and theneed to avoid unnecessary treatment to others. Likemany radiationoncologists, he can see thepotential toevolve the field into guiding radiation by tumour biol-ogy rather than just conventional imaging. “Weneed tobe able to predict the radiosensitivity of tumours,knowing how various subtypes express genes involvedinDNArepair.Wecanalsoexpect tomodulate thewaywe give radiation according to the structure of thetumour,wherewe could vary treatment depending onwhich part of it is growing, using functional imagingsuch as PET.We are already using PET to target vol-umes inHodgkin’sdisease that sparesother tissues.Butweneedmorebacking for research into radiobiologyandexperimental radiotherapy.”

Expect many of these themes to be aired at theEBCC, and for radiation oncologists to be pretty vis-ible, such as one of Fourquet’s most well-known andclosest colleagues,HarryBartelink, long the radiationexpert at theAmsterdamNational Cancer Institute.

Fourquet’swifeNicole is also inmedicine,work-ing as a health geographer, and they have three chil-dren, oneofwhomis abiologist, andonegrandchild.That no doubt sparks conversation about his mainaim– to drive techniques such as gene profiling for-ward into everyday guidance for radiation. That’sambitionenoughhe feels, and in anycasehecan seeno reason to leave France’s premier cancer insti-tute.AndwithMarieCurie’s laboratory preserved ina small museum on the site, there is certainlymoti-vation to build on her legacy.

Umberto Veronesi on conserving surgery aloneagainst surgeryandwholebreast irradiation is that youhave three to four times the number of recurrencesif you don’t do radiotherapy, and we know in thelonger term we see recurrences elsewhere in thebreast, evenclonal recurrences– thesameas theorig-inal tumour – far from the initial site.”

Asheadds, the trialsmustgoon. “But theapproachgoes againstwhatwehave learnedaboutbreast cancer– the host, genetic predisposition and precancerouslesionsmakeup thebackground fordeveloping thedis-ease and the effect of radiation on the whole organ iswhy itworks. There is no logic to applying a small vol-ume of radiation just because you can.”

Wheremultidisciplinarity is becomingespeciallyimportant now is in untangling the impact of themanycombinationsof treatmentoptionsopeningupwith targeted agents. The problem is, saysFourquet, that there is sometimes scant regardfor designing trials that demonstrate the efficacy/toxicity balance. “In the conventional surgery,chemotherapy, radiotherapy sequence, there canbetrials to insertmorecyclesofchemotherapy, each timepostponing radiotherapy, despite the fact we haveshown that the interval between surgery and radio-therapy may have an impact on local control. Youcouldmakea small gainbyaddingachemocycle andlose it by delaying radiotherapy, and the patients getmore treatment for no benefit.” Resources such asAdjuvant! Online also make no mention of radio-therapy, he notes.

Things get more complex with the addition ofagents such asHerceptin (trastuzumab),which canimprove adjuvant chemotherapy in 20%of patients.“In the first trials itwas givendifferently – inEuropein the largeHERAtrial itwas startedafter theendofall therapy, including radiotherapy. But in theUS, itwas startedwith chemotherapy and continued dur-ing radiotherapy–but itwasnot tested, just decided.Herceptin is known to improve the radiosensitiveeffect in vitro, the same type of effect we see withanthracyclines and other drugs. It also has potentialcardiotoxicity, so giving it at the same time as radio-

CoverStory


“Wemust coordinate trial design with medical oncologists

and industry. It’s too late when the trials are running”

e-GrandRound


Neutropenia in cancer patients:risk factors and management

Neutropenia – low levels of neutrophils – poses a serious threat to patients on chemotherapy. It

exposes them to the risk of infection – including potentially fatal infections – and also leads to

delays in treatment and reductions in dose intensity, which can compromise the chance of a

favourable outcome.Awareness of risk factors and prompt action are essential.

Severe neutropenia places patientsat high risk of serious infection.The lower limit of normal blood

neutrophil count is approximately2000/mm3. Counts below this are clas-sified as neutropenia, and graded accord-ing to severity. Counts below 500cells/mm3 are categorised as grade 4,between 500 and 1000 as grade 3,between1000 and1500 grade2, and theleast severe – between 1500 and 2000cells/mm3 – grade 1.

Neutropenia increases suscepti-bility to infection, particularly in can-cer patients. We have known sincethe early 1960s that both durationand severity of neutropenia are factorsthat lead to febrile neutropenia – feverand infection – in cancer patients.The duration of neutropenia is par-ticularly important in terms of therisk of infections.

Some key lessons in the manage-ment of febrile neutropenia in cancerpatients have been learned since the1960s. We have learned to anticipatethe problem, and to see and evaluateour patients promptly when any sign ofan infection occurs. We have learned

The European School of Oncology pres-ents weekly e-grandrounds which offerpar ticipants the oppor tunity to dis-cuss a range of cutting-edge issues,from controversial areas and the latestscientific developments to challeng-ing clinical cases, with leading expertsin the field. One of these will beselected for publication in each issueof Cancer World.In this issue, David Dale, of the UniversityofWashington, inSeattle, USA, reviews therisk factors associatedwith neutropenia incancer patients treated with chemother-apy, together with management strate-gies to reduce adverse outcomes.Jeffrey Crawford, of the Duke UniversityMedical Center, in Durham, North Car-

olina, USA, poses questions that explorethe issue further. The presentation issummarised by Susan Mayor.

The recorded version of this and other e-grandrounds, together with 15 minutes ofdiscussion, is available at www.e-eso.net/home.do

where to examine the patient, lookingparticularly at the skin, themouth, thearea around the anus, and the abdomenfor signs of infection.A complete bloodcount should be taken, includingwhite blood cell count (WBC),WBC differential, haemoglo-bin, haematocrit and plateletcount. If there is fever andsevere neutropenia, it is essen-tial to start antibiotics promptly.These basic clinical practicesare extremely important for thewelfare of our patients.

For the past few years, I havebeen working with my col-leagues in theANC (Awarenessof Neutropenia in Chemother-apy) study group towards defin-ing as precisely as possible therisk factors associated withinfection, fever, reduction inchemotherapy and unfavourableoutcomes in cancer treatment.Or, looked at from another per-spective, we have beenworkingto identify the factors that lead toa favourable outcome.

RISK FACTORSMostclinicianswhohavebeen inpractice for a longtime will have had expe-riences of patients doingunexpectedly poorly ordying early in cancertreatment. This riskheightens concern aboutproviding good care andemphasises the need toknow the landmarksalong the way to avoidthis very unfavourableoutcome.

The figure belowoutlines the factors thatare associated withneutropenia in cancerpatients as well as theprognostic factors or risk

factors for unfavourable outcomes inpatients receiving chemotherapy.

One of the most important findingsmade by the ANC study group a fewyears ago is that the greatest risk offebrile neutropenia in a patient receiving


e-GrandRound

a course of chemotherapy iswith the firstcycle. The figure opposite (top) showsthe hazard ratio or risk of febrile neu-tropenia in patientswith non-Hodgkin’slymphoma receiving standard-doseCHOP(cyclophosphamide, adriamycin,vincrinstine and prednisolone) or equiv-alent chemotherapy. There is a majorpeak of febrile neutropenia occurringabout 10 days into treatment – at thetime of maximum neutropenia withthese standard drugs. Later cycles tendto be associated with less severe risk offebrile neutropenia.

Many factors may account for thisobservation, including dose reductionsand adaptation of the haematopoieticsystem after an episode of neutropenia.It is important to realise that neutrope-nia is a predictable result of exposing thehaematopoietic system to standardmyelotoxic chemotherapy drugs. Thispattern of febrile neutropenia peaking inthe first cycle of treatment is observedacross awide spectrumof different typesof cancer, indicating that it is a generalpattern and that great vigilance is

required with the first cycle oftreatment with myelotoxicagents in all types of cancer.

In the course of our research,we looked at risk factors for neu-tropenia. The figure opposite(bottom) shows important andcommon risk factors, identifiedusing a riskmodel basedon1246patients with non-Hodgkin’slymphoma who were receivingCHOP.The easily identified riskfactors, shown here for patientswith lymphoma but more gen-erally applicable, are: age, albu-min (as a proxy for nutritionalstatus), the intensity ofchemotherapy, the startingwhiteblood cell or neutrophil count,and the presence of hepatic dis-ease. The more risk factors, thegreater the risk. Being aware of

PROMPT TREATMENT IS KEY

The risk of febrile neutropenia (FN) rises steeply in cancer patientsthe longer severe neutropenia persists unchecked

Source: Adapted from Luiz Meza et al. Proc Am Soc Clin Oncol2002; 21: abstract 2640

RISK FACTORS AND COMPLICATIONS

Knowing what to look out for is key to avoiding the worst outcomes

PS, performance status; BSA, body surface area; BP, blood pressure;BL counts, blood leukocyte counts; Hb, haemoglobin; LDH, lactatedehydrogenase; BUN, blood urea nitrogen; BOI, burden of illness;Source: GH Lyman The Oncologist 2005; 10:427-437. Reproducedwith permission of ALPHAMED PRESS

these risk factors helps health pro-fessionals to anticipate the problemof febrile neutropenia.

Multivariate analysis shows thatage is a very important risk factor,and all older cancer patients need tobe aware that they are at greaterrisk of febrile neutropenia whenstarting chemotherapy, usually notjust because of their age but alsobecause of the comorbidities thataccompany the ageing process.

MORTALITY, MORBIDITYAND COSTSPatients who have febrile neu-tropenia that makes them sickenough to be admitted to hospitalhave a high risk of an unfavourableoutcome.A study by Kuderer et al,which looked at more than 40,000adult cancer patients treated inlarge US hospitals, found a mor-tality rate of 9.5% (Cancer 2006,

106:2258). This increasedto 21.4% in those withmorethan one comorbidity. Otherrisk factors formortalitywerefungal infections, sepsis andpneumonia. Mortality isobviously a severe concern,but hospitalisation and pro-longed illness also carrymajor healthcare costs.

Myelosuppressivechemo-therapy-inducedneutropeniacauses a range of problems,including febrile neutropeniaand increased risk of severeinfection. It also leads todelays in chemotherapydosesand dose reductions. Thedose may be reduced eitherby giving a smaller amount ofdrug, or by extending the timeover which it is given, result-ing in a reduction in doseintensity. Both can lead toreduced survival.

There are reasonablygood data to indicate thatdose intensity is very impor-tant. The strongest datacome from studies in early-stage breast cancer.A retro-spective study carried outby Bonadonna et al, follow-ing up patients for at least20 years, showed thatrelapse-free survival andoverall survival decreased inline with chemotherapydose intensity (NEJM 1995,332:901–906). Survival ina study by Pfreundschuhand colleagues of patientswith non-Hodgkin’s lym-phoma (another chemo-therapy-sensitive cancer)showed similar results(Blood 2004, 104:634–641).There may be some cancerswhere chemotherapy is less

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Five significant risk factors for febrile neutropenia have beenidentified – the more risk factors a patient has, the higher theirrisk of febrile neutropenia

RDI relative dose intensity, ANC absolute neutrophil countSource: Personal communication, Lyman et al, ANC study group,Duke University, USA

THE FIRST CYCLE CARRIES THE HIGHEST RISK

The greatest risk for febrile neutropenia comes 10days after the start of chemotherapy in patientswith aggressive non-Hodgkin’s disease

In patients with the five most common cancers, themajority of severe neutropenic episodes (between53% and 71%) occur with the first cycle

CUMULATIVE RISK FACTORS

Source (left): Lyman GH, Morrison VA, Dale DC et al. Risk of febrile neutropenia among patients with intermediate

grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leukemia and Lymphoma 2003, reprinted by

permission of the publisher (Taylor & Francis Group, http://www.informaworld.ocm)

Source (right): Adapted from J Crawford et al. J Natl Compr Canc Netw 2008; 6:109–118

effective, but overall it is clear thatgiving full-dose, or standard-dose,chemotherapy is the way to achievethe best outcome for patients.

It is very important to be aware thatrelative dose intensity (ameasure of thedelivered dose intensity as a proportionof the standard dose intensity) is oftenunderreported in randomised con-trolled trials and long-term outcomesare also not reported. However, whendata are available, we have found thatdose reductions are very common. Thestrongest data suggestthat a reduction in thedose to less than 85%of what would be pre-dicted to be optimaltherapy is quite com-mon in many cancers(Dale et al, JNCCN2003; 1:440-454).

A study of breast can-cer adjuvant chemother-apy for a large USpopulation showed that

around 50% of patientsreceived less than full-dose chemotherapy. Thisis a concern, and weshould aim to optimisetherapy by finding waysto give treatment at thedose that has beenshown to be effective inrandomised trials.

MANAGEMENTSTRATEGIESTo reduce the risk ofneutropenic events,including infections,and to avoid dose reduc-tions in the course ofgiving cancer chemo-therapy, our focus hasbeen on prevention.Treatment of patientswith febrile neutrope-nia admitted to hospital

has improved modestly over the years,with better supportive care and betterantibiotics, but problems remain, andprevention is themost important strat-egy to reduce the risk of undertreatingor infections in the course of givingcancer chemotherapy.

There are three approaches:� delay or reduce the drugs� administer prophylactic antibiotics� givehaematopoietic growth factors or

myeloid growth factors in a prophy-lactic strategy.

Dose reductionThere is little or no evidence that using adosebelow85%of that recommended isfavourable for anypatient group, althoughit is a common strategy in palliative careto try tomaintain apatient’s quality of lifeand days that they have to live.

Prophylactic antibioticsA large randomised trial conducted byCullen et al., comparing the quinoloneantibiotic levofloxacin with placebo inpreventing infection associatedwith can-cer chemotherapy in a large and diversegroup of patients, mostly with solidtumours, showed that the antibioticreduced the occurrence of febrile neu-tropenia. However, it did not reducedeaths (NEJM 2005, 353:988-998).

There are several issues associatedwith this approach, including that therisk of giving prophylactic antibiotics tothe large numbers of patients undergo-ing treatmentwith cancer chemotherapymay result in the development of resist-ant organisms that might cause infec-tions later in cancer treatment.

A second international study withlevofloxacin in patients with cancerand neutropenia, carried out by Bucan-eve and co-workers, also showed that itwas effective in reducing febrileepisodes (relative risk 76%), but therewas no significant effect on infectiousdeaths or overall deaths (NEJM 2005,353:977–987). The results show thebenefits of antibiotics in reducing thenumber of bacteria in the short term.However, based on clinical experience,this is only a short-term effect, becausethe body surface is a rich place forbacteria and fungi to grow, and sup-pressing some organisms enables oth-ers to rapidly emerge.

Haematopoietic growth factorsHaematopoietic growth factors havebeen a research interest of mine for along time, both at basic and clinical lev-els. Colony stimulating factors, or


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MULTIVARIATE ANALYSIS OF RISK

An analysis of risk factors in patients whose treatment was reducedto less than 85% of recommended dose intensity showed thatbeing aged over 60 was the biggest single risk factor

*Adjusted for year of treatment, planned duration of treatment andpractice siteSource: GL Lyman et al. Incidence and predictors of lowchemotherapy dose-intensity in aggressive non-Hodgkins’s lymphoma:A nationwide study. JCO 2004; 22:4302-4311Reprinted with permission. © 2008 ASCO. All rights reserved

DOSE REDUCTIONS

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myeloid growth factors, werediscovered in the 1960s, utilisinga simple Petri dish culture sys-tem. Discovering how to growblood cells in vitro was a dra-matic event – very important inthe history of haematology andin the development of modernmedical oncology.

