Cancer World 45

Luzia Travado: improving outcomes for patients by attending to their distress To cut ornot to cut? Why that is now a team decision Redefining the role of pathologists in the eraof personalised treatments Helping countries take that first step towards cancer control

Luzia Travado

Education & knowledge through people & facts

Number 45, November-December 2011

CancerWorld

45N

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BER-DECEM

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CANCER WORLD NOVEMBER/DECEMBER 2011 1

Contents

3 EditorialTo cut or not to cut? Why surgeons dont have all the answers

4 Cover StoryLuzia Travado: improving outcomes for patients by attending to their distress

15 e-Grand RoundPrognostic and predictive markers in colorectal cancer: implicationsfor clinical management

24 Best Cancer Reporter AwardHope for me, and for others who come after: award-winning article explores theimpact of a new network of early trial centres

34 MasterpieceRedefining the role of pathology: how Giuseppe Viale embraced thenew responsibilities of the molecular era

42 Impact FactorAn important piece of the localised prostate cancer puzzle?Front-line therapy in lung cancer with mutations in EGFR

50 NewsroundSelected news reports

58 Systems & ServicesTaking the first step on the road to cancer control: how two proposed registryprojects could help

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantAlexandra Zampetti

Editorial AdvisorsJacques BernierFatima CardosoFranco CavalliAlberto CostaVincent T. DeVita

Contributing WritersMarc Beishon, Federico CappuzzoSimon Crompton, James DenhamJanet Fricker, Victoria LambertLorenza Landi, Anna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonAlexandra Zampetti

Art EditorJason Harris

ProductionHarrisDPIwww.harrisdpi.co.uk

Printed byGrafiche Porpora

Cover photographJorge Nogueira

Published byEuropean School of Oncology

Direttore responsabileAlberto Costa

Registrazione Tribunale di RomaDecreto n. 436 del 8.11.2004

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

Copyright 2011 European School of Oncology.All rights reserved

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


Editorial

Formore than one hundred yearscancerwas considered anexternalentity growing into the body andacting against it. The approach to treatmentwas: seek and destroy. Aggressive surgery,heavy radiotherapy, intensive chemotherapywere the norm. We now know that cancercells result from genetic changes to normalcells, and we now try to cure them withoutcausing too much damage to healthy cells.Consequently, surgery has becomemore andmore conservative.

When surgery was the principal way oftreating most cancers, any cancer that wasinoperable for instance because it was solocally advanced that excision would inflictunacceptable functional damage was, bydefinition, incurable. Nowadays, the use ofcombination treatments, radiotherapy and/ormedical treatment can dramatically reducethe level of local invasion,making it possible tooperate on previously inoperable tumours.

There are other ways in which the con-cept of operability is changing. For instance,poor cardiovascular health was always seenas a barrier to conducting cancer surgery.However, good pre-operative medical treat-ment can now address this problem andallow surgery to take place. Meanwhile,many surgical procedures that were onceconsidered highly risky are now undertakenfar more frequently, as cancer surgeonsimprove their results by specialising in par-

Alberto Costa GUEST EDITOR

ticular types of surgery. Even the old rule ofsurgery that you dont operate on a patientwhose cancer has clearly spread to key organs no longer applies. A greater focus on sup-portive care now means many more inter-ventions are carried out to improve quality oflife, for instance by treating intestinal occlu-sions or painful compressions.

With the greaterweight given to the voiceof thepatient, their views are also influencingthe concept of operability.Difficult as it is forhealthprofessionals to accept, patients some-times refuse surgery because they dread theconsequences of surgerymore than the can-cer itself, and they may not fully grasp theimplications of their decision. The finalwordmust be theirs, but effective communica-tion and goodpsychological support canhelpthem make a more informed analysis of thepotential risks and benefits to reach the bestdecision for them. Some tumours will, ofcourse, remain inoperable, and patients andhealth professionalswill still sometimeshaveto accept this very frustrating reality, andleave the cancer to grow.

With multiple factors now influencingthe concept of operability, the decision onwhether or not to operate can no longer beleft up to surgeons. The right decision canonly bemade through evaluation by special-ists from multiple disciplines, communi-cated effectively to the patient, who willhave the final say.

To cut or not to cut?Why surgeons dont have all the answers

Alberto Costa is the scientific director of ESO, coordinator of the Breast Unit at the Maugeri Foundation, Pavia, Italy, and executivedirector of the Breast Unit of the Italian-speaking region of Switzerland (Canton Ticino), Bellinzona and Lugano, Switzerland

CoverStory

4 CANCER WORLD NOVEMBER/DECEMBER 2011

Luzia Travado:improving outcomes for patientsby attending to their distress

Marc Beishon

At a busy hospital in the centre of Lisbon, Luzia Travadomanaged to transform the role of health

psychology from an intervention of last resort to a place in the frontline of cancer care, by

showing time and againwhat can be achievedwhen you listen to patients andhelp themuse their

own coping skills. Her determination to improve the psychosocial care offered to cancer patients

hasmade her a familiar face at seminars and conferences across Europe and beyond.

Given that a diagnosis of cancer oftenhas a devastating emotional impacton people it is surprising that it is onlyrelatively recently that distress hasstarted to be seen as the sixth vital

sign to check forwith patients. That is no fault of theadvocates of psychosocial care in oncology, whohave been patiently building up an impressivearmoury of evidence for the role of health psychol-ogy in cancer. But themedical model in oncology which is still catching up with the fifth vital sign,namely pain is a tough mindset to change (theother four signs being, of course, temperature, bloodpressure, pulse and respiratory rate).If you assess pain properly youmight also be on

yourway tomanaging distress, as pain also has a psy-chological component, says Luzia Travado, head ofclinical psychology atHospital deSo Jos inLisbon,Portugal. But if you dont ask the right questions at

the right times you wont know what the patient isalso enduring from a range of sources of emotionaldistress, not just pain, and so you could be neglect-ing a very important area of intervention.If you dont deal with distress which can

develop into depression, anxiety andmaladjustment patients will not have the best quality of life andclinical outcomes they might have had otherwise.They could stay in hospital longer, derive less bene-fit from chemotherapy, be a greater burden on theirfamilies and have a shorter overall survival.About 50%of cancer patientswill suffer fromdis-

tress that may develop into psychological condi-tions such as depression, she says, which indicatesthe scale of potential need for support.Theevidencebase for the impactofpsycho-oncol-

ogy interventions throughout thepatient cancer jour-ney is already strong and growing fast, adds Travado.But there is still a lot of denial about theneed to cope

CoverStory


JORGENOGUEIRA

with distress from both health professionals andpatients, and the provision of psycho-oncologists inhospitals in countries such as Portugal is verymixed.At my hospital we have a team of seven clinical psy-chologistsworking inmultidisciplinary teams inbreastcancer, other cancer types and major health eventssuchasburnsand trauma. Inotherhospitals theremaybeonly onepart-timepsychologist or psychiatrist andthere is only somuch they can do.AcrossEurope too, the availability of psychosocial

services varies greatly, although detailed figures arehard tocomebyatpresent. If you lookatwhetherpsy-cho-oncology services are included innational cancerplans, a report from 2009 showed that of the 19countries that had plans in Europe all specified pal-liative care and rehabilitation, and 16 specified psy-chological support, she says. But the focus was on

palliativeandend-of-lifecare, and fewplans todayhaveinformation about evaluating any typeof cancer serv-ice, let alone psycho-oncology.She points also to a global survey of professionals

working in psychosocial care that reports on whereservices are being offered, noting that it is by nomeans certain that themost cancer-oriented institu-tionscancer centres anduniversity hospitals haveregular psycho-oncology services for patients, and inother settings such as out-patient clinics and privatepractice they are rarely offered.Thebaselinedata about existing services shouldbe

boosted by a psychosocial oncology action project,part of the healthcare work package in the EuropeanPartnership for Action Against Cancer (EPAAC),which isproposing first tomap thecoverageof servicesand then develop and pilot education tools for com-

We are part of the frontline team and not a separate

department dealing with a different part of a patient

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JORGENOGUEIRA

Travados interest in therapywas sparkedbyayear-longstay in the USwhen she was just 17, as she was for-tunate togainaplaceonan intercultural exchangepro-grammethathadbeenestablishedafterWorldWar II.I finished my high school in America and learntabout the importance of contributing to society inPortugal we had been used to the state providing forus. I spent time visiting people in awar veteranshos-pital and learnthowto listen to their life storiesoftenthey had no other visitors.Back in Portugal, Travado decided not to do

biology (toomuch labwork), and considered geol-ogy before landing in clinical psychology at LisbonUniversity, and was fortunate to learn from a pro-fessor who had worked with the famous psycholo-gist Jean Piaget, and had imported cognitivebehavioural therapy (CBT) from California. I didmy post-grad work on psychotherapy, focusing onwhatwe call a constructivist approach,whichwe arenow linkingwith psycho-oncology. Broadly, its aboutpatient-centred care and means attending to apatients own preferences and decisions, and under-standing what their resources are, and then helpingthem to explore alternatives based on what theyalready know, and so helping them to function.Its about respecting their ownequilibriumand is

theoppositeof apaternalisticmodel, inwhichdoctorsand specialists pretend they know everything andpatients should learn fromthem. I tellmystudents thattheymust learn from their patients about how theyfunction and what they use to deal with difficulties,and so build their self-esteem and confidence.She adds that the cognitive behavioural model

arms youwith brief, effective techniques and inter-ventions for reducing patients symptoms of dis-tress, anxiety, depression and pain andhas provedto be a great foundation for clinical health psychol-ogy, as has been extensively demonstrated by inter-national colleagues such as Maggie Watson at theRoyal Marsden in the UK. But Travado was verymuch on her own to start with.She was trained first in clinical psychology with

peoplewho didnt have physical problems thatwas

munication skills and psychosocial care, initially incountries with low provision. Travado is leading thisproject, on behalf of theNational Coordinating Bodyfor Oncological Disease in Portugal, with a range ofpartner organisations.These include the InternationalPsycho-Oncology Society (IPOS, for which she iscurrently treasurer) a global organisation that is nowpromoting psychosocial services as part of standardcare, which she says is being endorsed by an increas-ing number of cancer societies and patient groups.Themost high-profile support recently has come

from the World Health Organization, which is cur-rently involved in discussing the possibility of IPOSbecoming a non-governmental organisation (NGO)partner to establish psychosocial care in cancer con-trol programmes. In developing countries carryingout cervical cancer screening and treatment, forinstance, it is hard to overestimate the importance ofintegratingcounselling intocare, aswell as trainingpro-fessionals in communications skills both corner-stones of psycho-oncology.In Travado, the psycho-oncology movement has a

tremendously energetic and passionate expert to helppromote such support and itmustnot be anoptionalextra forhealthcare systems, she says. All patientswhoneed psychosocial care are entitled to it it should beconsideredahuman right in the samewayas treatmentfor physical illness. Indeed, according to a recentreport shementions fromtheUSInstituteofMedicine,Cancer care for thewholepatient:meetingpsychoso-cial needs, it is just not possible now to deliver high-quality care without integrating the approaches andtools that are already available for taking care of psy-chological health. Every cancer centre under the USNationalCancer Institute isnowrequired tohaveapsy-cho-oncology programme.Psychosocial burdenscanbemore threatening in

many cases than the disease itself, says Travado.Evenwhenacancer is treatable someonemay feel indespair andnotcope.Whatweneed to impressonpol-icymakers and themedical community is thatwearepart of the frontline team and not a separate depart-ment dealing with a different part of a patient.