Probably themost importantfinding in this research was thediscovery of the specific factorsthat regulate haematopoiesis.Out of this work came the drugwe call G-CSF – granulocytecolony stimulating factor –whichis a relatively small glycoproteinproduced in many cell types inthe body, in response to a rangeof stimuli including injury orinfection. Over time, it waslearned that the levels ofG-CSFin the body regulate the produc-tion of neutrophils.

We now know that levels of G-CSFincrease abruptly when a patient devel-ops an infection. However, becominggradually neutropenic – as occurs withcancer chemotherapy – does not usuallycause G-CSF levels to rise until neu-trophils have reached a very low level.The problem with the onset of neu-tropenia after cancer chemotherapy isthat the signal to recover neutrophilsoccurs late, and gradual recovery occursif you wait for this natural response.

This understanding led to the devel-opment of an important clinical use ofG-CSF as a drug to accelerate neu-trophil recovery after chemotherapy.G-CSF has often been compared toGM-CSF – granulocyte-macrophagecolony stimulating factor – because ithad similar effects in the early studiesin the Petri dishmodel. However, GM-CSF is a distinctly different moleculeand is produced by different cells, par-ticularly T-cells andmonocytes. Exper-imental studies have shown that

deficiencies of G-CSF cause neu-tropenia, but deficiencies of GM-CSFdo not. GM-CSF is a very differentagent biologically, with different clini-cal effects.

G-CSF/FILGRASTIMG-CSF, or filgrastim (a G-CSF ana-logue), has a helical structure, whichgives themolecule its three-dimensionalshape,which is key for interactingwith itsreceptor onmyeloidcells.G-CSF acts specificallyon myeloid cells thathave a receptor for themolecule.G-CSFstimu-lates neutrophil prolifer-ation and accelerates thedelivery of neutrophilsfrom the bone marrowinto the blood. Normalneutrophil developmentand deployment occursat three levels. In themarrow, cells develop

from stem cells to mature neu-trophils. In theblood,neutrophilsflow alongwith the red cells, butthey stick at sites of inflamma-tion. In the tissues, theymigrateto fulfil their function in the con-tainment and killing of bacteriaand in mounting a response toinfection.

In studies to understand therole of G-CSF, we gave theseagents to healthy young and eld-erly volunteers. We were inter-ested in the ageing process andwhether older people wouldrespond less well. The studiesshowed that age does not blockthe response to G-CSF. Thebottom line is that a wide rangeof patients with differentcomorbidities and varying inmany other factors, includingage, all respond toG-CSF quitewell, if they have haematopoi-

etic cells in their marrow that are capa-ble of responding.

An important point in termsof oncol-ogy practice is the effect of G-CSF andGM-CSF on marrow transit time. Inour studies we looked at how theseagents stimulate the flowof cells throughthe bone marrow. With no drug, thetime for production of a neutrophil, fromthe last stage of dividing cells to amatureneutrophil in the marrow and its entry

NORMAL NEUTROPHIL KINETICS

REDUCED DOSE INTENSITY IS COMMON

The number of breast cancer patients found to be on a reduceddose intensity is a cause for concern, given what is known aboutthe impact of reductions in dose intensity on survival

Source: GL Lyman et al. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: A nationwidestudy of community practices. JCO 2003; 21:4523–4531.Reprinted with permission. © 2008 ASCO. All rights reserved.

that G-CSF acceleratesneutrophil recoveryafter chemotherapy;the return of bloodneutrophils was muchfaster in the G-CSFtreated patients.

In subsequent clini-cal trials, Timmer-Bonte and othersdemonstrated the sameeffects of G-CSF use toprevent febrile neu-tropenia with lessmyelotoxic chemother-apy regimens. For exam-ple, in the trial byCrawford et al, therewas approximately a60% risk of febrile neu-tropenia. In the Tim-

mer-Bonte trial, patients hadapproximately a 30% risk of febrileneutropenia, and G-CSF treatmentalso reduced this risk by about 50%(Proc ASCO 2004, 23:726).

This is such an important develop-

into the blood, was about six days. Giv-ingG-CSF accelerates the time format-uration of neutrophils and their entryinto the blood.We showed thatG-CSFcan reduce the time formaturation anddeployment of neutrophils by about50%, reducing the time for cellsto transit through themarrow tothe blood from approximatelysix to three days. By stimulatingneutrophil production and entryinto the blood, G-CSF helps toincrease the accumulation ofthese cells at sites of infectionand inflammation.

Crawford and Trillet-Lenoirand their co-workers were earlyinvestigators of G-CSF incancer chemotherapy; theirwork emphasises the princi-ples mentioned above. Theirreports were the first todemonstrate a reduction in theoccurrence of febrile neu-tropenia in randomised con-trolled trials (NEJM 1991, 325:164-170; EJC 1993, 29A:319-324). Their studies showed

ment that there have beenmany effortsto improve on it over the years. Themost valuable was the development ofthe pegylatedmolecule (pegfilgrastim),adding polyethylene glycol, making theG-CSF molecule bigger and therebyreducing its renal clearance.

A clinical trial carried out by Vogeland co-workers showed that using peg-filgrastim in patients who were treatedwith less intensive chemotherapy andwhose risk of febrile neutropenia wasonly approximately 20% virtually elim-inated the risk of febrile neutropenia(JCO 2005, 23:1178-1184).

ISSUES IN THE USE OF G-CSFAlthough these data are very soundand we can rely on them to set theguidelines in cancer practice, manyquestions remain. These includewhether the dose of G-CSF can bereduced, whether there is a differencebetweenG-CSF and pegylatedG-CSF,the place of GM-CSF versus G-CSF,and the use of G-CSFwith other drugssuch as corticosteroids, which also

raise neutrophil counts. Thereare also questions about tim-ing – should we give G-CSFearly, late, or for a few days?Many of these questions havegeneral answers, althoughmosthave not been subjected to largerandomised trials.

Because themyeloid growthfactors G-CSF and GM-CSFcan stimulate proliferation ofboth the normal and leukaemiccells, researchers and physi-cians have been concernedabout the potential risks asso-ciated with their use. Recentlythe ANC study group per-formed ameta-analysis to inves-tigate the risk of myelodysplasiaand leukaemia associated withthe use of G-CSF as part ofsupportive care for patients


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BENEFIT OF G-CSF/FILGRASTIM

G-CSF/filgrastim has been shown to result in a significant reductionin cases of febrile neutropenia among cancer patients receivingchemotherapy

Source: Adapted from J Crawford et al. NEJM 1991; 325:164–170;V Trillet-Lenoir et al. Eur J Cancer 1993; 29A:319-324

BENEFIT OF CSF/PEGFILGRASTIM

Pegfilgrastim virtually eliminated febrile neutropenia in cancerpatients at 20% risk of developing the condition

Source: Vogel et al. First and subsequent cycle use of pegfilgrastimprevents febrile neutropenia in patients with breast cancer: Amulticenter, double-blind, placebo-controlled phase III study.JCO 2005; 23:1178–1184Reprinted with permission. © 2008 ASCO. All rights reserved.

receiving cancer chemotherapy.A sys-tematic review of randomised trialscompared the outcomes for cancerpatients receiving either chemother-apy alone or chemotherapy plusG-CSF. The study showed a small butstatistically significant increase in theoccurrence of leukaemia in patientswho were randomised to receiveG-CSF. On the other hand, overallmortality rates were lower in thepatients treated with G-CSF. TheG-CSF treated patients also receivemore chemotherapy – a finding thatcomplicates the interpretation of thesedata, because many commonly usedmyelotoxic drugs can cause leukaemia.There are also other limitations thatmake these data and similar studiesdifficult to interpret. The trials wereobviously not conducted to seewhether treatment causes leukaemia;it is only observed as an adverse effect.There were also variations between tri-als in the way adverse effects weredescribed and how long the patientswere followed before the results of thetrial were reported. Some of the ‘con-trol’ patients may also have been givenG-CSF, if they seemed to need it. Thisstudy was presented and discussed atthe American Society of Hematologymeeting in December 2009.

Nevertheless, the increase inleukaemia with G-CSF treatment wasabout 0.4% and supportive care withG-CSF is associated with an absolutereduction in all-cause mortality ofabout 3%–4%.

ASCO guidelines on the use ofwhite blood cell growth factors recom-mend that G-CSF should be usedwhen there is a risk of febrile neu-tropenia of greater than 20%, unless thetreatment is symptomatic or palliative,when dose reduction is usually appro-priate. The guidelines also say that pri-mary prophylaxis – the use of CSFs forprevention in the first cycle of treat-

ment – should always be considered forolder patients, or where the patient’smedical history or other disease char-acteristics suggest that there is sub-stantial risk of febrile neutropenia.

TheNational Comprehensive Can-cer Network (NCCN)CSF guidelinesrecommend focusing on three aspectsof each patient when determining riskfor febrile neutropenia:� Patient-related aspects: age, gen-

der, performance and nutritionalstatus, comorbidities,

� Treatment-related aspects: neu-tropenia, drugs – anthracyclines,relative dose intensity,

� Cancer-related aspects: some can-cers, including haematologicalmalignancies and lung cancer, andall cancers at advanced stage, pre-dispose patients to infections.

The NCCN growth factor algorithm

for prophylaxis with growth factorsaddresses whether chemotherapy iscurative, intended to prolong survival orto help with symptommanagement, orpalliative. For cases with a >20% risk offebrile neutropenia with chemotherapy,the CSFs have a benefit that should beconsidered. CSFs should not be usedwhere the estimated risk is less. Insummary:� UseG-CSF if there is a high risk of

febrile neutropenia (>20%) withcurative intent, to prolong survival,to improve quality of life.

� Consider G-CSF if risk of febrileneutropenia is 10%–20%.

� Do not use G-CSF if risk of febrileneutropenia is <10%.

Each patient should be assessed fortheir risk of febrile neutropenia, anddecisions on whether to give CSFsshould be based on this risk.

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BENEFITS OUTWEIGH RISKS

A review of randomised controlled trials showed a small but significant rise in leukaemia among cancerpatients receiving G-CSF as supportive care, but this was far outweighed by the fall in mortality

Source: American Society of Hematology Meeting, December 2009

CONCLUSIONSNeutropenia, febrile neutropenia andreductions in chemotherapy dosingremain serious problems in medicaloncology. Delivering chemotherapyat standard doses and on schedule isimportant in optimising outcomes.

There is good physiological and clin-ical evidence for the use of G-CSF toprevent febrile neutropenia and ame-liorate the myelotoxicities of cancerchemotherapy. Evidence-based med-icine and clinical guidelines supportthe use of G-CSF to prevent

chemotherapy-induced neutropenia.Prophylactic antibiotics are alterna-tives to the CSFs. Treatment offebrile neutropenia, when it occurs,requires very careful attention to thepatient, prompt antibiotic therapyand good hospital care.


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Jeffrey Crawford (JC), of the Duke University Medical Center, in Durham,North Carolina, USA, explored some of the issues further with David Dale (DD).

JC:Can we generalise that the standard doseof chemotherapy is standard for all patients, ordo we need to think about differences inpatients in terms of tolerance to chemotherapy?DD: It is important to see the differencesbetween patients and patient groups.Ageis a critical differentiating factor: it bundlestogether comorbidities and many otherfactors. Patients over the age of 65, or cer-tainly over age 70, should always be con-sidered at risk and therefore potentialcandidates for some prophylactic strategy.A second differentiating factor is thepatient’s blood cell counts. Patients whohave evidence of previous haemotoxicityfrom drugs or disease are at greater risk,particularly if they have a low white cellcount or lowneutrophil count. The generalphysical examination andbasis blood countalso help us to easily identify patients atgreater risk of febrile neutropenia andother complications.Another differentiating factor is the spe-cific drug to be given in the plannedchemotherapy regimen. This is a compli-cated area, because there are so manydrugs and combinations. The NCCNguidelines (readily available at nccn.org)provide the best information availableabout relative risk of neutropenia andsevere neutropenia with different drugs.JC: Should there be differences in dosingbased on different ethnic populations?DD:There areprobably ethnicdifferences,

butwedonot knowverymuchabout them.For example, theAfrican/American popu-lation tends to have somewhat lower base-linewhite blood cell andneutrophil countsthan other groups, but seems to toleratechemotherapy equally well.JC: How should one calculate the dose ofchemotherapy for an obese patient?DD: This is another confusing area. Wegenerally use the body surface area orideal bodyweight instead of bodymass, asthe index for dosing, but there is a point atwhich there is considerable uncertainty.JC:Larger patients tend to beunderdosedif youuse the ideal bodyweight rather thanthe actual body weight when deliveringstandardchemotherapydoses.Even thoughthey are getting larger total doses, the bodysurface area corrects formost of that.Oneof the concerns about the poor outcomesfor obesewomenwith adjuvant breast can-cer may be that they are relatively under-dosed. Some data suggest that they haveless neutropenia, so you should at leastuse the standard of total body weight andsurface area in your calculations.There is also literature around about theimportance of neutropenia as a surrogateendpoint for chemotherapy effectiveness.There aredataon lymphomaandother set-tings that patients who develop somedegree of neutropenia have a betteroutcome than thosewhodonot.The samehas been shown in advanced-stage lung

cancer. This getsback to theques-tion, if we couldindividual isetherapy, whatwould be theright dose?Presumablywhat is happeningis that there is enoughpharmacogenomicvariation in how individuals handle drugsthat one dose probably does not fit all.But knowing the dose that achieves cyto-toxic effect on the patient and that treatstheir tumour requires further study.JC: Can you comment on the functionaleffects of G-CSF and GM-CSF?You spokeabout neutrophil numbers, but what arethe functional effects when these cytokinesare active in our bodies?DD:This is a very interesting area.G-CSFhasmany effects beyond stimulating neu-trophil production. It also activates manyprocesses in the cell. For example, it stim-ulates the formation of the enzymes thatgo into the granules of neutrophils, par-ticularly the primary granules that areinvolved with the killing of organisms.G-CSF also ‘primes’ neutrophils, so thatthey have a greater metabolic burst andgreater oxygen and glucose consumptionwhen they are exposed to bacteria or otherforeign particles.All of these changes canbe seen as part of the host response toinfection to enhance the body’s capacity todeal with an infection.

New York’s Memorial Sloan-KetteringCancerCenter, argues that the assump-tion that usingMRI to select patients forbreast-conserving therapywould reducethe need for re-excision, reduce localrecurrence, and even improve long-termsurvival does not seem to have beenborne out in practice. “At present, nostudies have provided support for any ofthese improved clinical outcomes,” shewrites. “However, breast MRI has beenshown to result in additional biopsiesand costs, increased patient anxiety, anddelays in the start of definitive treat-ment.” She points out that whileaccepted practice is for MRI-detectedabnormalities to bebiopsiedbefore alter-ing surgical treatment plans, somepatients choose to forgo thesebiopsies oradditionalwork-ups andopt to go straightfor mastectomy, “because of concernsabout delaying definitive therapy.”

MRI for breast cancer:who benefits, who is harmed?� Emma Mason

At the European Breast CancerConference in Barcelona thisyear, one of the closing debates is

entitled: “This house believes thatMRIfor breast cancer is standard of care” –thus tapping into a controversy that hasbeen the subject of much research anddiscussion in recent months and years.

For many it is not at all clear thatmagnetic resonance imaging (MRI)should be used routinely in the diag-nosing, staging and treatment of breastcancer. In fact, a number of influentialvoices have been asking whether MRIdoesmore harm than good, particularlybefore surgery in women with uncom-plicated early breast cancer.

Speaking against the motion atEBCC7 in Barcelona will be LawrenceSolin, chairman of the Departmentof Radiation Oncology at the AlbertEinstein Medical Center, in Philadel-

phia, USA. In a recent article for TheBreast (in press) Solin argues that amed-ical test or treatment should be of ben-efit to patients if it is to be used inroutine clinical practice, and that, for thetypical patient with early-stage breastcancer, “no suchbenefit has been showntodate for the routineuse of preoperativebreast MRI beyond the benefit alreadyconferred by conventional breast imag-ing (i.e.mammographywith correlationultrasound as indicated).” Thus, he con-cludes, the routine use of preoperativebreastMRI for early-stage breast cancerpatients is unwarranted.

Others go further, pointing to apoten-tial link between increased use of MRIand a rise in the rate of mastectomies,manyofwhichmaybeunnecessary. In aneditorial for the Journal of Clinical Oncol-ogy last September, Monica Morrow,head of the Breast Surgery Service at


CuttingEdge

When a woman is diagnosed with breast cancer, and a technique exists that could identify

additional lesions in the same or the opposite breast, what possible reason could there be for not

using it?Unnecessary delays and unnecessarymastectomies to name but two, say the opponents

of routineMRI. The debate continues.

CuttingEdge


GETTYIM

AGES

systemic therapies such as endocrine orchemotherapy.

“There’s fairly convincing evidencethat says thatMRI shows a lot of small-volume disease that’s always been thereand that’s successfully treated withradiotherapy, but when we see it wefeel obliged to do something about it,and that something is usually mastec-tomy,” she said.

“So far what we know aboutMRI isthat it doesn’t increase your likelihood ofgetting negative margins with a singlelumpectomy. It does not decrease therisk of unexpected conversion fromlumpectomy to mastectomy, andalthough the data with longer-term fol-low-up are still very limited, what thereare show that it doesn’t decrease the riskof local recurrence in the breast.

“So, of any of the potential benefitsto patients, none of them have beenproven.What we do know is that it candelay treatment, it results inmore biop-sies, and it increases cost.”

In a review of preoperative MRI,published in CA: A Cancer Journal for


CuttingEdge

A VERY GOOD TECHNIQUEAt the heart of this debate is the undis-puted fact that MRI is an extremelygood imaging technique. It can detecttumours that are missed by more con-ventional techniques such asmammog-raphy and ultrasound, it is better atcorrectly assessing tumour size anddetecting additional foci of disease(multi-focal ormulti-centric cancers, orboth), and it is better at detecting abnor-malities in the dense breasts typicallyseen in younger women.

Francesco Sardanelli, professor ofradiology at the University of MilanSchoolofMedicineandheadof theRadi-ologyUnit at the IRCCSPoliclinico SanDonato inMilan, Italy, pioneered theuseofMRI inbreast cancer inEurope.Writ-ing inThe Breast (inpress), heargues thatthe detection capability of this imagingtechnique is such that itwouldbewrongto wait for conclusive evidence for oragainst preoperative MRI. “To deny thisexamination to all women newly diag-nosedwithbreast cancer is aquestionabledecision because the evidence is ‘uncer-tain’ rather than against a benefit frompreoperativeMRI.”

Morrowdisagrees. “It seemsvery obvi-ous that something that shows the cancerclearlymust be a good thing for patients,”she told Cancer World, “but there is anincreasingbodyof data that shows that, sofar, this doesn’t seem to be true.”

Indeed, the success with whichMRIpicks up even themost minor abnormali-ties is exactlywhere the problem lies, shesays, asmanyof thesewill be false-positives– benign abnormalities or cancers so tinythat theywouldbedealtwitheffectivelybyradiotherapy during or after surgery, or by

“The detection capability of this technique is such

that it would be wrong to wait for conclusive evidence”

This multifocal lobular breast cancer was pickedup using normal mammography (upper), butMRI was instrumental in clarifying the real extentof the disease (lower)By permission of Elena Cauzza

Clinicians last September, NehmatHoussami and Daniel Hayes make asimilar case. “Evidence consistentlyshows that MRI changes surgical man-agement, usually from breast conserva-tion to more radical surgery; however,there is no evidence that it improvessurgical care or prognosis.” Like Mor-row, they argue that the emerging dataindicate that MRI does not reduce re-excision rates and that it causes false-positives in terms of detection andunnecessary surgery.

The authors also point out that,while local recurrence rates are between5% and 10% for breast conserving sur-gery combined with radiotherapy, ameta-analysis has found that MRIdetected additional small cancers in thesame breast in 16% of cases on average.“That’s more than twice as many as thenumber of woman who ever developevidence of a recurrence,” says Mor-row, commenting on these findings,“and I think this is evidence that thistype of disease does not need to betreated surgically.”

From the patient’s point of view,MRI gives more information, but canincrease the complexities of the deci-sion-making process, for both her andher physician.

If anMRI showsup suspicious tissueelsewhere in the affected breast, or thecontralateral breast, then internationalguidelines recommend that an MRI-

CuttingEdge


“MRI changes surgical management, however, there is

no evidence that it improves surgical care or prognosis”

“When we see it we feel obliged to do something

about it, and that something is usually mastectomy”

CLAIMS AND COUNTERCLAIMS

Supporters of routine use of MRI argue that it offers a number of benefits:� by visualising the size and extent of the disease, it can enable surgeons to excise

the correct amount of tissue, removing the tumour entirely, while not removing unnec-essarily large quantities of healthy tissue;

� this, in turn, reduces the likelihood of re-excision to remove remaining tissue that turnsout to be cancerous;

� it can reduce rates of the tumour recurring in the same breast;� it detects other tumours in the same breast (ipsilateral cancer) or the other breast

(contralateral cancer), enabling surgeons, in theory, to remove all tumours in one go;� it can visualise whether preoperative treatment, such as radio-, chemo- or hormonal

therapy, is having an effect in shrinking a tumour before surgery, possibly enablinga lumpectomy to be performed rather than a mastectomy;

� it can visualise whether the same treatments are mopping up small cancerousdeposits after surgery;

� it provides better images of dense breasts;� it is better at detecting certain cancers, such as invasive lobular breast – a partic-

ularly aggressive cancer;� all of the above could lead to an improvement in recurrence and overall survival rates.

Opponents counter that, while many of the benefits listed above were expected when MRIwas first introduced for breast cancer, they have not been borne out in reality.They argue that, on the basis of the evidence so far, MRI:� does not increase your likelihood of getting negative margins with a single

lumpectomy;� does not decrease the risk of unexpected conversion from lumpectomy to

mastectomy ;� does not decrease the risk of local recurrence in the breast.

It does, however, lead to:� additional biopsies and costs;� increased patient anxiety, and� delays in the start of definitive treatment.

guided biopsy should investigate the tis-sue. This delays the diagnosis and thestart of treatment, and introduces yetanother procedure to undergo. Alreadyanxious and stressed by the initial diag-nosis of breast cancer, many womendecide that they can’t face the addeddelay anduncertainty involved in havinga biopsy, and opt to go straight to amas-tectomy in the hope that this will dealwith all the cancer in one go.

Other factorsmay also play a role inthe decision to opt for mastectomy,such as the availability of MRI-guidedbiopsies, how they are funded (does itrequire extra permission from thehealth insurers, hence further delay),cultural differences, the medical-legalclimate of a country and the availabilityof plastic surgery.

LOSS OF FOCUSThe radiologist, physician andpatient alsohave to focusonwhatis themain threat to the patient’slife. SylviaHeywang-Köbrunner,director of the ReferenzzentrumMammographie München, amammography reference centreinMunich,Germany, toldCancerWorld, “In my experience, whenyou do an MRI and find some-thing that is enhanced, that does

delay surgery. We all try very hard toschedule the biopsy quickly, but this canbe difficult and you may also need toconsider thewoman’smenstrual cycle, sothat youpick the right timeof themonth.”

Delaying treatmentof a large, grade IIItumouron thegrounds thatMRIhas indi-cated there may be an additional smalllesion could make things worse, sheargues. “For me, the big question is: do Ihelp thepatientby finding a small, 3- to5-mmlesionelsewhere in thebreastor in thecontralateral side, if the patient’s life isreally threatenedby the first, large tumour?

“Sometimespeoplewant to diagnoseevery little patch and are not aware ofwhat really threatens the patient’s life.Oneshould reallyconsiderwhichpatientscanwehelpwithMRIandwhichpatientsmight we delay the diagnosis and cause

more problems thanwe solve.“I think we should be very careful not

to over-read andovertreat.Westill need toprove whether, by finding additional tinyfoci, that’s helpful for thepatient, becausewe cause harm by converting from breastreconstruction tomastectomy if thepatienthas no better survival.”

WHO NEEDS MRI?So when should MRIs be performedand when not? Most commentatorsseem to agree about when they can beuseful, but there is less agreement aboutwhen MRI should be avoided, withsomeproponents of the technique argu-ing that it should always beusedbecauseof the extra information it provides.

Morrow and Heywang-Köbrunnerboth argue against usingMRI inuncom-plicated early breast cancerwhere otherimaging techniques suffice.

“I definitely would not recommendMRI in breasts that are adequatelyanalysed by mammography and ultra-sound, or by a combination,” says Hey-wang-Köbrunner. “This combinationhasan acceptable sensitivity [proportion oftrue-positives correctly identified], espe-cially for the lesions that are larger than5 mm; the false-positive rate is muchlower than MRI and, importantly,it’s very easy to clarify something thatI see. For instance, if I see something onmammography or ultrasound, a mam-mographically-guidedprocedure or ultra-sound-guided procedure can be donevery fast, it’s reliable and you have thepeople availablewho cando it and this issolved very easily.”

She does, however, recommend anMRI in dense breasts and where lobular


CuttingEdge

MRI scans have a high false-positive rate. On this scan, the areacircled in blue showed a highlysignificant signal, yet nothing wasfound on pathological investigation.The area circled in red was foundto be an invasive cancer, and thearea in green a fibroadenomaBy permission of Elena Cauzza

“Some people want to diagnose every little patch and

are not aware of what really threatens the patient’s life”

THE RIGHT QUESTIONSMorrow agrees that more research isneeded to establish where the informa-tion provided by MRI might help. “Forexample, one such clinical problem iswomen who received chemotherapyprior to surgery to shrink their cancers toallow a lumpectomy; it’s very difficult toevaluate how much cancer is actuallypresent. And that’s a place where MRIappears to be better than other toolsthat we have.”

What we don’t need, she says, isyet another general study ofMRI for allbreast cancer patients, “because I thinkthat question ‘can it findmore cancer?’has been asked and we know theanswer is yes, but that doesn’t say thatit benefits patients.” Questions aboutwhether MRI can identify a subset ofpatients who don’t benefit from radio-therapy or a subset who are appropriatefor radiating only part of the breast,would, however, be useful to investi-

breast cancer has been diagnosed,“because we know that mammographyandultrasound isweak in these situationsandmight not detect quite large tumoursthat could threaten the patient’s life, orwouldmakeachangeof therapynecessary.”

MRI may also be beneficial, sheadds, in women who are at high risk ofinherited breast cancer, in youngwomenwith dense breasts, in caseswhere thereis a big discrepancy in the size of thetumourwhenmeasured bymammogra-phy and ultrasound and possibly also tohelp a surgeon who is uncertain aboutwhether mastectomy or breast recon-struction is the best way forward.

Heywang-Köbrunner would like tosee research to findoutwhetherMRIcanoffer early evidence if a certain treat-ment, suchas chemotherapy, is notwork-ing. “If we can find this out early on, wecan suggest a changeof chemotherapy sothat the patient does not lose time on atreatment that is not going to work.”

gate, says Morrow. “There’s room formore of these trials that ask about thebenefit to patients.”

One thing thatmost people agree onis the need for expertise in the use andinterpretation of MRI. Alberto Costa,director of ESO (the European Schoolof Oncology), and coordinator of boththe Breast Surgery Unit at theMaugeriFoundation in Pavia, Italy, and theCan-ton Ticino Breast Unit in Lugano,Switzerland, summed it up: “You needto have a radiologist who is specialisedin magnetic resonance imaging andthen sub-specialised in breast cancer.Otherwise, MRI can create incredibledisasters. It’s a very good technique, anew technology, which could be of greathelp in genetically predisposedwomen,in preoperative medical treatment andin a number of other situations, butwhich, in not very expert hands, couldcreate damage because it can over-estimate the diagnosis.”

CuttingEdge


MRI tends to throw up more false-positives than either mam-mographyorultrasound, andgreat caremust be takenwhenusingpreoperativeMRI to guide decisions on surgery.The most frequent causes of false-positives include adenosis(a benign condition affecting the lobes in the breast) andbenign tumours such as fibroadenomas or papillomas. Less fre-quently, inflammatory changes, granulomas or lipo-fillingmaycause confusion.Lipo-filling is a new technique in plastic surgery whichinvolves aspirating fat tissue from another part of the patient’sbody and then re-injecting it into the areas of the breast thatare not completely filled, making it possible to shape the breast

better. But breast surgeon Alberto Costa warns that on MRIit can be mistaken for an area of cellular growth. “This hap-pened to me, when the radiologist saw this and rangme to saythat here were multiple recurrences and we needed to do animmediate mastectomy,” says Costa. “Luckily we worked outwhat the problem was.”Evenwhen theMRI shows real cellular growth, he adds, whileit may be cancer, it may also be general growth, such as a scar.“So if youdomagnetic resonance too soon after surgery, it’s biasedbecause it will flag up areas of cellular growth that are simply theprocess of scarring after surgery. So you never doMRI after sur-gery earlier than at least a month or six weeks.”

When MRI throws up false-positives

More research is needed to establish where the

information provided byMRI might help

From unwanted interferenceto indispensable partner

The patient advocate who helped open the minds of Europe’s cancer doctors

� Simon Crompton

As founding president of Europa Donna, the European Breast Cancer Coalition,

Gloria Freilich helped transform attitudes towards patient advocacy. She would like to see

further progress, particularly in regions that have been slow to accept a patient role, and advises

that her softly softly approach – building confidence and allaying suspicions – is the way to go.