CoverStory


They must learn from their patients about how they

function and what they use to deal with difficulties

to come soon but says she developed a passion forpsychology and patient narratives. However, therewere no jobs for a health psychologist in Lisbon, andshe left to try to establish aprivatepractice in anearbytown,whichwas to suffer an awful event. Therewasagasexplosion inahighschool twochildrendiedandthirteen had severe burns. I was asked to help thoseaffected and their parents with the ordeal.Travado then met the director of Hospital So

Jos at a community event in the town and, havingheard about her work, he invited her to join thehospital as a health psychologist working with burnpatients and others referred by the plastic surgeryteams. I was told, Put thiswhite coat on,write yourname on it and add psychologist and youll beOK,but some doctors said to me that I shouldnt bethere, but at a psychiatric hospital.Working on short-term contracts, it wasnt long

before shewasalsoasked to talk toheadandneckcan-cer patients, who like trauma and burn patients hadoften suffereddrasticphysical change. Iwas told thatas long as I could prove myself with the number ofreferrals, I couldhave a full-timeposition. Itwashardat first but I was very assertive. I said, The psycho-logical impact of a physical illness or traumacan leadto a patient becoming silent or angry: if you have oneof these, cometomeandIcanhelp themcopebetter.When askedwhy shewas a lonepsychologist in a

hospital thatdidnot evenhavea full-timepsychiatrist,Travado would reply that clinical psychology has itsownstatus as a science, and Ididnt recogniseanyoneas superior except a professor of psychology or thehospital director.The storywill be familiar to otherswho carved out

paths in psycho-oncology in the early days. Manydoctors would only call for me when they didntknowwhat to dowith a patient anymore. But Iwouldsee something extraordinary I would sit with thepatients, saying that the care team was concernedabout themand their treatment, and Iwould askwhatwas troubling themand empathise, saying how toughitmust be for them. Theywould then say everything

about their concerns and feel debriefed.No one hadspoken to them like this before not the doctors, northenurses by sitting by their bedside to askwhatwastroubling them. There were even some people whohad just pulled a sheet over their head suchwas theirfeeling of isolation.Amid all the psychotherapy theory, Travado has

adopted a straightforward approach to helpingpatients the best, and that is simply visiting thematthe bedside, or what she terms proximitywork. Inthe hospital, she and her team wear white coats,which at first sight seems as though that could dis-tance themselves frompeople. Butwewearwhitecoats as part of hospital regulations, as it showsweareprofessionals and that there is noquestionwearestaff. And very importantly, patients know we arepart of their healthcare team,which helps to lessenthe stigma of what we do they shouldnt feel theother teammembers think they are a problem.Whilepatients are inhospital, she says, it is impor-

tantnot tomakemoredifficulties for themby request-ing they visit a psychologist in anoffice. If they areonaward its because they need to be there, andwe canusually talk to them privately using curtains or in themeal rooms in thewards.Travado did indeed prove her worth, in doing

muchmore than stepping inwith problempatients albeit after fiveyearsor soof firefighting,workingaloneand running fromonepatient to another. Shecontin-ued with severe burns patients a speciality shemaintains today and became increasingly involvedwith cancer andother conditions such as spinal-cordinjury, stroke, parasuicide,morbidobesity andchronicpain. Shewas then able to integrate psycho-oncologymuch more into the multidisciplinary cancer teamsthatwere starting to develop, especially with a breastcancer surgeonwhowanted all the right people inhisteam, including Travado, social workers, physiother-apists, plastic surgeons andothers,whichwaspartic-ularly crucialwhenmastectomywas themainoption.But he still wanted a referral system so that

patients would have tomake different appointments

There were even some people who had just pulled a

sheet over their head such was their feeling of isolation

CoverStory


toparticipate in international networking at the IPOSWorld Congress, and was pleased to find that col-leagues abroad were working on similar cognitivebehaviour interventions, and that protocols such asSPIKES, for breaking bad news, were being intro-duced, basedon researchwithpatients. SPIKESwasdevelopedbyRobertBuckmanandWalterBaile (thelatter heads the Interpersonal Communication andRelationshipEnhancement (I*CARE)programmeatMDAnderson in theUS, a unit with which Travadocollaborates closely).In the last 10 years, Travado has engaged in a

whirlwindof national and international activities, hav-ing been asked to advise Portugals National Coor-dinator for Oncological Diseases the countryscancer czar on national psycho-oncology coordi-nation, andhelping to organise aEurope-wide round-table on cancer when Portugal had the EuropeanUnion presidency in 2007. The Slovenian follow-up in the following year led to theEPAACEuropeanpartnership action plan, she adds.With colleagueLuigiGrassi, a psycho-oncologist

in Italy, she secured a chapter onpsychosocial care inResponding to thechallengeof cancer inEurope, thebookproducedunder theSlovenian presidency. Thisis an in-depth piece on how cancer affects people atvarious levels socially and spiritually, aswell as psy-chologicallyandtells thestory so faron themain toolsfor measuring distress, the psychosocial interven-tions, and the training and standardsnowonoffer forclinical settingsThe chapter presented some simple tools such

as the distress thermometer, developed by a panelof the US National Comprehensive Cancer Net-work, which helps all healthcare professionals toscreen for distress, and which could help establishthe sixth vital sign in practice.That relates toher involvement inoneofhermost

important international researchprojects to date, theSouthern European Psycho-Oncology Study(SEPOS), which is a collaboration between profes-sionals in Portugal, Spain and Italy (and led by LuigiGrassi). Southern Europe has been underserved by

to see teammembers such asmyself, and Iwould beat the end of the list, she says. I said thatwould justaddmoreburden topeople and instead I developed aprotocol for apsychologist tobe in the roomwhen thesurgeon actually gives the diagnosis. This is the timewhen people really feel a great impact as they receivebad news and in many places it is often poorlymanaged by doctors. This initial part of the protocolis in two steps. The first is with the surgeon or oncol-ogist, so you can hear what is being said and see thepatients reactions. Then afterwards the patient goeswith thepsychologist to a separate roomfordiscussionabout their concerns.She explains that this model of providing psy-

chosocial care alongside other clinicians when andwhere it is needed also applies throughout the can-cer journey, includingdecisions about treatment, dif-ficult treatments such as chemotherapy, when thereare recurrences later on, andpalliative care, and is onethat has beenmost applied to breast cancer patientsat the Lisbon hospital.In particular we look after patients who have

recurrences here they do not tend to getmuch sup-port in many other places. When I was at an inter-national patient group conference in Munich Iheard from women with metastatic breast cancerabout their needs while they hadmedical care theirbiggest need was for psychosocial support, as arecurrence is the thing you fear themost after initialtreatment.A lack of referral to psycho-oncologists forrecurrences is a big gap in treatment it is vital thatwe do not lose them from our services at such a dra-matic time in their lives.AsTravadoadds, psychosocial caredoescomeon-

streamwell inmost places when people enter pallia-tive care, but this stage she feels can happen too latein thecancer journey and shewould like to seeoncol-ogists calling in such support earlier. I have alsoargued in an editorial that oncologists should havequality-of-life assessment as part of their standardagenda at all stages, she says.By the 1990s, Travado was able to build up a