Three years after taking up the presidency ofEurope’s first international breast cancercoalition, Gloria Freilich faced her most

embarrassing moment. It was 1997 and she hadstarted to address a major meeting of oncologists inLisbon, talking about her neworganisation, designedby women for women, called Europa Donna. Thena doctor stoodup and challengedher.What right dida layperson, he asked, have to address a thousandoncologists at a medical meeting?Freilich was flabbergasted.Many of the doctors

there were too. She gathered herself, and answeredthat she had a right to be there because shewas rep-resenting the other side of themedical equation– thepatient viewpoint. Then she carried on with herpresentation, uninterrupted.Recalling the event 13 years later, her presi-

dency of Europa Donna now in the past, it stillmakes Freilich’s toes curl. Nowadays, such an inci-dentwould be unthinkable. It’s amark of howmuchEuropaDonna has helped change attitudes that the

patient viewpoint is now intrinsic to top-level inter-national discussions about breast cancer. UnderFreilich’s leadership, aEuropeanbreast cancer organ-isation representing the interests of patients earnedaplace at the scientific tablenot by confrontation, butby instilling respect amongmedical colleagues. Theprocess hasn’t always been easy.So Freilich’s proudestmoment came three years

later when, after the end of her presidency, shestoodup again to speak, this time in Strasbourg to 90Members of the European Parliament and the thenEuropeanHealthCommissionerDavidByrne.WhenEuropaDonnahadbeen set up, its instigator, surgeonUmberto Veronesi, told Freilich that its aspirationshould be to address the European Parliament andgain its support for improving diagnostic and treat-ment services across the whole continent.Now, by a strategy of making the patient voice

indispensable rather than anunwanted interference,it had achieved this aim. In her Strasbourg address,Freilich emphasised the need for a European breast


Masterpiece

cousin and aunt had also died of thedisease shortly after diagnosis. Sothere was good reason for having acheck, even though there was asyet no national screening pro-gramme in the UK. When shearrived at the hospital, the mam-mogram machine had brokendown. So she had to go to another,where themachinery had a peculiarballoon contraption instead of aplate to hold the breast in place.“I must say, I remember it very

well because itwas very difficult notto laugh while it was happening,”says Freilich. “You were kind ofsquashed downunder this balloon,and itwas only a single viewof eachbreast, not two views as one wouldexpect now. And I was told thateverything was fine.”“That summer I went away on

holidaywithmyhusband to Italy. Itwas two months after I’d had themammogram, and pulling myswimsuit up I found a lump aboutthe size of a plum inmy left breast.I said nothing at the time, butwhenwe got back to London I rang thebreast surgeon’s secretary andmadeanother appointment.When Iwentin, I had a needle put into the lump.Shortly afterwards, I was tele-phoned atmyoffice – Iwasworkingas the fundraising officer for the

NationalAutistic Society at the time– and Iwas toldthere and then, on the telephone, that it was cancer.”It was a terrible blow. It felt like a family destiny

that she should die of cancer too. Freilich remembersbeing in such a state that she accidentally set fire toher dressing gown – thankfully shewas unhurt.Herhusband andher twin son anddaughter,whowere15years old and studying for their ‘O’ level exams, were“desolate”. So she returned to hospital andhad a seg-mental mastectomy and complete axillary nodeclearance. Histology came back with its analysis. Itwas not cancer.At the time, Freilich was overjoyed at the news,

but nowadays, she reflects, patientsmight sue under

cancer registry, rapid access to treatment,multidisci-plinary breast units and equalisation of servicesthroughout Europe. This prepared the ground formajor developments that have followed, such as theEuropean guidelines for quality assurance in breastcancer screening anddiagnosis –nowa fundamentaltool that Europa Donna coalition members use toadvocate for better services in their countries.Appropriately enough, Freilich’s role in this trans-

formation started from her own distressing experi-ences of cancer. It all began with an error. In 1983,living inLondon, she decided she should have a gen-eral health check-up andmammogram.Hermotherhad died of breast cancer 10 years earlier, and her

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DAVIDBISHOP

similar circumstances. She had to perform an enor-mous psychological turnaround and was left withconflicting emotions – a knowledge of how gru-elling a diagnosis of cancerwas, an awareness of theinadequacies of some services, but also a deep grat-itude at being spared.

GETTING INVOLVEDTo this point, almost every experience she hadhad ofcancer had been negative. The one thing that hadimpressed herwas the care given to her at theRoyalFree Hospital (the misdiagnosis had been a labora-tory error). She stayed in touch with her surgeon,Santilal Parbhoo, and offered to help with a breastcancer research appeal hewas setting up. Freilich setabout raisingmoney, not only for clinical researchbut

for a new clinic forwomen at high risk of breast can-cer, and a new computerised call and recall system.On the basis of her successwith this, shewas invitedto help set up and run newpatient services, as a full-time, professional job.With a background inmusic – she had studied to

be a pianist and opera singer before starting a family– she was aware of gaps in her scientific knowledgeand attended lectures for medical students. “I wasallowed to build upmy knowledge and confidence,”she says. “So I started to suggest, there’s little here toinformor support patients.Couldn’twedo somethingabout that? I took a counselling course and pre-pared to set up this organisation for patients, whichin 1987 becameCancerkin.”Cancerkin, whichFreilich led as chief executive


Masterpiece

Freilich was overjoyed, but nowadays, she reflects,

patients might sue under similar circumstances

Cancerkin, Hyde Park, 2005. Every other year, patients, families, friends, healthprofessionals and celebrity supporters gather in London’s most famous park for a10km walk to raise funds for the breast cancer advocacy group

DAVIDBISHOP

until two years ago, was the first hospital-based,dedicated breast cancer charity in the UK, con-cerned with treatment, supportive care, educationand research. “Treat the patient, not just the cancer”was, and still is, its philosophy.It was one of the firstmanifestations inBritain of

what started to become known as breast canceradvocacy. Its services were, in part, inspired by theAmerican Reach to Recovery Programme, whichFreilich visited in 1986 as part of her personalresearch into how best to offer support to womenwith breast cancer. It trained carefully selected vol-unteers –womenwho had had breast cancer them-selves – as counsellors to visit patients in their ownhomes and support them, their families and friends.Soon the charity outgrew the one room it had

been allocated in the Royal Free Hospital – soanother Freilich-coordinated fundraising pushresulted in a newCancerkin centre being opened atthehospital in 1990. Itwas the first on-site dedicatedbreast cancer support centre in the UK.Freilich speaks fondly of themedical staff at the

Royal Free – theway doctors supported her venturesthroughout, invitedher tomultidisciplinarymeetingsand gave seminars to patients and volunteers. But thefact is that in her nationalwork, and the internationalwork that followed, she has had to address a problemthat was rife 20 years ago, and still common:doctors did not provide information tocancer patients or involve them indecision-making. More than any-thing, women like her, and hermother, needed someone totalk to. Freilich acknowl-edges that it was per-sonal experience thatdrove her on to cor-rect this.“The kind of sup-

port we offered wascompletely missingfor my mother and

me. If you don't have information about a condition,you can build pictures in your mind that can be soharmful and so negative and can affect the way yourecover or the way you respond to treatment. But itwas unusual for hospital doctors to havemuch timeto spend with patients beyond the hospital envi-ronment. The role of the breast care nurse was notvery well developed at that time. So I considered itimportant that patients had someone else to turn tofor support.“I think it’s about cooperation. In the past,

patients have traditionally deferred completely todoctors,which I believe iswrong.But I don’t go alongwith the idea thatwomen are equipped tomake theirown independent decisions. They need to beinformed sufficiently to be able to make sensibledecisions in collaboration with doctors.”

EUROPA DONNAIf it was an error that contributed to the founding ofCancerkin, it was a chance meeting that led toFreilich becoming Europa Donna’s first president.Her valuable work at the Royal Free led to herbeing invited onto aReach toRecovery internationaladvisory committee, under the auspices of theUICC (International Union for CancerControl) inGeneva. After attending a Reach to Recovery con-ference in Trieste in 1992, she shared a taxi back to

the airport withUmberto Veronesi, andasked himwhat had happened tohis plans to set up aEuropean

“If you don’t have information, you can build pictures

in your mind that can affect the way you recover”

Masterpiece


With renowned concert pianist AlfredBrendel. Having trained as a pianist andopera singer herself, Freilich put hermusical connections to good use,organising fundraisers for Cancerkin.This picture was taken following aGala Concert featuring Brendel withLondon’s Philharmonia Orchestra,at the Royal Festival Hall,September 2004

breast cancer coalitionalong the lines ofthe American NationalBreastCancerCoalition.Veronesi admitted thatthings had not got off theground as rapidly as he’dwished. Freilich said shewas interested in becom-ing a representative inLondon, and theyexchanged addresses.Three weeks later,

she received a box full ofall the papers relating tothe proposed organisa-tion. She was keptinformed of all corre-spondence, but didn’t have any official role.But a yearlater, in 1993, shewas invited to attend a conferenceof EUSOMA, the European breast cancer special-ists, in Paris. At the end, Veronesi made a surpriseannouncement: a newbreast cancer coalition calledEuropa Donna was to be formed, and its first presi-dent would be Gloria Freilich.Nobody was more surprised than Freilich. It

took some backtracking – establishing a workingparty and organising elections – for the body to actu-ally come into being, with Freilich formally at thehelm. With enthusiastic representatives of breastcancer patient groups in Italy, Germany, Belgium,Austria, Switzerland and the UK, the objectiveswere agreed: enhancing the role of women in con-trolling breast cancer; promoting improvements inthe standards of diagnosis and management acrossEurope; promoting equality of access; making part-nerships with clinicians and scientists; influencingEuropean and national politicians. “From the earli-est days, wewere greatly helped by the valuable sup-port of Alberto Costa and the European School ofOncology, with whom Europa Donna has workedclosely throughout its history,” stresses Freilich.The launch conference was held at the Euro-

pean Institute of Oncol-ogy in Milan in 1994.“At that time the advo-cacy concept wasbarely understood,” saysFreilich. “Immediately,we had to overcome sus-picion of our motivesand establish a clearunderstanding of ourmission. We began tomake our presence feltthrough involving our-selves in breast cancerpublic education, hold-ing conferences andpatient meetings, lobby-ing decision makers,

publishing newsletters, holding media campaignsand generally coalition building.”OneofEuropaDonna’s early undertakings – a15-

country survey of women’s experiences of breastand gynaecological cancers carried out in 1996–con-firmed the absolute legitimacy of what it was tryingto do. “Someof their experienceswere pretty ghastly.I think many women felt able, for the first time, tovent feelings they would never have shared with amedical expert. You could tell that people had suf-fered psychological angst, damage, and the surveydrew attention to aspects of treatment and careacross Europewhere improvements could or shouldbemade.”The fact that Europa Donna – the name is Ital-

ian for ‘European woman’ – was envisaged as a ‘sis-terhood’ is important, says Freilich. It isn’t that theorganisation has excluded men – supporting malefamily members and friends is an important objec-tive, and many male clinicians, most importantlyVeronesi andCosta, have been influential in drivingthe organisation forward. “But I suppose thatwomen, by virtue of our biology, have various timesof our liveswhen important events and diseases hap-pen to us alone, and because we have the child


Masterpiece

“We had to overcome suspicion of our motives and

establish a clear understanding of our mission”

A milestone in patient advocacy. The European Breast CancerConference is the first European scientific cancer conferenceto include patient advocates as equal partners. As EuropaDonna president, Freilich was a co-founder of EBCC, and ispictured here at its first conference, September 1998

bearing responsibility, all the gynaecological side ofit ismore or less out in the open.We’re used to com-municatingwith each other about these issues, andeven in countries where topics like cancer are notopenly discussed, women do get together and sup-port each other in many different ways.”Nevertheless, the fact that breast cancer – and

even the breast itself – is still a taboo subject insome countries, has been a consistent hurdle. Theoriginal logo design for EuropaDonna was a breast,but was vetoed because of sensitivities – instead,it became a map using women’s silhouettes. Thevery word cancer is still barely spoken publicly insome regions – an additional barrier to gettingpatients to feel confident about talking to othersabout their condition.“In some countries, if it becomes widely known

that there is cancer in the family, it can cause all sortsofproblems, influencingmarriageprospects, for exam-ple. I suppose it startswith the assumption that if youhavecancer, youhaveanuntimelyend.That’snotnec-essarily the case anymore, and I think that as peopleacquire confidence about adiagnosis of cancer beingproperly treated and the possibility of making a goodrecovery, then fears and superstitions will graduallysubside.We are alreadymaking a difference.”There have been other significant problems:

creating objectives to work towards on a Europeanlevel has been immensely difficult, given the cul-tural disparity and variations in health care systemsand economies between EUMember States. Theidea of patients having a say in their own care isstill anathema to some doctors – like the oncolo-

gist who stood up to challenge Freilich in 1997.“Not all countries are readily accepting of layper-

sons’ involvement,” says Freilich. “But you changethings by driving up levels of understanding andconfidence, by encouragingmore interplay betweenthe layperson and themedical profession. Themed-ical professionals have to feel confident that they’renot going to be overrun by women wildly makingdemands they can’t meet. You change things byshowing examples ofwhat has been already achieved,and which they can emulate.”The merits of a professional multidisciplinary

approach to breast cancer, which Europa Donnaadvocates, are still not always appreciated. Wher-ever this is the case, EuropaDonna has had to workhard to persuade medical professionals to linkwith their colleagues to found multidisciplinarybreast units.But Freilich assesses the organisation’s achieve-

ments over 16 years as considerable: its influence inthe setting of European standards of breast cancercare; its planting of the patient perspective firmly inthe centre of high-level clinical and political discus-sions; the growing acknowledgement of the need formultidisciplinary breast units.

“I did have a very strong feeling about Europa Donna.

I thought it would be wonderful to do it”

Masterpiece


A powerful alliance. Breast care nurse Sylvia Denton (right)was among the first advocates for patients to be treated bya multidisciplinary breast team, including a specialist breastnurse – key issues for Europa Donna. President of the UK

Royal College of Nursing (2002–2006), she is pictured herewith Freilich at the Europa Donna conference, Paris 1999,

where she led a one-day course on endocrine therapy aimedat nurses from Europa Donna’s member states E

UROPADONNA

ONE AIM, MANY CULTURESShe is proud that Europa Donna membership nowextends to44countries.She’sproud tooof the link thatshe forgedwithEORTC(theEuropeanOrganisationfor Research and Treatment of Cancer) andEUSOMA to found the biennial European BreastCancerConference.And she’s certainly proud of thecoalition’s relationshipwith theEuropeanParliament.But she is also realistic. “We wanted to equalise

the standard of diagnosis and treatment right acrossEurope, and one has to acknowledge it’s going to bea long time before that happens. We’ve latelyembraced countries like Kazakhstan, Kyrgyzstanand Georgia, and our Russian-speaking EuropaDonna Ukraine Forum is able to help them withtraining and education. But things are going to hap-pen more quickly in some countries than others.Because of these variations, I think there could bemore regionalisation within Europa Donna in thefuture in order to concentrate help where it can begivenmost effectively.”She sees improving screening as key to sparking

developments in all areas of cancer services. “Wheregood screening programmes have been established,those standardshave tended tocarry through into sur-gery andoncology aswell,” she says.Though there arequestionsbeing raised in theUKabouthowmany livesa national breast cancer screening programme reallydoes save,Freilichbelieves that if theprogrammesareestablished to a high standard, and women are pro-videdwithquality informationabout theprosandconsof screening, the benefits outweigh the risks.