teamofhealthpsychologists, and in2000 she started

CoverStory


Travado did indeed prove her worth, albeit after 5 years

of working alone, running from one patient to another

be different, such as helping patients to come toterms with difficult treatments they may have firstrefused. You have to understand concerns, lettingpatients talk without interruption and allowing themtobring theirownagenda to thediscussion.Asmalldif-ference in a doctors communication approach canmake a big difference in outcomes.TheSEPOSgroup, sheadds,hasdeveloped train-

ing modules for cancer doctors, and in PortugalTravadohasbeen instrumental in launchinganationalcommunication skills training programme in 2009,althoughshehasbeen running local training formuchlonger. A hundred cancer professionals more thanexpected turned up at the national launch event inLisbon to hear invited speakers such asSPIKESpro-tocol developerWalter Baile, and Lesley Fallowfieldfrom theUK the latter has carried out considerableresearch into communications skills in cancer.We then ran workshops inmain cities, targeting

cancerphysicians,oncologists andothers,but surgeonswere the ones who needed themost support for thisskill, and Iworkedwithmyhusband, JoaquimReis also a health psychologist to produce a two-setDVDthat includescommunication techniquesandanintroduction to the SPIKES breaking bad news pro-tocol, as an educational tool to support this training.But as inmany other countries, communication

skills training is not mandatory and is still scarce inmedical education. Iof coursewould like it tobemuchmore widespread. Travado adds that when otherhealthcare professionals are properly trained, theycan pick up distress in a tiered system, as patientsmove around clinics. For example, we are workingwith oncology nurses at the hospitals chemotherapyoutpatient day clinic in Lisbon to assess distress lev-els before chemotherapy treatment, where they canrefer thosewhoare sufferingmore tomy team.Com-munication skills can also help prevent physicianburnout, she adds.Although she is critical of the medicalmodeland

prescribing drugs as a first choice for dealingwith thesymptomsofdistress, she iskeen topointout that there

A small difference in a doctors communication

approach can make a big difference in outcomes

CoverStory


servicescomparedwith thenorth, andakeypart of theproject has been developing communication skillsfor healthcare professionals and also carrying outresearch thatwecouldapply across the regionandnotreinvent thewheel in each country, she says.Given thatmany hospitals do not have a full psy-

cho-oncology service, it is oftenup to oncologists andnurses toprovide themain support roles, andSEPOShas foundthat thevastmajorityofcancerdoctors in thethree countries had receivednoor very little commu-nication skills trainingduring theirmedical education.Although they felt proficient in talkingwith patients,says Travado, learning how to communicate withempathy is a difficult technique formany but oncethey practice asking about a patients concerns andfeelings in role-play trainingsessions, theoutcomescan

MEASURING THE SIXTH VITAL SIGN

The concept of a distress thermometer emphasises thatdistress level is a vital sign, just like temperature andblood pressure, that can and should be measured on aregular basis.Patients are asked to circle their distress level over thepast week on a scale of 0 to 10, and to check yes orno to a list of specific stressors that are listed underfive main headings:Practical problems (e.g. childcare, housing, treatmentdecisions)Family problems (e.g. dealing with children or partner,ability to have children)Emotional problems (e.g. depression, fear, sadness,loss of interest in usual activities)Spritual/religious concernsPhysical problems (e.g. appearance, diarrhoea,fatigue, memory/concentration, mouth sores, sexual)

The distress thermometer screening tool was developedby the US National Cancer Center Network, and can beaccessed under their guidelines for supportive care atwww.nccn.org

disclose a cancer diagnosis with the majority ofpatients. You cant adjust to something you dontunderstand, and a psychologist then cannot helpthem. Iused to findpatientswhowere angrybecausethey thought they were being given inferior treat-ment, but they hadnt been told the truth. Followinga survey in Portugal that showed that 85% of peoplewanted toknowaboutacancerdiagnosis, the situationhas begun to improve, she says.At Lisbon, Travados team has several of the

major cancers especially breast cancer and headand neck firmly integrated into psycho-oncology,but by nomeans all.A few surgical teams have beenless receptive. Personally, she focuses primarily onbreast cancer and palliative care, and has estab-lished teamworking protocols andhospital educationprogrammes in both, as well as also supervisinghealth psychology students. Ongoing researchincludeswomens subjectivemeanings about breastcancer and how they affect the type and intensity oftheir emotional reactions and coping.An initiative that she is especially proudof is help-

ing to setupaPortuguesepatient group forbreast can-

isnogreatdividing linebetween theprofessionsofpsy-chologyandpsychiatry in the field, at least among thosewho support the aims of IPOS. Close internationalcolleagues such asGrassi andBaile, and alsoWilliamBreitbart in theUSandSylvieDolbeault inFrance, arepsychiatrists. It is still common, though, for anti-depressants and tranquillisers tobeprescribed, includ-ing bymedical oncologists.People in southern Europe can have different

psychosocial needs to other populations, she adds.Many cancer patients in Portugal are older peoplewith little formal education, and they often adopt amore fatalistic and spiritual approach to their con-dition, in linewith the fadomournfulmusic traditionin the country. That does not mean people neces-sarily feel hopeless in other countries fatalism canbe seen as negative, but not here, says Travado,whohas also explored the role of spirituality in a SEPOSstudy, finding it is a protective factor against depres-sion, which is important in countries with a strongreligious background.But in Portugal, as in other parts of southern