A royal occasion. HRH the Duke of Gloucesterjoined other distinguished patrons, majordonors, medical experts and dedicatedvolunteers for the launch of Cancerkin’s 20thanniversary, in Goldsmiths’ Hall, the City ofLondon, April 2007

Though she is no longer in full-timeemployment in the cancer world, fullretirement doesn’t seem an option. Theset of oil paints, brushes and canvases shewas presented with when she left Can-cerkin remain largely untouched, await-ing adaywhen shehas timeonherhands.HerworkwithEuropaDonna continuesin her capacity as founding president.She remains involved with ESO and

many cancer projects, such as theLookGood…FeelBetter programme,which provideswomen affectedby cancer with access to cosmetics to address theeffects some cancer treatments can have on one’sappearance. In 2008 shewas appointed a trustee ofthe Bowel and Cancer Research Trust at the RoyalLondonHospital, and shewould love to see some ofthe growth in interest and resources that breast can-cer has experienced in recent decades spill over intothese less well publicised fields.Was it really chance, luck, mistakes that led her

guiding role in these influential breast cancer bodies,as she implies?Hermodesty is misleading. The rea-sonbehindFreilich’s rise in thecancerworldbecomesclearer when I ask her exactly what it was thatVeronesi saw inher, after that conversation in a taxi –whatmadehimwant to invest such responsibility andtrust in her. She thinks carefully before answering.“I think he had made some enquiries about my

work in London and probably heard a few goodreports. I tend to make things happen. I’m a veryentrepreneurial person, and I think that if I want tomake something happen, and work hard enough atit, I willmake it happen. I did have a very strong feel-ing about Europa Donna. I thought it would bewonderful to do it.”Skill at fundraising, organising people andmak-

ing alliances, driven by personal conviction. It’s apotent combination, which has significantly drivenon the cause of user involvement in Europe. It is acombination still vitally needed in cancer organisa-tions around the world.


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DAVIDBISHOP

ImpactFactor

Future directions inmultimodality therapy for NSCLC

� Anne Tsao, Jack Roth and Roy Herbst

Patients with stage III non-small-cell lung cancer comprise a heterogeneous population; the

role of surgical resection in this setting has been controversial. Albain and colleagues recently

demonstrated that trimodality therapy with lobectomy had clinical benefit for patients with

pathologic nodal N2 stage III NSCLC.

The role of surgical resection instage III non-small-cell lung can-cer (NSCLC) is controversial,

as the population of patients with thisdisease is rather heterogeneous.Albainet al. reported the results of a phase IIItrial that compared definitive concurrentchemotherapy and radiation to tri-modality therapy with concurrentchemotherapy and radiation followed bysurgical resection in 396 patients withpathologic nodal stage 2 (pN2) IIIANSCLC.1 The study results suggest thatsuch patients may have a survival ben-efit from trimodality therapy if a lobec-

tomy can be performed. These findingscontradict those reported by vanMeer-beeck et al., who did not find a survivalbenefit for trimodality therapy in anypatients with pN2 stage III NSCLC.2

The trial by Albain et al. was aninternational, multicentre study thatrequired pathologic proof of N2 dis-ease, confirmation by a thoracic sur-geon that tumours were resectable andexclusion of N3 disease (stage IIIB).In the intent-to-treat analysis, patientswho received trimodality therapyhad a median overall survival of 23.6months comparedwith 22.2months in

the definitive chemoradiation arm(P=0.24). At five years, the absolutedifference in survival between the twogroups was 7%, in favour of the surgeryarm. Although overall survival was notsignificantly different between thegroups, median progression-freesurvival was better in the trimodalityarm (12.8 months vs 10.5 months,P=0.017). The local relapse rate was10% in the surgery arm, comparedwith22% in patients who did not receivesurgery, with the greatest effect onrelapse achieved at the primary tumoursite (2% vs 14%, respectively). Distant


This article was first published inNature Reviews Clinical Oncology 2010 vol.7 no.1, and is published withpermission. © 2010Nature Publishing Group. doi:10.1038/nrclinonc.2009.174, www.nature.com/nrclinonc

ImpactFactor

relapse rates did not differ between thetwo groups. One of the suggested rea-sons for the lack of improvement inoverall survival, despite the enhancedprogression-free survival, was theincreased mortality in the trimodalityarm after pneumonectomy comparedwith the chemoradiation arm; 14 of the16 deaths in the trimodality armoccurred after pneumonectomy,whereas a total of four deaths occurredin the definitive chemoradiation arm. Inan exploratory subgroup analysis,patients who underwent lobectomy hada significant overall survival benefit com-pared with a matched cohort in thechemoradiation arm (33.6 months vs21.7 months, P=0.002).The findings of this studyhave impli-

cations for two important surgical issues.First, patients who underwent pneu-monectomy (especially right-sided) hadsignificantlyworse outcomes than thosewho were not surgically treated; theexploratory subgroup analysis reported amedian survival of 18.9months for suchindividuals, comparedwith 29.4monthsin a matched cohort of patients whoreceived chemoradiation alone. Oneshould note that some of these pneu-monectomies could have been avoided,as 13 (45%) of the29patientswhosedis-ease was downstaged to pT0N0 afterconcurrent chemoradiation had under-gone pneumonectomy. Operative mor-tality with pneumonectomy was 26%.Although these results were from anexploratory matched-pair analysis thatwas not preplanned, the data suggestthat pneumonectomy should be avoidedafter combined chemoradiation. Otherstudies, however, have reported muchlower operative mortality for pneu-monectomy after induction therapy. Thereason for this discrepancy among clin-ical trials is not clear.3

Secondly, the trial by Albain et al.1

supported the use of trimodality therapyin patients with solitaryN2 diseasewho

were candidates for lobectomy; how-ever, the benefit was less clear inpatients with multistation N2 disease.The subgroup analysis showed improvedsurvival with trimodality therapy only ifone N2 nodal station was involved,rather than multistation N2 disease.However, patients whose disease wasdownstaged to N0 after neoadjuvanttherapy had the highest median overallsurvival (34.4 months); 76 of 164patients who underwent thoracotomywere downstaged to N0. This findingseems to be independent of the numberof nodal N2 stations originally involvedbefore the administration of neoadju-vant therapy and, therefore, supports theuse of surgical resection in patientswithmultistation N2 disease if neoadjuvanttherapy accomplishes adequate down-staging. Themedian survival for patientswith residual nodal disease followingresection was 26 months, which sug-gests that these patients may also ben-efit from surgery if operativemortality islow. Future advances in survival forpatients with pN2 stage IIIA disease,therefore, will be dependent onimprovements in systemic therapy andin appropriate selection of patients fortrimodality therapy.In addition to defining the role of

surgery in patients with stage IIINSCLC, this trial also influences thefuturemanagement of locoregional dis-ease by suggesting that patients withdownstaged N2 disease have superiorsurvival. A similar survival benefit inpatients with downstaged disease haspreviously been reported in other neoad-juvant trials.2,4,5 Use of advanced sys-temic therapies, therefore, may lead toimproved survival outcomes in thesepatients. Personalisedmedicine, or theselection of patients for specific sys-temic therapies, has already beenembraced in the metastatic NSCLCsetting. This approach could now beincorporated into the management of

patients with locoregionally advanceddisease, as selection criteria for mosttrials do not categoriseNSCLCbeyonddisease extent and stage.In the future, systemic treatment

will be optimised according to tumourhistology and molecular profiles, withthe potential goal of replacingchemotherapy with novel targetedagents to limit toxic effects whileimproving efficacy.Molecular selectionhas been incorporated into the man-agement of metastatic NSCLC – theselection of patients with EGFRmuta-tions who are sensitive to receptor tyro-sine kinase inhibitors (TKIs) hasresulted in improved survival.6 How-ever, a prior study7 of unselected patientswith stage IIINSCLCwhowere treatedwith epidermal growth factor receptor(EGFR) TKIs and radiation did notdemonstrate a survival benefit.Whether subgroups of patients with

specific EGFRmutations would bene-fit from EGFR TKI-based therapy,therefore, remains unclear. Recently,patients with NSCLCs that expressedthe EML–ALK4 fusion protein wereshown to benefit from ALK inhibitortreatment8, and insulin-like growth fac-tor receptor inhibitors seem to workeffectively in patients with squamous-cell-carcinoma histology.9

Whether these targeted agentsshould be administered alone, withchemotherapy, or with radiation ther-apy as neoadjuvant or combined defin-itive treatment remains unknown atthis time.The issue of what sequence of

administration of therapy is optimal inthe trimodality setting remains contro-versial. The German Lung CancerCooperativeGroup conducted amulti-centre phase III trial in 558 patientswith NSCLC that compared neoadju-vant chemotherapy with postoperativeradiation therapy versus neoadjuvantchemoradiation. This study reported


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increased mediastinal downstagingwith chemoradiation, albeit without adifference in overall survival betweenthe two arms.5 Surgery after chemora-diation is more technically challengingthan it is after chemotherapy alone,and carries a two- to three-fold higheroperative mortality.2,5 Neoadjuvantchemotherapy followed by restagingand surgical resection in a patientwhose disease was successfully down-staged followed by adjuvant radiother-apy to the mediastinum is alreadycommonly utilised in clinical practice.In the era of molecularly targeted ther-apies, whether bimodality neoadjuvanttreatment is preferable to radiother-apy after surgical resection remains tobe determined. The sequencing oftherapy administration should beexplored but only in parallel with iden-tifying predictive biomarkers and util-ising the appropriate targeted agents formaximum benefit.Selection of patients for aggressive

trimodality therapy is currently based onclinical prognostic factors, which arenot ideal for identifying individuals whowould benefit from treatment.Advancesin prognosticmolecularmodelling needto be developed further and incorpo-rated into the clinical management ofpatients with NSCLC.One example is the LungMetagene

genomic profiling analysis, which mayidentify distinct populations of patientswith stage IANSCLCwho have a highrisk of disease recurrence despite sur-gical resection.10

Other genomic-profiling platformsare under investigation. These prog-nostic technologies must be incorpo-rated into multimodality trials andvalidated to optimise therapy and iden-tify patients who might require anaggressive approach to treatment. One

potential future scenario would be toreserve trimodality therapy for patientswith pN2 stage IIINSCLCwho have ahigh likelihood of disease recurrenceaccording to these prognosticmodels, inwhom the high risk of local recurrencewould, therefore, justify the potentialadded risks of surgical resection in tri-modality therapy. Patients whosetumours have a favourable prognosticmolecular signature would receivedefinitive concurrent chemoradiation.Based on the results of theAlbain et

al. study,1 we believe that surgical resec-tion (lobectomy) after neoadjuvantchemoradiation inmedically fit patientswith pN2 stage III NSCLC can beconsidered as a therapeutic option.ManyUS cancer centres already incor-porate surgery after either neoadjuvantchemotherapy or chemoradiation forpatients with pN2 NSCLC. Incorpo-ration of novel targeted agents and pre-dictive biomarkers to personalisesystemic therapy is ultimately likely toimprove clinical outcomes. Moreover,prognostic molecular models, such asthose that involve genomics, may aidtailoring of how aggressive the multi-modality therapy should be for eachindividual patient. These new tech-nologies have the potential to enablefurther optimisation and refinement oftreatment for patients with stage IIINSCLC.

References

1. KS Albain et al. (2009) Radiotherapy plus

chemotherapy with or without surgical resection

for stage III non-small-cell lung cancer: a

phase III randomised controlled trial. Lancet

374:379–386

2. JP van Meerbeeck et al. (2007) Randomized

controlled trial of resection versus radiotherapy

after induction chemotherapy in stage IIIA–N2

non-small-cell lung cancer. JNCI 99:442–450

3. R Stupp et al. (2009) Neoadjuvant

chemotherapy and radiotherapy followed by

surgery in selected patients with stage IIIB non-

small-cell lung cancer: a multicentre phase II

trial. Lancet Oncol 10:785–793

4. KS Albain et al. (1995) Concurrent

cisplatin/etoposide plus chest radiotherapy

followed by surgery for stages IIIA (N2) and IIIB

non-small-cell lung cancer: mature results of

Southwest Oncology Group phase II study 8805.

JCO 13:1880–1892

5. M Thomas et al. (2008) Effect of preoperative

chemoradiation in addition to preoperative

chemotherapy: a randomised trial in stage III non-

small-cell lung cancer. Lancet Oncol 9:636–648

6. M Fukuoka et al. (2009) Biomarker analysis

from a phase III, randomized, open-label, first-

line study of gefitinib versus

carboplatin/paclitaxel in clinically selected

patients with advanced non-small cell lung

cancer in Asia (IPASS) [abstract]. JCO 27:8006

7. K Kelly et al. (2008) Phase III trial of

maintenance gefitinib or placebo after concurrent

chemoradiotherapy and docetaxel consolidation

in inoperable stage III non-small-cell lung

cancer: SWOG S0023. JCO 26, 2450–2456

8. JP Koivunen et al. (2008) EML4–ALK fusion

gene and efficacy of an ALK kinase inhibitor in

lung cancer. Clin Cancer Res 14:4275–4283

9. D Karp et al. (2008) High activity of the anti-

IGFR antibody CP-751871 in combination with

paclitaxel and carboplatin in squamous NSCLC

[abstract]. JCO 26:8015

10. A Potti et al. (2006) A genomic strategy to

refine prognosis in early-stage non-small-cell

lung cancer. NEJM 355:570–580

Practice pointSurgical resection (lobectomy) afterneoadjuvant combined chemoradia-tion can be considered as a therapeu-tic option in medically fit patientswith pN2 stage III NSCLC.

Author affiliations: Department of Thoracic and Head & Neck Medical Oncology (Anne Tsao and Roy Herbst) and Department of Thoracic & Cardiovascular Surgery (Jack Roth),University of Texas MDAnderson Cancer Center, Houston, Texas

This article was first published inNature Reviews Clinical Oncology 2010 vol.7 no.1, and is published withpermission. © 2010Nature Publishing Group. doi: 10.1038/nrclinonc.2009.173, www.nature.com/nrclinonc

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Sunitinib versus interferon-αin metastatic RCC

� Jason Faris and Dror Michaelson

Motzer and colleagues presented updated results from amulticentre, phase III trial of sunitinib

versus interferon-α as first-line treatment for patients withmetastatic renal-cell carcinoma. Theobserved improvement in overall survival for patients treatedwith sunitinib further establishes

this agent as the reference standard for first-line treatment of good-risk and intermediate-risk

patients with metastatic renal cancer.

The care of patients withmetastatic renal-cell carci-noma (mRCC) has advanced

substantially in the past few years,with the approval of targeted therapiesincluding sunitinib, bevacizumab,sorafenib, temsirolimus and evero-limus.Approximately three-quarters ofrenal cancers are clear-cell carcino-mas, and most tumours of this histo-logic subtype have inactivatingmutations of the von Hippel–Lindaugene. This inactivation ultimatelycauses increased secretion of vascularendothelial growth factor (VEGF).1

A recent publication of updatedresults from a randomised phase IIItrial by Motzer and colleagues hasdemonstrated that sunitinib improvesoverall survival compared with inter-feron-α as first-line therapy in patientswith mRCC. Sunitinib is an orallyadministered, multitargeted tyrosinekinase inhibitor (TKI) that affectsmultiple receptors, including theVEGF receptor. In two phase II stud-ies of patients with cytokine-resistantmRCC, treatment with sunitinibresulted in overall response rates of33% and 40%, with a large percentage

of patients achieving stable diseaseor better.2 Median progression-freesurvival (PFS) was around 8.8–8.9months.2,3The results of these studiesled to accelerated approval of suni-tinib by the US regulatory agency, theFDA, in January 2006 for the treat-ment of advanced kidney cancer.The phase III trial of sunitinib

was an international trial performedin 101 centres, in which patients withtreatment-naive mRCC of clear-cellhistology were randomly allocated toeither six-week cycles of sunitinib(50 mg once daily for four weeks

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followed by two weeks off therapy) orinterferon-α (9 million units subcu-taneously three times per week).3

Randomisation was stratified bypatients’ baseline levels of lactatedehydrogenase, performance statusand history of nephrectomy. Patientswith a poor performance status, brainmetastases or significant cardiovas-cular disease were excluded. The pri-mary endpoint was PFS as assessedby the Response Evaluation Criteriain Solid Tumors (RECIST). Second-ary endpoints included objectiveresponse rate, overall survival, qualityof life and drug safety. A preplannedinterim analysis demonstrated a sig-nificant six-month improvement inmedian PFS for patients who weretreated with sunitinib.Given the improvement in PFS,

the study protocol was amended toallow crossover from interferon-α tosunitinib upon disease progression.After an extended follow-up, Motzer

and colleagues have now reportedupdated results, including overall sur-vival.4 The objective response rateswere 47% and 12% for sunitinib andinterferon-α, respectively (P<0.001).The median overall survival was 26.4months for sunitinib and 21.8 monthsfor interferon-α (P=0.051). The dif-ference in overall survival reachedstatistical significance (P=0.0096) ina multivariate analysis that controlledfor performance status, haemoglobinlevels, time from diagnosis to treat-ment, corrected calcium levels, alka-line phosphatase levels, lactatedehydrogenase levels and the numberof metastatic sites.The borderline significance of the

P-value for the unadjusted overallsurvival data may have been a conse-quence of the crossover and admin-istration of post-study treatments.Each of these effects may haveobscured the overall survival benefitof sunitinib. The authors attempted

to control for these effects by per-forming exploratory analyses. Afterexcluding the 25 patients who crossedover to the sunitinib arm, medianoverall survival was 26.4 months(range 23.0–32.9 months) in the suni-tinib arm versus 20.0 months (range17.8–26.9 months) in the interferon-αarm (P=0.036). In contrast to thesmall number of patients who wereallowed to cross over, most patientsreceived post-study treatment. Fol-lowing discontinuation of interferon-α, nearly 60% of patients receivedalternate therapies, including otherVEGF inhibitors, cytokines, mTORinhibitors or chemotherapy, and morethan half of these patients receivedsunitinib.4 Once the patients whoreceived post-study treatment hadbeen excluded from the analysis, thedifference between the groups inmedian overall survival became muchmore prominent – 28.1 months ver-sus 14.1 months (P=0.003).

In support of the valid-ity of these exploratoryanalyses, when a Wilcoxonanalysis was performedinstead of logrank calcula-tion, the P-value was0.0128. As the Wilcoxontest preferentially weightsearly events, this statisticaltest may be more appropri-ate than logrank calcula-tions, given the observedeffects of crossover andpost-study treatment.4 Thus,the adjusted data from theexploratory analyses form acompelling argument for atrue overall survival bene-fit. This argument is partic-ularly relevant when oneconsiders the extendedmedian overall survival ofpatients in the interferon-αgroup – almost 22 months,


OVERALL SURVIVAL AND PROGRESSION-FREE SURVIVAL ACCORDING TO RISK STATUS

Risk groups Sunitinib Interferon-αOverall survival (months)

All risk groups 26.4 (23–32.9)1 21.8 (17.9–26.9)

Good risk (n=143) NR2 NR2

Intermediate risk (n=209) 20.7 (18.2–25.6)3 15.4 (13.6–18.2)

Poor risk (n=23) 5.3 (4.2–10)4 4.0 (2.7–7.2)

Progression-free survival (months)

All risk groups 11 (11–13)5 5 (4–6)

Good risk (n=143) 14.56 7.9

Intermediate risk (n=209) 10.66 3.8

Poor risk (n=23) 3.76 1.2

1P<0.051. 2Median overall survival not reached in either group; 3Hazard ratio 0.787, 95% CI 0.617-1.004;4Hazard ratio 0.660, 95% CI 0.360–1.207; 5P<0.001. 6Hazard ratio and confidence intervals not available.

Abbreviation: NR, not reached

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compared with the historical survivalof 13 months before the advent oftargeted therapies.4

Similar statistical issues werenoted in TARGET (TreatmentApproaches in Renal Cancer GlobalEvaluation Trial), which was a phaseIII trial of sorafenib versus placebo inpatients with mRCC who had beentreated with prior cytokine therapy.5

Although a difference in PFS of 2.7months that favoured sorafenib wasdemonstrated, overall survival did notdiffer between the groups (P=0.146).When patients in the placebo armwho crossed over to the sorafenibarm were excluded from the analysis,the difference in overall survivalbecame significant.5 The medianoverall survival of patients in theplacebo group was more than 15months, which is longer than the his-torical survival of patients treatedwith immunotherapy. This improve-ment in overall survival of patients inthe placebo group might have beenrelated to the effects of crossover andpost-study treatment. Similarly, inanother phase III trial, patients withmRCC whose disease had progressedon VEGF-targeted therapy were ran-domly allocated to receive everolimusor placebo.6 PFS improved by 2.1months in the everolimus arm, but nodifference was observed in overallsurvival. Since the protocol permittedcrossover to everolimus upon diseaseprogression, the lack of an overallsurvival benefit was not surprising.Allowing patients to cross over to aneffective therapy is arguably the onlyethical option and, therefore, selec-tion of PFS as the primary study end-point may be necessary in the contextof crossover designs precipitated byincreasingly available and effective

targeted therapies.Two phase III studies –Avastin for

Renal Cell Cancer (AVOREN)7 andCancer and Leukemia Group B(CALGB) 902068 indicated signifi-cant improvements in PFS for beva-cizumab plus interferon-α comparedwith interferon-α alone. This effectapplied to patients in the good-riskgroup (12.9 months vs 7.6 monthsin AVOREN, 11.1 months vs 5.7months in CALGB 90206) and inter-mediate-risk group (10.2 months vs4.5 months in AVOREN and 8.4months vs 5.3 months in CALGB90206).The magnitude of the PFS benefit

seemed to be smaller than that ofsunitinib. However, definitive con-clusions about the magnitude of thisbenefit cannot be drawn until a directcomparison of these two agents ismade in a randomised trial. The effi-cacy of single-agent bevacizumab inthe first-line setting merits evalua-tion, and the relative toxicity profilesof different regimens might influencethe selection of first-line treatment.For poor-risk patients, tem-

sirolimus remains the standard first-line treatment, because of a provenbenefit in PFS and overall survivalin a randomised, phase III trial.9 Theefficacy of sunitinib in this populationof patients remains to be demon-strated. Many patients with poor-riskdisease were excluded from the phaseIII trial of sunitinib, which limited thestudy’s ability to detect a difference inoverall survival. Some data suggestsunitinib may be effective in this set-ting. In an international expanded-access programme, in which 4564patients with mRCC were treatedwith sunitinib, 13% (n=582) of par-ticipants were considered to have

poor performance status.10 Amongevaluable patients in this subpopula-tion (n=319), the median overallsurvival was 6.7 months, which com-pared favourably to historic overallsurvival in patients with a poor per-formance status. Poor-risk patientscomprised 9% of this group and had amedian overall survival of 5.3months.10

Sunitinib seems to improve overallsurvival compared with interferon-α, afinding that adds to previously pub-lished data of superior PFS. Althoughthe statistical significance of theimprovement seems to be marginal atfirst glance, the effect of sunitinibon overall survival is almost certainlyunderestimated. Sunitinib remainsthe standard first-line treatment forgood-risk and intermediate-riskpatients with mRCC, although theavailability of multiple other targetedagents highlights the need for con-tinued clinical research.Areas for ongoing and future inves-

tigations include combination regi-mens, sequencing of targetedtherapies, intermittent dosing strate-gies and incorporation of individualisedbiomarker and pharmacodynamic pro-files to predict response and resistanceto therapy.


Practice pointFirst-line sunitinib improves pro-gression-free survival in good-riskand intermediate-risk patients withmRCC, and confers an overallsurvival benefit compared withinterferon-α

Author affiliations:Massachusetts General Hospital Cancer Center, The Claire and John Bertucci Center for Genitourinary Cancers, Boston, MassachusettsCompeting interests: Dror Michaelson declares associations with the following companies: Amgen, Genentech, GlaxosmithKline, Pfizer, Wyeth

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

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

Doxorubicin unnecessaryfor standard-riskhepatoblastoma� New England Journal of Medicine

Cisplatinmonotherapyachievedsimilar ratesofcomplete resection and survival as cisplatin

plus doxorubicin in children with standard-riskhepatoblastoma, a recent trial – SIOPEL 3 – hasconcluded. As had been predicted, there was lesstoxicity for patients receivingmonotherapy.

The International Childhood Liver TumourStrategyGroup3 (SIOPEL3) trial represents a con-tinuationof twoearlier trials. In SIOPEL1, investi-gators identified two pretreatment prognosticfactors – intrahepatic tumour extensionand lungmetastases – when they administered cisplatin-doxorubicin. Basedon these findings, they estab-lished twopretreatment risk groups: standard risk(tumour confined to the liver and notmore thanthree hepatic sectors) and high risk (tumoursinvolving the entire liver andbeyond). In SIOPEL2(a pilot study for the current trial), researcherstried cisplatin monotherapy for the first time,using insights from an earlier trial (JCO 2000,18:2665–2675) that showed a multi-agentanthracycline-free regimenwas just aseffectiveascisplatin-doxorubicin, butwithnocardiotoxicity. Inthe current SIOPEL 3 trial, Giorgio Perilongo andcolleagues, from the Department of Pediatrics atthe University Hospital of Padua, Italy, set out toanswer thequestionofwhetherdoxorubicincouldbe safelyomitted fromthe treatmentof standard-risk hepatoblastoma, andwhether cisplatin alone

with cisplatin-doxorubicin compared to 20.6%for cisplatinmonotherapy. No differences in tox-icityornephrotoxicityweredetectedbetween thetwo groups.

“The resultsofSIOPEL3areveryencouraging,”write the authors. “It has long been known thatsurgery has an excellent success rate in childrenwith hepatoblastoma and that hepatoblastomasare very sensitive to cisplatin. However, theSIOPEL 3 trial shows that a selected group ofpatients with hepatoblastoma can be cured witha strategy consisting of cisplatin monotherapyadministeredpreoperatively andpostoperatively.”

The limitednumberofpatientsmeant that theauthors couldnot statistically prove their conclu-sion that the two regimens were comparable.However, the similar rates of event-free survivalandoverall survival “provide support” for thenon-inferiority of cisplatinmonotherapy, they argue.

Emerging evidence suggests that few hepa-toblastomas with pure foetal histologic featuresand lowmitotic rate seemtobecurableby surgeryalone, and that small-cell undifferentiated histo-logic features may have a negative impact onsurvival, regardlessof tumourextension. “Therefore,theconceptualizationof futureclinical trials shouldtake intoaccount thedata fromall available trialsto refine theappropriate therapy for subgroupsofpatients with limited-extension hepatoblastomaand to properly balance efficacy and long-termtoxicity,” write the authors.

� G Perilongo, R Maibach, E Shafford et al.

Cisplatin versus cisplatin plus doxorubicin for

standard-risk hepatoblastomas. NEJM 22 October

2009, 361:1662–1670

couldbeas effective as cisplatinplus doxorubicin.A total of 92 institutions from 24 countries wereinvolved in the study.

Between June 1998 and December 2006,after receiving one cycle of cisplatin (80 mg/m2body-surface area per 24 hours), children withstandard-riskhepatoblastomawere randomised toreceive cisplatin (n=126) or cisplatin plus dox-orubicin (n=129), administered in three preoper-ativecyclesandtwopostoperativecycles. Standardrisk features were defined as tumours entirelyconfined to the liver, and involvingnotmore thanthree hepatic sectors.

During the trial, the protocol was amended,and childrenwith alpha-fetoprotein levels of lessthan100ng/mlwereexcludedbecauseof “mount-ingevidenceof apooroutcome in thesepatients,”write the authors.

The rateof complete resectionwas chosenastheprimary studyendpoint,write theauthors, firstbecause it allowedthemtoobtainmeaningfuldata“regarding the treatmentof a very rare tumor in areasonable time frame,” and second “becausecomplete resection is the universally accepted,singlemost importantprognostic factor for long-term overall survival and event-free survival inchildhood hepatoblastoma.”

Theratesofcomplete resectionwere99%withcisplatin and95%with cisplatinplusdoxorubicin,withadifferenceof3.9%(95%CI0.3%–8.1%). Thethree-year event-free survival was 83% in thecisplatin group and 85.5% in the cisplatin-dox-orubicingroup, and the three-yearoverall survivalwas95%in thecisplatingroupand93%in thecis-platin-doxorubicin group.

Acutegrade3or4adverseeventswere74.4%

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Preserving function whentreating brain metastases� Lancet Oncology

Patients with brain metastases treated withstereotatic radiosurgery (SRS) plus whole-

brain radiation therapy (WBRT) are at greater riskof a decline in learningandmemory function thanthose receiving SRS alone, a recent study hasfound. The researchers, led by Eric Chang from theMD Anderson Cancer Centers, in Houston, Texas,conclude that their study supports the use ofSRS alone combinedwith closemonitoring as theinitial treatment strategy for cancer patientsnewly diagnosed with between one and threebrain metastases.

For more than 50 years WBRT has served asthe standardpalliative treatment for brainmetas-tases,with randomised trialsmore recently estab-lishingadditionalbenefitswhenWBRT is combinedwith surgeryorSRS.Changandcolleaguesunder-took thephase III randomisedtrial to test theirpre-diction that the learningandmemory functionofpatientswhounderwentSRSplusWBRTwouldbeworse than that of patients who underwent SRSalone. “Weproposed thatmemorywouldbe likelyto be affected by radiation therapy, given theadverseeffectsof radiationonneurogenesisof thehippocampus,” write the authors.

Between 2001 and 2007, patients withbetween one and three newly diagnosed brainmetastases were randomly assigned to SRS plusWBRT (n=28) or SRS alone (n=30). Theresearchersmeasured participants’ neurocogni-tive function using a short battery of neuropsy-chological tests, where the primary endpointwas changes in the memory function assessedthrough significant deterioration (5-point dropscompared to baseline) in the Hopkins VerbalLearning Test-Revised (HVLT-R) assessment.

Results at four months showed that 52% ofpatients randomly assigned to SRS plus WBRTshowed a significant drop in HVLT-R total recallcompared to 24%assigned to SRS alone.

Furthermore, at fourmonths therewere fourdeaths (13%) in thegroup receivingSRSaloneandeightdeaths (29%) in thegroup receivingSRSplusWBRT. Themedian survival for patients in theSRS

groupwas15.2monthscomparedwith5.7monthsin the SRS plusWBRT group. After one year, 73%of the surviving patients in the SRS plus WBRTgroupwere free from recurrence, comparedwith27%of surviving patients receiving SRS alone.

The trialwas stoppedat fourmonths inaccor-dancewith thepredeterminedearly stopping cri-teria, which specified that if the probability ofone treatment armbeingbetterwas greater than0.975 then the trial should be suspended.

“This studyprovides level1evidencetosupporttheuseof SRSalone in the initialmanagementofpatients newly diagnosedwith one to three brainmetastases,” write the authors. “We recommendthat initial SRSalone combinedwith close clinicalmonitoring should be the preferred treatmentstrategy for such patients."