Europeespecially, it has taken time fordoctors to fully

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JORGENOGUEIRA

A roomful ofexperience. Insight,support and advicefrom fellow patientsand survivors can beimmensely important,so at the So JosHospital, Viva MulherViva is consideredpart of the care team

cer patients within her hospital. Viva Mulher Vivastarted in 2003 to bring professionals and patientstogether, and isnot a typical advocacygroup. Thoughwe were providing the best care as professionals,patients were not seeing how others were goingthrough the experience of having cancer if theycould see that,wecould show themthat a goodqual-ity of life is possible. And we wanted patients to feelwelcome in thehospital, and that it is their institution it doesnt belong to healthcare professionals andthatwecouldcollaborate together inmakingpatientsexperiences less traumatic andmore hopeful.It was my vision that women survivors of breast

cancer should be part of the team, bringing theirexpertise in tohelpothers going through the treatmentprocess and complement the professionals role, andwe have taken to heart the tagline of the EuropeanCancerPatientCoalition [ECPC], Nothing aboutuswithoutus, andwehave joinedECPCas amember.The emphasis is on the patients experience and

quality of life, with awareness events, calendars,DVDs (addressing topics such as intimate relationsand sexualmatters), and communication training forvolunteers, who wear pink T-shirts in the hospitaland visit breast cancer patients in treatment, in closecollaboration with the psycho-oncology team. Weencourage women to be more assertive about theirhealthcare and tomake informeddecisions there isa tendency here for people to be passive in front ofauthority figuresandto victimisethemselvesafter trau-maticevents.Wewant tohelp themparticipate in theirhealthcare and wellbeing, and gain more control formaking better choices to maximise treatment andimprove their quality of life.Thepartnershipbetweenpsycho-oncologists and

patient advocacy groups such as ECPC is critical toimprovingmultidisciplinary care, she adds, and bothare primemovers inEPAACs psychosocial oncologyaction initiative.As treasurerof IPOS,Travado isearmarkedforpos-

siblepromotion to thepresidency, but this isnot inhersights at present.The societyhas annual conferences,

whicharewell attended, andwhicharenowreceivinghundreds of abstracts, and has recently developed afederation of psycho-oncology societies for nationaland regional groups, but there is nopressingneed yetto establish a European branch.What we are doing at a high level is pressing for

the IPOSstatement onpsychosocial care to be takenupaswidelyaspossible.Onegreatqualityof thestate-ment, as she points out, is its simplicity:1. Quality cancer care must integrate the psy-

chosocial domain into routine care.2. Distress should be measured as the sixth vital

sign after temperature, blood pressure, pulse, respi-ratory rate and pain.Wedidwant a thirdpoint, for psycho-oncology to

be included innational cancer plans, butwe left it outbecause toomanycountries still dont haveplans, shesays. The IPOS core curriculum, developed recentlywithESO, is also an important step forward, she adds(see alsoCancerWorldMarchApril 2007).Travados husband, Joaquim, is now working in

social healthmarketing, a field that interestsher as itsabout the use of marketing principles to influencehumanbehaviour, suchas smoking, to improvehealthorbenefit society. Shehas twochildrenand is a fitnessand dance activist, which no doubt helps fuel herenergy levels at work.International colleagues couldhardly speakmore

highly of Travado, describing her as the leading Por-tuguese authority on psycho-oncology and an impor-tant organiser and voice now in cancer control policyin Europe, as well as a pioneer of integrated psy-chosocial care in breast cancer and palliative care.Ill be happy when psycho-oncology is recog-

nised in all national cancer plans and distress isroutinely assessed and managed throughout thecancer journey, she says. As one policy makersaid, after he had heard Travado speak at the Euro-pean Cancer Conference in Ljubljana in 2008,Now I finally understand what this is all about, sothere is a good chance these aims will be realisedsooner rather than later.

Ill be happy when ... distress is routinely assessed

and managed throughout the cancer journey

CoverStory


e-GrandRound


Prognostic and predictivemarkers in colorectal cancer:implications for clinical management

Only two biomarkers for colorectal cancer are currently used in the clinic. However, efforts to

find genetic patterns that distinguish between tumours with good or poor prognosis, or between

patients who do or dont respond to various therapies, may offer the basis for identifying sub-

groups of colorectal cancer similar to those now used in breast cancer.

Colorectal cancer is a very het-erogeneous disease, possiblyeven different diseases hittingthe same organ. This has huge implica-tions for clinical practice. For example,in the adjuvant setting, our ability toaccurately predict the prognosis for apatient is around 50% in stage II/IIIresected disease. This is the clinical real-itywe face every day, sowe are unable toinform our patients of their prognosiswith more than about 50% accuracy.

Even our best-guess models, basedon traditional histopathologicalmarkerssuch as that lymph node metastaseswould be associated with a worse out-come than no lymph node metastases,are not straightforward. For example,some patients who have no lymph nodemetastases but have T4b tumours fareworse than patients with lymph nodemetastases (see table overleaf). This indi-cates that our current understanding ofhow colorectal cancer behaves in thebodyandmetastasises is probably flawed.

Colorectal cancer is also heteroge-neous in the metastatic setting. This iswhere drug efficacy needs to be pre-

The European School of Oncology pres-ents weekly e-grandrounds which offerparticipants the opportunity to discussa range of cutting-edge issues, fromcontroversial areas and the latest sci-entific developments to challenging clin-ical cases, with leading Europeanexperts in the field. One of these isselected for publication in each issue ofCancer World.In this issue, Sabine Tejpar, from the Uni-versity Hospital Gasthuisberg, Leuven,Belgium, provides an update on theimplications for clinical management ofdevelopments in prognostic and predic-tive markers for colorectal cancer (CRC).Daniel Helbling, Onkozentrum Zurich,Switzerland, poses questions arising

during the e-grandround live presenta-tion. It was summarised by SusanMayor.

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

dicted to obtain the best possible out-come for the patient. With the recentdrugs, not just targeted agents but alsochemotherapy, we have accepted sur-vival curves showing that drug A or Bworks in a subset of the population, forexample cetuximab in unselectedpatients (see figure, below right). How-ever, these curves also indicate a wholeset of patients that do not benefit fromthese drugs, and we are unable to sepa-rate the patient groups, even thoughweuse the drugs in our daily practice. Wesee these types of curves repeatedly formany types of drugs, both standard ther-apies and targeted agents, with a groupof patients that benefits and a groupthat does not. This is because of theinherent heterogeneity of colorectal can-cer, which we need to understand inorder to better target therapy.

Continuing with the example ofEGFR monoclonal antibodies, thereare two key messages. Firstly, thesedrugs are remarkably effective as

monotherapy. This is crucial because ifa drugworks as amonotherapy, itmeansthat it addresses the biology underlyingthe disease. The second point is thelimited groups of patients inwhich theywork: 10% in monotherapy if patientsare unselected; 25% in monotherapy ifpatients are KRAS wild type. To do agood jobwemust identify the subgroup


e-GrandRound

upfront, andwe are not yet at that stage.Many pathways are involved in colo-

rectal cancer, and any one of these couldbe affected in a particular colorectalcancer patient. This means there aremany different versions of the one dis-ease that we call colorectal cancer, butwe currently have only twomarkers thathave beenmore or less validated:KRASandmicrosatellite instability (MSI). Thefirst of these is used to predict responseto EGFR targeted therapies and thesecond for prognosis in stage II disease.