The recommendation comes despite dif-ferences in recurrence favouring joint SRS andWBRT treatment. The risks of learning dysfunc-tion, said the authors, outweighed the benefitsof freedom from progression. Nevertheless,patientswho opt for SRS alonemust bewillingto commit to close clinical monitoring after-wards. “Applicability of the findings is depend-ent on the willingness of patients and theirphysicians to adhere to a schedule of closemonitoring, having consistent access to high-quality MRI, having access to a neurosurgicalteamwilling and able to perform salvage resec-tionswhen indicated, andapplying strict physicsquality-assurance procedures for stereotacticradiosurgery,” they emphasise.

In an accompanying editorial, JonathanKnisely from the Yale Cancer Center in NewHaven, Connecticut, concludes: “The improve-ment in both quality of life and survival associ-ated with management by SRS alone show it tobe the best approach. Nevertheless, exquisitelydetailedMRI studies for planning SRS are crucialfor the successful adoption of SRS alone.”

� EL Chang, JS Wefel, KR Hess et al.

Neurocognition in patients with brain metastases

treated with radiosurgery or radiosurgery plus whole-

brain irradiation: a randomised controlled trial. Lancet

Oncology November 2009, 10:1037-1044

� JPS Knisely. Focused attention on brain

metastases. ibid pp 1024

Long-term follow-upof adjuvant NSCLC trials� Journal of Clinical Oncology

Twolarge randomised clinical trials of adjuvantchemotherapy followingsurgery innon-small-

cell lung cancer (NSCLC), published in the sameissue of JCO, yielded, in the words of editorialwriter Jean Yves Douillard, “discordant” results.The International Adjuvant Lung Trial (IALT), at amedian follow-up of 7.5 years, showed fadingeffects for adjuvant chemotherapy on survival;while theNorthAmerican Intergroup JBR.10 trial,with a median follow-up of 9.3 years, demon-strated that survival benefits weremaintained.

Thebestmanagementofearly-stageNSCLC isrecognised to be surgical resection with curativeintent. However, even with complete resectionpatients remain at significant risk of relapse anddeath. Recently, three randomised phase II trialsand ameta-analysis have shown significant sur-vival benefit for adjuvant cisplatin-basedchemotherapy for selected patients with com-pletely resectedstage II and IIIANSCLC. “Long-termfollow-up of patients in these trials is critical toassesswhether chemotherapy is associatedwithasustained survival benefit and to identify any latetoxicities that may be attributable to adjuvanttherapy,” write the authors of the IntergroupJBR.10 trial.

In the larger, IALT, trial, RodrigoArriagadaandcolleagues, from the Institut Gustave-Roussy inParis, France, randomly assigned 1867 patientswith completely resected NSCLC to three or fourcyclesof cisplatin-basedchemotherapy (n=932)ortoobservation (n=935).Resultsatamedianfollow-upof7.5 years showedabeneficial effect of adju-vant chemotherapy on overall survival (HR 0.91;95% CI 0.81–1.02; P=0.10) and on disease-freesurvival (HR 0.88, 95% CI 0.78–0.98; P=0.02).Furthermore, a significantdifferencewas foundforoverall survival results before and after five yearsof follow-up (P=0.006).

“Although the initial benefit during the firstfive years (reduction of the risk of death) was14%,after fiveyears, the riskofdeathwas reducedbyonly9%withadjuvant chemotherapyand thisdifferencewas no longer statistically significant,”

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comments Jean-YvesDouillard, fromCentreRenéGauducheau, (St Herblain, France), in an accom-panying editorial.

Ananalysisofnon-lung-cancerdeaths for thewholeperiod showedahighermortality rate in thechemotherapy arm (HR 1.34, 95% CI 0.99–1.81;P=0.06. “In the IALT trial, the cumulative lung-cancer-related death rate still favours chemo-therapybutanexcessofnoncancer-relateddeathsoccurred in the chemotherapy arm as comparedwith the observation arm raising the questionof a possible detrimental long-term effect ofchemotherapy,” writes Douillard.

“This analysis not only confirms a beneficialsurvival effect of adjuvant cisplatin-basedchemotherapy during the first 5 years of follow-upbut interestingly showsasignificant interactionbetween the treatment effects according to theduration of follow-up,” says Arriagada and col-leagues, adding that their findingsalso raiseques-tions about potential negative long-term effects.

An additional noteworthy finding from theanalysis, add the authors, is that a major effect isconfirmed in termsof reductionofdistantmetas-tases in thechemotherapyarm,with theexceptionofbrainmetastases. “If this finding is also reportedin other cisplatin-based chemotherapy trials, itwouldargue forexplorationofotherpotential pre-ventive treatmentmodalities for patients at highrisk of brain failure,” they conclude.

In the smaller phase III Intergroup JBR.10 trial,led by Charles Butts from the Cross Cancer Insti-tute in Edmonton, Alberta, Canada, 482 patientswith completely resected stage IB or II NSCLCwere randomly assigned to receive four cycles ofvinorelbine/cisplatin (n=242) or observation(n=240).Atamedian follow-upof9.3years, resultsshowed patients in the chemotherapy arm con-tinued to experience significant survival advan-tages compared with patients in the observationarm (HR 0.78, 95% CI 0.61–0.99; P=0.04). Theabsolute improvement in five-year survival wasfound tobe11%(67%forpatients randomised tochemotherapy versus 56% for observation).

Subgroupanalysis revealed trends for survivalaccording to disease stage. Patients with stage IINSCLC had a significant benefit in survival fromchemotherapy (HR0.68,95%CI0.50–0.92;P=0.01),while there was found to be no chemotherapy

Long-term results of the International Adjuvant Lung

Cancer Trial evaluating adjuvant cisplatin-based

chemotherapy in resected lung cancer. ibid pp 35–42

� JY Douillard. Adjuvant chemotherapy for non-

small-cell lung cancer: it does not always fade with

time. ibid pp 3–5

BRCA1 mutation raisesrisk of contralateralbreast cancer� Journal of Clinical Oncology

Theriskofwomenwith inherited formsofbreastcancer developing contralateral breast cancerdepends on the age they first developed breastcancer and the type ofmutations they inherit. Inthe largest risk estimates studyyetofmutations inbreast cancer, German researchers showed therisk tobehigher forwomenwithBRCA1mutationsthan BRCA2mutations.

It is well known that women with BRCA-inherited formsofbreast cancerareatan increasedrisk of developing second cancers later in life,often in theopposite (contralateral) breast. Feelingthat a more accurate measure of contralateralbreast cancer riskwasneeded, investigators, ledbyMonika Graeser, from the University HospitalCologne, Germany, decided to undertake a studyinvestigatingpatients’ individual risks. The researchwas undertaken by the German Consortium forHereditaryBreast andOvarianCancer, an initiativeinvolving 12 university centres which, in 1996,establisheda large registry to collect comprehen-sive genotype and phenotype data on familieswith suspected hereditary breast cancer.

Altogether2020womenwithunilateral breastcancer, enteredon the registry between1996and2008,were included in theanalysis, comprising978index patients and 1042 relatives.

Results showed that 25 years after the firstbreast cancer, the cumulative risk for contralateralbreast cancer was 47.4% (95%CI 38.8%–56.0%)for patients from families with BRCA1 or BRCA2mutations.People fromfamilieswithBRCA1muta-tions had a 1.6-fold (95%CI 1.2-fold to 2.3-fold)higher risk of contralateral breast cancer thanpeople from families with BRCA2 mutations.

survival benefit for stage IB patients (HR 1.03,95%CI 0.70–1.52; P=0.87).Within stage IB, how-ever, tumour sizewas predictive of chemotherapyeffect. Patientswith tumours 4 cmor larger in sizederived clinically meaningful benefit fromchemotherapy (HR0.66,95%CI0.39–1.14;P=0.13),while thosewith tumours smaller than4cmdidnot(HR1.73, 95%CI0.98–3.04;P=0.06). Furthermore,in the JBR.10 trial, theauthors foundnodifferencebetween the groups in the rate of death fromother causes or second cancers.

“This updated analysis with more than nineyears of follow-up confirms a significant survivalbenefit for adjuvant chemotherapy in early-stageNSCLC. The survival benefit is seen in the stage IIpatients. No evidence of unexpected late toxicityor increase in second malignancies from adju-vantchemotherapywasobserved,”writeButtsandcolleagues, adding that their study represents thelongest reported follow-up data of any of therecent adjuvant NSCLC trials.

Longer follow-up in the adjuvant setting isneeded, writes Douillard in his editorial, in orderto assess cure. He suggests that the discordantresults may in part be accounted for by differ-ences between the two trials, including in thewaythey defined lung-cancer and non-lung-cancer related deaths, and differences in studypatient populations, use of postoperative radia-tion and types of chemotherapy.

With regards to chemotherapy, the JBR.10trial used only a single regimen of cisplatin andvinorelbine,whilepatients in the IALT trial receivedcisplatin, alongwith one of four drugs (vindesine,vinblastine, etoposide or vinorelbine).

“The choiceof drug to combinewith cisplatinmaybecrucial. Todate, vinorelbine is theonly thirdgeneration drug to demonstrate consistentimprovement in survival on a long-term basis,”writesDouillard, adding that cisplatinandvinorel-bine should be the recommended regimen for adurable and reproducible benefit.

� CA Butts, K Ding, L Seymour et al. Randomized

phase III trial of vinorelbine plus cisplatin compared

with observation in completely resected stage IB and

II non-small-cell lung cancer: updated survival

analysis of JBR.10. JCO 1 January 2010, 28:29–34

� R Arriagada, A Dunant, JP Pignon et al.

ImpactFactor


Younger age at first breast cancerwas associatedwith a significantly higher risk of contralateralbreast cancer in patients with BRCA1mutations,with a trend observed for patients with BRCA2mutations that was not statistically significant.AmongpatientswithBRCA1mutationswhowereyounger than40 yearswhen first diagnosedwithbreast cancer, 62.9%haddeveloped contralateralbreast cancer 25 years on, compared with only19.6% among those whose first diagnosis camewhen theywere older than50. Importantly, writethe authors, there was no indication that the riskof contralateral breast cancer levelledoffwithin25years following first breast cancer.

“To our knowledge, this study is the first toshow that patients from families with BRCA1mutations face a significantly higher contralat-eral breast cancer risk compared with patientsfrom families with BRCA2mutations,” write theauthors, adding that the estimated absoluterisks in the study were considerably lower thanin other studies. “(This) may be of particularclinical relevance for women trying to decidewhether to undergo contralateral prophylacticmastectomy at the time of breast cancer diag-nosis,” they suggest.

Inanaccompanyingeditorial, JudyGarberandMehra Golshan of Brigham andWomen’s Hospi-tal comment that the data fromGraeser and col-leagues suggest that surgeons, inparticular, shouldrecognise thatpatients couldbemutationcarriers,based on age at diagnosis, family history, ethnic-ity andhistologic features, andoffer to refer themfor genetic testing as appropriate.

At least as important for more matureBRCA1/2 carriers, they add, is the fact that thestudy showed the risk of contralateral breastcancer was less compelling for these patients.“There is less justification for contralateral pro-phylactic mastectomy for this group, and theordeal of bilateral reconstruction of greater con-sequence,” they write.

� MKGraeser, C Engel, K Rhiem et al. Contralateral

breast cancer risk in BRCA1 and BRCA2 mutation

carriers. JCO December 10 2009, 27:5887–5892

� JE Garber, M Golshan et al. Contralateral breast

cancer in BRCA1/BRCA2 mutation carriers: the

story of the other side. ibid pp 5862–5864

Home care nursingimproves chemotherapytoxicity symptoms� Journal of Clinical Oncology

Home care nursing (HCN) programmesfor patients with colorectal and breast

cancer receiving oral chemotherapy bothimproved symptoms and resulted in reduceduse of medical services, reports a UK study.

Capecitabine, an orally administeredchemotherapy for adjuvant/metastatic col-orectal cancer and metastatic breast cancer,produces toxicity in up to 26% of non-pre-treated patients and 45% of pretreatedpatients. An earlier, separate, systematicreview had found evidence for the benefitsof home care programmes for patients withincurable cancer to be unclear. In the firstsupportive care randomised trial to test theeffects of interventions in patients receivingoral chemotherapy, Alex Molassiotis andcolleagues, from the School of Nursing, Mid-wifery and Social Work at the University ofManchester, UK, set about investigatingwhether HCN might be a potentially valu-able service to offer patients.

In the study, 110 patients with colorec-tal cancer and 54 patients with breast can-cer who were all receiving oral capecitabinewere randomly assigned to receive either ahome care programme delivered by a nurse,or standard care for 18 weeks (i.e. six cyclesof chemotherapy). Standard care consistedof information about the drug and itsadverse effects provided by the clinicianand accompanied by written information(with patients provided with emergencyhotline phone numbers), while the HCN pro-gramme included symptom assessment,patient education and/or treatment ofsymptoms on the basis of agreed protocols,and one standard home visit.

Significant improvements were observedamong patients assigned to the home caregroup for the first four cycles in relation tooral mucositis (P=0.001), diarrhoea(P=0.031), constipation (P=0.002), nausea

(P=0.006), pain (P<0.0005), fatigue(P<0.010) and in relation to insomnia for allsix cycles (P<0.0005).

Furthermore, although visits to GPs weresimilar for the two arms, there were signif-icantly lower numbers of calls to the hospi-tal emergency hotline (32 for HCN vs 91 forstandard care, P=0.0005) , lower utilisationof other health care services (35 for HCN vs74 for standard care, P=0.008) and lowernumbers of inpatient days in the home caregroup (57 for HCN vs 167 for standard care,P=0.02).

“An HCN, symptom-focused interven-tion appears to be an effective way of sup-porting patients,” write the authors, addingthat although this may not be feasible forlarge numbers of patients who receive oralchemotherapy, resource savings in otherareas of health care utilisation might offsetthe HCN costs.

Improvements in toxicity were most evi-dent in the first two cycles of chemotherapy(i.e. the first six weeks), supported by boththe single toxicity score and the analysis ofeach individual symptom. “This suggeststhat the most crucial time to provide a sup-portive care intervention in patients receiv-ing capecitabine is during the first two cyclesof treatment. Although patients generallyreceive information and education abouttheir chemotherapy before starting treat-ment, they may feel overwhelmed with suchinformation, and re-education and supportduring the first few weeks of treatmentseems an appropriate and useful approach.Also, such an intervention maintains bettercontinuity of care and a more positive expe-rience of treatment,” write the authors,adding that the generic approach to symp-tom management makes this interventionappropriate for other oral chemotherapies.

� A Molassiotis, S Brearley, M Saunders.

Effectiveness of a home care nursing program

in the symptom management of patients with

colorectal and breast cancer receiving oral

chemotherapy: a randomized, controlled trial.

JCO 20 December 2009, 27:6191–6198

� Peter McIntyre

Cancer patients and their friends and families are uniquely placed to challenge fears andmis-

perceptions that hamper prevention and contribute to late diagnoses, poor treatment and the

social isolation of patients.Acting locally but using the Internet to organise globally, patient advo-

cacy groups are extending their support and campaigning work to all corners of the world.

The past decade has seenchanges in public awarenessabout cancer thatmay be as pro-

found as the changes in treatment. Justas treatment is shifting to a more tar-geted approach, so too have the voicesof cancer become more individualand targeted.