We tend to simplify thewaywe lookat the biology of tumours. For example,having found the role of EGFR sig-nalling in non-small-cell lung cancer, orthe role of HER2 signalling in breastcancer, we assume that these pathwaysact in the same ways in other diseases.However, we know that EGFR in non-small-cell lung cancer does not act inthe same way as the EGFR pathway incolon cancer. Having identified a path-way, we have to look at which disease itis working in, and remember the effectof the pathway can be completely dif-ferent according to the tumour type.KRAS mutations have different rolesin pancreatic cancer, melanoma andcolon cancer. This means that we haveto look at tumour environment speci-ficity for each marker.

RELATION BETWEEN TUMOUR SUBSTAGE AND SURVIVAL

These relative survival figures, based on expanded SEER data and presented according to AJCC substagingfor stage II and III colon cancers, indicate flaws in our current understanding of how colorectal cancer behavesSEER Surveillance, Epidemiology and End Results. Source: SB Edge, DR Byrd, CC Compton et al. (eds)

(2010) AJCC Cancer Staging Manual, 7th edn. Springer, reprinted with permission Springer 2010

PROGRESSION-FREE SURVIVAL FOR CETUXIMAB IN UNSELECTED PATIENTS

The heterogeneity of colorectal cancer is demonstratedtime and again by graphs like this one for cetuximab asa monotherapy in unselected patients, showing somepatients derive benefit while others dont

Source: DJ Jonker et al (2007)

Cetuximab for the treatment of

colorectal cancer. NEJM 357: 2040

48, reprinted with permission

Massachusetts Medical Society 2007

develop small bowel insteadof largebowelcancer, and further refinement is neededwith modelling of the effect of multiplegenes in dedicatedmodels.

Furthermore, while tumour initia-tion is something thatwe should be ableto understand in appropriate mousemodels that assess whether particularmutations lead to tumour development,in clinical practice this isnot what you are treat-ing. In clinical practice,patients present withmetastatic disease thathas evolved in ways wedo not yet understandand cannot yet model.Molecularly, this is prob-ably quite far from thesimple situation oftumour initiation.

Metastatic disease isseveral years removedand can have a lot ofnew alterations thatwould be very difficultfor researchers to map.It would be very diffi-cult to make a mousemodel of the wholemetastatic cascade. In addition, everytime you give drugs to a patient you areprobably changing the identity of thetumour, particularly with very targetedagents such as anEGFR inhibitor or anHGF (hepatocyte growth factor)inhibitor. Thiswill probably remove cer-tain cell populations andenable others totake over as part of a resistant mecha-nism.A static image of a patients tumouris probably not correct and it might bethat we should biopsy multiple timesduring treatment to check themolecularidentity over time. Thismay explainwhycurrent biomarkers do not correlatewellwith outcome, because they do notreflect the actual disease in a patient.

Recent studies have demonstratedtumour plasticity. For example, a study

TUMOUR ORIGINColorectal cancer originates from thevery undifferentiated stem cell com-partment in the colon. This is importantfor everyday functioning of the bowel,but the negative impact is that colontumours have properties of self-renewal,de-differentiation and plasticity. Thismeanswe are facedwith a very difficultdisease. We are not sure which cells inthe bowel give rise to the majority oftumours, and it is not something wecurrently take into account. There isprobably a lot of refinement needed interms of cell subtype and cell origin.

A distinction that we often forget tomake, andwhich is very relevant, relatesto the primary tumour site betweentumours originating from the right side ofthe colon, which is the mid-gut inembryonic origin, and those from the leftside of the colon, which is the hind-gut.Themid-gut andhind-gut have differentorigins, driven by different genes.Tumours arising on the right side,whichgoes almost to the hepatic flexure, prob-ably have inherently different biologycompared to left-sided tumours.

Data reported by Arnaud Roth atASCO two years ago showed Kaplan-Meier survival curves forpatientsbasedonthe origin of their tumour (see figure,right). Patientswhose tumours had a left-sided origin had better prognosis thanthose with tumours originating on theright.This is because thedrivingbiology isdifferent,withdifferent genes in tumoursoriginating on the left versus right.

CURRENT DESCRIPTORS OFCRC HETEROGENEITYAt themoment, only theKRAS andMSImarkershavemade it intoclinicalpractice.We are all accustomed to the Vogelgram,which suggests APC, KRAS and TP53are needed to drive colon cancers. How-ever, althoughaveryusefulmodel, it is notclear if this is the way all colon tumoursprogress. Most of our mouse models

giving aMAPkinase inhibitor to aBRAFmutant cell line or to aKRASmutant cellline showed that the cell lineswere ableto escape the drug in a few months. Inthe BRAFmutation, this was achievedsimply by amplifying the BRAF chro-mosome, and in the case ofKRASmuta-tion, theKRASchromosome (Sci Signal2010; doi: 10.1126/scisignal.2001148;

Sci Signal 2011; doi: 10.1126/scisig-nal2001752). So, there is a very targetedand selective way of acquiring resist-ance towhatever drug treatmentwe aregiving,which I think happens frequentlyin patients as we treat them.

Question: If they amplify these cells, thegenes, can it not be circumvented by givingmore of the drug, and increasing the dose?Answer: Yes, that could be a solution ifyou know that it is going on, but theremight be somedose-limiting toxicity.How-ever, what really struckme in these reportswas the very targeted way that the canceruses the genetic instability that underliesall cancers to simply select cells that areresistant to the drug being used, so thosecloned cells survive.

e-GrandRound


SURVIVAL ACCORDING TO PRIMARY TUMOUR SIDE

Differences in survival according to the side the tumour originatesreflect a difference in tumour biologySource: Arnaud Roth, presented at ASCO 2009

Question: What do you think aboutsequencing thewhole genome for apatient?Answer:There are fantastic technologies athand and sequencing apatients tumour atrepeated time points will be feasible andcost-effective in the future. The problem ishow to interpret that information:whichofthemarkers is the important oneandwhichtherapeutic drug do you link to this?

Our current efforts are focused ontaking a stepback: taking a very unbiasedapproach, not dividing the disease intoMSI+ orMSI or toKRAS+ orKRAS.We should adopt a very comprehensiveapproach, including analysing DNA,RNA, andprotein, andmeasuring every-thing without a hypothesis, and biologymay become apparent in that informa-tion. Very useful information is emergingin the Cancer Genome Atlas on coloncancer in 2011.

We are trying to generate subgroupssimilar to those nowused in breast can-cer, which are based on gene expres-sion and show both prognostic andpredictive relevance. To gain the neces-sary critical mass of information, largeconsortia will be needed, and everyonewill have to share information, includingdoctors, patients, and the pharmaceuti-cal companieswho often have very largeseries of well annotated samples fromclinical trials.

There is another factor underliningwhy collaboration is necessary. Even ifyou have full sequencing for a patientand have identified all the mutations there are 71 mutations on average forcolorectal cancer (BVogelstein,Science2007, 318:110813) you still do notknowwhat thesemutationsmean for thepatient, nor the drugs he or she willrespond to, because amap of themuta-tions does notmean thatweunderstandwhat they are doing.

The big challenge now is to get func-tional annotations of the mutations wesee. We have identified some of themutations, includingKRAS andBRAF,

andwe know that there isHER amplifi-cation butwehaveno ideawhat they aredoing. One way to do functional anno-tation is to use cell lines and mousemodels, and this is ongoing but it istime-consuming anddifficult and some-times unproductive. Another way is toexplore what these genes are doing inpatients. If youhave a very specificmuta-tion in a patient, for example a deletionofPTEN, and look at howpatients withthis amplification respond to differentdrug treatments, you will probably beable to learn about the function of themutation, because it will showhigh sen-sitivity or resistance. This is using thepatient as the ultimate test tube, whichis necessary because in vitromethods arenot always successful.

Question: Are these small trials, whereyou just test out hypotheses in certainmutations and certain drugs with a lownumber of patients?Answer: A ballpark figure from ourexperience is around 6080 patients,often in phase II trials. As long as youhave a clear map of the molecularalterations you are looking at, so thebiomarker is clear, and you track itthroughout a trial, for example with anIGF inhibitor versus a C-MET inhibitor,and you see that the biomarker predictssomething completely different in thesetwo trials, then you have learnt somethingabout the pathway of your biomarker.Question:You justmentioned thatpatientshave mutations in 71 genes, on average.How many pathways are relevant incolorectal cancer, if 71 genes are affected?Answer:BertVogelsteinpresenteda schemaof all the relevant pathways at ASCO lastyear and ended up with about 15, includ-ing Wnt and Hedgehog (JCO 2009, 27Suppl 15). But we cant yet put a numberto this. We now have enough samples forcolorectal cancer analysed worldwide toget a first grip on the subgroups; however,the static versus dynamic element probably

makes this more complex.Clinical trials with targeted agents

have been very helpful. We never reallyknew where to position KRAS in coloncancer signalling until EGFR inhibitorscame along. We now know much moreabout KRAS thanks to the cetuximabandpanitumumab trials. This is just oneexample, butmanymore trialswith otherdrugs are coming through. It will beinteresting to seewhether other receptortyrosine kinase inhibitors will show thesame influence ofKRASmutations.

BIOMARKER DEVELOPMENTThe necessary factors for biomarkerdevelopment include: Agoodunderstandingofwhat is going

on inmetastatic colorectal cancer Therapies with known targets Knowledge of the effect of target

inhibition Tractable risk/benefit profile Biomarkers that have a large impact ValidationThe first step is a good understanding ofwhat is happening in the disease.Wedonot really yet have that. We do havesome therapies with known targets,although a lot have no clear cellular anti-cancermechanisms,whichmakes it dif-ficult to make biomarker/therapyrelationships. Validation is essential,requiring large datasets for which wehave to learn to collaboratemuchmore.

KRAS AND MSIKRAS andMSI are the first biomarkersin colorectal cancer.However, we some-timesoversimplify things.WeknowMSIis a marker for good prognosis and wewould like to be able to use it in clinicalpractice,but thereare somepitfalls.Thereis a different incidenceofMSI in stage IIand III tumours, as for many markers.However,manypublications report stageII and III series together, or analyse theeffect in a compound way. We must bevery cautious and try to be as precise as


e-GrandRound

In contrast, a clinical trial fromour group(see figure, p 20, right) showed a verystrong prognostic effect of high MSIversus MSS, unlike the Sargent data.The difference in results between simi-larly powered studies suggests there isstill something thatwe are not capturing,andmore and larger studies are needed.

The take homemessage onMSI sta-tus is that, althoughwewould love to saythatMSI is a simplemarker of prognosisand response toadjuvant treatment, thereare several unresolved issues, includingsporadic versus hereditary MSI, the roleof CIMP, the role of BRAF and theimpact of novel therapies.Weshouldnotembrace biomarkers if they do not haveclear validation for clinical practice.

Question: In clinical practice, do youmeasure MSI and do you consider it intreatment decisions for stage II patients?Answer: At the moment, I do not makedecisions based onMSI status, although Iacknowledge it is a very strong marker

possible in studying the effect of a bio-marker in a homogeneous population.

Not only does the incidence ofMSI,and maybe also its prognostic value, dif-fer between stages II and III, but theprognostic value alsodiffers according tothepresenceor absenceof othermarkersand features.The tablebelowshows thatMSI and 18qLOHbehave differently asmarkers in stage II and III disease.

The take homemessage is to be veryprecise about the disease group you arelooking at andnever forget that amarker,as simple as itmay seem,may have hid-den complexity, such as interactionwithstage or other markers.

MSI instability is a good prognosticmarker in univariate analysis. The sameis true for 18qLOH as a marker of poorprognosis. However, would the 18qinformation still matter if you knew theMSI status of your patient? In themicrosatellite stable (MSS) population,which is the largest population, 18q is nolonger prognostic (see figure, aboveright). Thismeans 18q only gives usefulinformation if you do not know themicrosatellite status. This is just one ofmany examples where you might seestrong effects of a marker in univariateanalysis, yet it is no longer present in

multivariate analysiswith relevant inter-acting markers.