There has been a marked rise inpatient-centred groups that reflect theexperience of having cancer and the pri-orities of thosewho are being treated andwho give voice to their concerns andthose of their families.

Although there are sometimes dis-agreements between patient advocacygroups and health policy makers andproviders, as these groups havematured,they have generally established goodrelationshipswith researchers, the phar-maceutical industry andhealthcare pro-fessionals with benefits to both sides.

Modern health services have come torecognise that patient advocacy groupsprovide them with a more authenticvoice of patients than they can achievethrough other forms of consultation.

Patient advocacy groups are increas-ingly addressing the public directly toraise consciousness of their specialneeds. In part this may be a drive toattract funds for research, treatment andcare, but it is also to do with buildingpublic awareness about cancer, in thehope that a better educated public willlead to greater pressure onpolicymakersand funders to give a higher priority totheir particular area of interest.

Whilemany campaigns are nationaland focused on improving access andservices in a single country, the increasein Internet access enables patients andtheir groups to share experiences andinformation globally, and to combine

local and Europe-wide campaigns.The over-riding mission of Europa

Donna, the European Breast CancerCoalition, is to ensure that all Euro-pean women have information aboutand access to state-of-the-art earlydetection, diagnosis and treatment ofbreast cancer. It promotes the Euro-pean guidelines for quality assurance inbreast cancer screening and diagnosisand works to ensure that nationalhealth systems throughout Europemeet these standards.

Member groups in 44 Europeancountries from Albania to Uzbekistantake part in Europa Donna actions. Itscentral organisation, based in Milan,has a responsibility to raise awarenessEurope wide, as their constitution putsit, “enhancing the power of action byEuropean women to gain control ofthis disease.”


PatientVoice

Spreading the wordHow patient groups are delivering life-saving messages to all corners of the globe

PatientVoice


PREVENTIONAs part of their advocacy brief, in 2008EuropaDonna launched BreastHealthDay (15 October) to reach out to ayounger cohort of women tomake themmore aware of the growing evidenceabout breast cancer prevention(www.breasthealthday.org).

Susan Knox, chief executive ofEuropa Donna, and a patient herself,said, “We had been working for a longtimeoncampaignsdealingwith theprob-lemsofearlydetectionand treatment,pri-marily with a population of women aged40andover.Therewas a growingbodyofepidemiological evidence about the

Spreading the word. Europa Donna enlisted theaid of international tennis champion ArantxaSánchez-Vicario (left) and the technology of the‘e-card’ to spread the message about howimportant physical activity is to breast health.Pictured with Sánchez-Vicario are the directorand president of Europa Donna, Susan Knox(centre) and Ellen Verschuur (right)

WACHHOLDERPHOTOGRAPHY

The campaign was launched with apress conference in Brussels at whichPeter Boyle, former Director of IARC,the WHO agency for epidemiologicalresearch on cancer, presented the mostup-to-date knowledge on breast cancerprevention. Local campaigning was also

amount of breast cancer that canbepre-ventedbyhealthy lifestyle choices.Thereare more than 430,000 new cases ofbreast cancer in Europe each year. Wecouldavoidandpreventperhapsasmuchas 30% of these by changing life style.”

OnBreastHealthDay2009,ArantxaSánchez-Vicario, the Spanish tennis starwho won 10 Grand Slam titles in the1990s, joinedEuropaDonna to launcha‘GetMoreActive’ campaign to highlightthe10%–16%ofbreast cancers thatmaybe due to inactivity. Now in her late 30s,Sánchez-Vicariowas chosenas someonewho would have a positive impact onyounger women throughout Europe.

“It is also to do with the hope that a better educated

public will lead to greater pressure on policy makers”


PatientVoice

“These prevention messages can be used by all breast

cancer groups as they are applicable everywhere”

PATIENT POWERShe sees the local groups in countriesand individuals who speak out abouttheir experiences as being at the heart ofwhat the Max Foundation does. “Overthe past six years we have been verysuccessful in building patient support

meetings and patients' associations incountrieswhere therewasno concept ofemotional support for cancer patients.We also have now these amazing groupsofpeoplewhoare givingback to thecom-munity and living very successful andproductive lives and literally changingthe faceof cancer in their communities.”

In2007,TheMaxFoundationdesig-

carriedout in21countries tomarkBreastHealthDay,usingpamphlets andpostersproduced by Europa Donna for its 44member countries.

TheBreastHealthDay initiative gen-erated 250 media and blog postings in22 countries, underlining the impactthat a well-plannedcampaign can havebothEurope-wideandin individual countries.From 2010, EuropaDonna plans to makethe campaign globalrather than just Euro-pean. Susan Knoxsays, “These importantprevention messagescan be used by allbreast cancer groupsas they are applicable everywhere; wewould like tohelp spread themtowomenand girls across theworld.”

Thishubandspokespatternofcentralsupport and national groups is alsoadoptedbymany of the advocacy groupsfocused on some rarer cancers.

TheMaxFoundation supports peoplewith chronic myeloid leukaemia (CML)and their associations. It administers apatient assistanceprogrammetobring thelife-savingdrugGlivec (imatinib) topeoplein under-resourced countries. Executivedirector Pat Garcia-Gonzalez is the step-mother of Max Rivarola from Argentina,who died fromCML in 1991, aged 17.

“We have now these amazing groups of people who

are changing the face of cancer in their communities”

MAXFOUNDATION

Images of hope and determination. Painted by Diogenes andDavid, CML patients in the Philippines, these pictures (part ofthe Max Foundation’s Colors of Hope Gallery) make a powerfulpoint about how cancer need not stop you leading a productivelife – a message still rarely heard in many developing countries

PatientVoice


groups in countries where they don’texist. It workedwith emerging groups inZimbabwe, Hong Kong and Lithuaniathat gain greater awareness throughactivities like the World Walk. In Zim-babwe, where 180 people joined thewalk, Christine Mungoshi, director ofthe Zimbabwe Brain Tumor Associa-tion, appeared on television. She said, “Itwas a true awareness raising event, asmany people were not aware of theimpact of brain tumours and also theexistence of our organisation.”

In oneAsian country a philanthropistwhohad a familymember recently diag-nosedwith a brain tumour saw thewalktaking place and immediately offeredfunding for a brain tumour centre.

The strength of the global coalition isreflected in the World Walk project. In2009, 182organisations around theglobesupported theWorldWalk and Interna-tionalBrainTumourAwarenessWeek. Intotal, 38,114 participants in 13 coun-trieswalked226,590kms, the equivalentof five times around the world at theEquator. They raised the equivalent of2.5million euros, all ofwhich is retainedby local groups for local brain tumourcharities and research organisations.

These organisations don’t alwayshave the same priorities. “We recognisethat every country is different culturallyand that resources vary,” says KathyOliver. “Weencourage andnetworkwiththem. We don’t push a particular mes-sage when we know it is not going to berelevant in that country.”

The Max Foundation too exceededits target for this year. It aimed to collect1000messages on theTributeWall dur-ingOctober, and succeeded in collecting1500messages from 54 countries.

nated the month of October for a ‘cele-brationof life,’and in2009 raised thepro-file of its ‘MaximizeLife’campaignwith aTributeWall, where families post uplift-ingmessages, and aColors ofHope pic-ture gallery where patients and familycarers use art to express their emotions(www.themaxfoundation.org).

PatGarcia-Gonzalez says, “Wewereatthe point where we wanted to do twothings. One was for each association toknow that there are others around theworld in a situation that is very similar,doing the same thing they are doing, andthe other is for the world to hear howimportant it is tohaveaccess to treatmentin developing countries.

“The literature tells you thatCML ispredominant inmales and that the aver-age ageatdiagnosis is between55and60years old. What we found in developingcountries is that it was a very young pop-ulation– young guys of 28 to30years oldin the prime of their lives. We are usingthe experience of CML to get people tounderstand that cancer is a real disease indevelopingcountries and it is very impor-tant to pay attention to it.”

One key aim is to reduce stigma. “Weare working in places where ‘cancer’ is avery scary word. People get fired fromtheir jobs. Your sister is not able to getmarried if you have cancer. If you can geteven one person who is living a very pro-ductive lifewithcancer togetout thereandstart saying that, then we are changingthe way that cancer is perceived. Peoplewill bemorewilling to go to thedoctor andthat this may lead to early detection andmore likely good clinical outcomes.”

As an alliance of support, advocacyand information groups for brain tumourpatients andcarers indifferent countries,

the International BrainTumourAlliance(IBTA) also recognises country groups asa crucial element.

Co-directors Denis Strangman andKathyOliver helped form the IBTA outof personal experience.Denis’wifeMargdied of glioblastoma in 2001, whileKathy’s son has lived with a braintumour since diagnosis in 2004. KathyOliver believes this shapes the organi-sation. “Everybody who works for theIBTA is a volunteer, including the twodirectors, and has hands-on experienceof the brain tumour journey, either ascaregivers or relatives.”

TREATMENT AND SUPPORTKathy points out that many messagescentral tocombatingothercancersarenotrelevant for the 200,000 people a yearworldwidewhodevelop aprimarymalig-nant brain tumour. “I don’t wish to takeanything away from these campaigns,but in the case of brain tumours, preven-tion, screening and lifestyle issues aren’trelevant. They attack anybody from tinybabies to the elderly. There is noway youcanprevent thembecausenobodyknowswhat causes themand screening is unre-alistic, so it really needs a strong focus ontreatment and support.”

“Thedire prognosis and lack of fund-ing for research, together with misdiag-nosis and delayed diagnosis, make thisan extremely tough disease.”

In 2007 the IBTA launched its ‘WalkAround the World’ event, with spon-soredwalks in dozens of countries beforeor during International Brain TumourAwareness Week in the autumn(www.theibta.org).

The IBTAencourages the establish-ment of brain tumour patient support

They raised the equivalent of 2.5m euros – all retained

by the local groups for local brain tumour organisations

They worked successfully in India,Malaysia, thePhilippines andChile andmade contact with new groups inMau-ritius, Cameroon and Azerbaijan. TheHenzo group in Kenya organised anevent in Nairobi and invited the mediaand people from the community, andlaunched themselves as aCMLpatients'association. “It became something veryexciting for us to start to put together thismovement of people changing the faceof cancer in developing countries,” saysPat Garcia-Gonzalez. “I think that themain benefit is thatmany of these youngpatient associations in countries wherewe campaign are able to get visibility.”

THE INTERNETAND SOCIAL NETWORKINGAll these organisations have used theInternet and social networking sites togreat effect.

The Europa Donna Breast Health Daywebsite (breasthealthday2009.org) fea-tures an attractive ‘e-card’, which com-bines information about the key healthbenefits of exercise with some clevergraphics of bouncing balls – repre-senting both various breast sizes andvarious sports activities – and a catchytune. You can send this by e-mail to anywoman to encourage them to becomemore active; the ‘e-card’ also encour-ages the recipient to then forward themessage to her own friends.

Between October 2009 and theend of the year, about 5000 e-cardswere forwarded in this way to womenin 58 countries and many more weresent out directly from the site.

“The e-card to me is one of the mostexciting aspects of the programme,”says Susan Knox. “Younger peopletoday are really learning through inter-active websites so we felt that thiswould be attractive to younger womenand a way for them to communicatewith each other. It enables us to reachout with importantmessages to womenacross the globe.”

KathyOliver is alsoenthusiastic aboutthe potential of new technology toincrease the power of campaigns. “Wekeep finding more organisations eachyearbecausemore andmorepeoplehearabout the walk. I don’t know how we allsurvivedwithout the Internet in termsofcommunication.People readabout things


PatientVoice

“The main benefit is that young patient associations in

countries where we campaign are able to get visibility”

A global event for local benefit. The Walk Around the World concept, developed by the International BrainTumour Alliance, neatly links locally organised sponsored walks to the global goal of collectively coveringenough ground to encircle the globe – pictured here is the 2008 'brain trekking' walk in Hong Kong

BRAIN

TREKKING,HONGKONG

on a campaign like this is very minimal.TheWorldHealthOrganization and theEuropean Commission have major pre-vention programmes, and I would hopethat eventually we can link our projectwith one of these. Otherwise it will beextremelydifficult forus todo thekindofstudies we would need to measure theimpact our programme is having. Howmany people are changing their lifestyleand howmany are even seeing themes-sages?Those are keyquestions that needto be answered.”

TheCMLAwarenessCampaignwillalso continue, andTheMaxFoundationtoo is looking to combine efforts with

larger cancer organisations toreach patients who

are under-

served. Pat Garcia-Gonzalez says, “Wehope to get a little bit more visibilityglobally, but I amprimarily interested inreaching each and every person whocan benefit from treatment for CML.”

The Walk Around the World eventwill step out again in 2010 – IBTAAwareness Week will be from Sunday31October to Saturday 6November. Itis a tool, says Kathy Oliver, both tosupport individuals and to help changethe face of treatment and support.

“Whenmy son was first diagnosed,I knew nothing about brain tumours.My immediate feelingwas that wemustbe the only people in the world whohave this problem. Through coalitionslike the IBTA and the many excellentbrain tumour patient groups aroundtheworld, people with a rare cancer likea brain tumour can be comforted by thefact that they are not alone.

“In a relatively short time since, wehave seen a greater focus of attentionnotjust on brain tumours but on other rare

cancers too. There is stilla tremendous amount ofwork to do in theseareas, but we are wit-nessing the emergenceofmore targeted ther-apies, genetic profil-ing and othercutting-edge aspectsof treatment whichappear promising.

“What’s more,we are seeing increased collab-

oration on a global scale not just withpatient groups but with the scientificcommunity as well – and that is a verypowerful direction.”

PatientVoice


on the Internet and want to do it them-selves.We have people contacting us allthe time saying, ‘What a great idea, Iwould like to organise this.’ It gathers itsownmomentum.”

TheMax Foundation not only uses awebsite to host its picture gallery andTribute Wall but also has its own Face-bookpage topublicise its campaigns.PatGarcia-Gonzalez says, “We like to usehuman power, but we don't believe youhave to spenda lot ofmoney todoacam-paign.A lot of it is about giving a little bitof funding to the groups in thecountry toorganise this event. I think we gave atotal of around US$ 15,000 (11,000euros) to put together 40 events in 22countries.”

However shehas awordofwarningabout relying too heavily on the Inter-netandsocialnetworking. “Oneof thebig lessons we learned was if youwant to do a campaign in countrieswhere access to the Internet is notso broad youhave to use a combi-nation of low tech andhigh tech.

“In these countries, we cre-ated a real wall where peopleput their messages on paperand then we put them ontothe Internet. You have to be able tohave someone on the groundworking ina very old-fashioned way.”

THE FUTUREBreast Health Day will continue as anannual event on 15 October 2010 andbeyond, and Europa Donna plans toextend its prevention campaign globallynext year. However, in-depth evaluationwill be also be needed, says SusanKnox.“Theamount ofmoneywehave to spend

Different cultures,same message.The virtual wall ofhope (top) offers aspace for communi-cation and solidarityfor CML patients andtheir families with broadband access. Real wallsof hope, like this one in Malaysia, are morerelevant in many settings (themaxfoundation.org)

“We like to use human power but we don’t believe

you have to spend a lot of money to do a campaign”

Documents

Cancer World 35