E5202 is the first trial to use riskassessment based on 18q/MSI todetermine treatment in stage II coloncan-cer (www.clinicaltrials.gov). High-riskpatients, defined as MSS and 18qLOH,are treated with chemotherapy. Low-riskpatients, defined as MSI-high and MSSwith no 18q, undergo only observationand no treatment. The design is flawed,however, as 18q does not matter in MSSdisease, and thesepatients are still at highrisk. This design was based on a combi-nationof twounivariate analyses thatwerenot put into amultivariate analysis.

Another interesting study was pre-sented by Dan Sargent atASCO 2008.He conducted a pooled analysis ofmul-tiple trials in patients with stage II andIII tumours, comparing patients treatedin the adjuvant setting with those whowere untreated (see figures, p 20, left,centre). Patients with high MSI whowere untreated did much better thanMSS patients. However, this effectcompletely disappeared in the treatedpatients, and it might be that giving5FU to patients with highMSI is harm-ful because the benefit of being MSIdisappears.

e-GrandRound


PROGNOSTIC VALUE OF MARKERS IN STAGE II AND III TUMOURS

The prognostic valueof these markers(looked at in isolation univariate analysis)varies accordingto the stage ofdisease, which hasimplications for howstudies of biomarkersare designed andreported

Source: Arnaud Roth, presented at ASCO 2009

PROGNOSTIC VALUE OF 18QLOHON MSS STAGE II DISEASE

18qLOH and microsatellite instability (MSI)status are both good prognostic markers whenused alone, but for patients known to bemicrosatellite stable (MSS), 18qLOH loses itsprognostic valueSource: Arnaud Roth, presented at ASCO 2009

ined, T4, poor differentiation, and obstruc-tion.MSI patients are often poorly differ-entiated,which is high risk, andT4,whichis also high risk. So, on the one hand youhave MSI telling you that this is a goodprognosis patient, and on the other handthere are high-risk features telling you

that this is not a good prognosis. If youcombine all these factors in amultivariaterisk model, you would still be wrong in asmall number of cases if you usedMSI asa standalonemarker.A paperwas recentlypublished by Frank Sinicrope and DanSargents group looking at the differencebetween sporadic and hereditary MSI,which reports intriguing findings thatagain warrant further detailed investiga-tion into MSI as a standalone marker(JNCI 2011, 103:863875).Question:Doyouuse clinicalmarkers, ordo you not consider any markers?Answer: We use clinical markers fromASCOguidelines, as these have quite a lotof data behind them. I am not discourag-ing people from usingMSI, but you haveto be aware of themargin of error, and theneed for further studies.

PETACC3 provided a very largeseries of 1400 patients to look at multi-ple markers (Clin Cancer Res 2009,15:552833). It showed how the inte-gration of molecular markers oftenchanges the view that youhave based ona single marker, and the impact of inte-grating variables such as T stage and


e-GrandRound

and a good basis for patient risk stratifica-tion. However, I presented data atASCO2010 on the uncertainty that still exists ifyou use MSI for treatment decisions instage II patients. In stage II patients, wealso useASCOclinical high-risk criteria,such as fewer than 12 lymphnodes exam-

THE EFFECT OF TREATMENT BY MSI STATUS CONFLICTING TRIAL RESULTS

A study by Dan Sargent and co-workers showed that patients with high MSI lost their survival advantage when treated with 5FU (left and centre graphs);however, in a study conducted by Sabine Tejpar and colleagues, patients with high MSI (MSI-H) responded much better to 5FU treatment than MSS patients

patients with high MSI; microsatellite stable (MSS) patients.

Sources: Dan Sargent, presented at ASCO 2008 and Sabine Tejpar, presented at ASCO 2009

SUBGROUPING BASED ON GENE EXPRESSION

This analysis ofunprespecifiedgene expressionidentified four mainsubgroups thatseem to be inagreement withother studies, butnot with currentlyused descriptorsof the diseaseCC colon cancer.

Source: Swiss Group

of Bioinformatics in

Lausanne, presented

at AACR 2011

N stage. These are very large effects thathave not beenmodelled sufficiently, andoffer important work for the colorectalcancer community that can easily beperformed over the next few years.

EvaBudinska andMauroDelorenzi,of the group at the Swiss Institute ofBioinformatics in Lausanne, took mul-tiple data sets and looked at gene expres-sion in an unprespecified way, trying toidentify spontaneous subgroups in thedisease (see figure, p 20, lower). Resultsshowed subgroups, in agreement withother studies. I thinkwe are at the pointof identifying the subgroups in coloncancer just as in breast cancer. This fig-ure simplifies the subgroups into fourcolours, numbered 1, 2, 3, and 4(although there were a few more).

These subgroups, which are sponta-neously present in the disease, correlatepoorly with current descriptors of thedisease, including clinical descriptorssuch as stage, T or N status, and evenKRAS, BRAF or MSI. This means thesubgroups better describe theongoingdiseaseprocess thancur-rent markers. The existing celllines can be compared to seewhether they match the patientsubgroups, aswell asmousemod-els. This means we can nowrefine the tools that we use inthe lab, such as cell lines, toensure theybettermatch the truesubgroups present in tumours.Another similar studyusedunsu-pervised subgrouping analysis ofcolorectal cancer (BMC MedGenomics2011, 4:9), and I thinkthese studies are going to be veryimportantover thenext fewyears.

The same message is emerg-ing from recent work on KRAS,questioning whether all KRASmutations have the same effect.The table above summarises theincidence of different KRASmutations. There may be differ-

ences between mutations, and maybeevenbetweendifferent patientswith thesamemutations.

In some patients a RAS mutationmay activate theRAFMAPkinase path-

way, but in other patients the samemuta-tionmay activate another pathway, suchas PI3 kinase orRAL (see figure below).Just becausewe haveKRASmutants orwild types does not mean the two typeshave homogeneous biology.

To find proof of this we looked atgene expression data in patients withBRAF mutations, patients with KRASmutations and those with neither ofthese mutations (double wild type).Results showed that BRAF-mutantpatients have some genes always on andsome genes always off, while these arereversed in wild type patients (Popoviciet al, manuscript in preparation). Theconclusion is of very homogeneous dis-ease inBRAFmutants, so thismarker isindicating something useful.

However, this division of geneexpression is not nearly as clear inKRASmutants versus wild types. There stillseem to be different groups of KRASmutants, which are quite different interms of gene expression. This indicates

KRAS is not a marker of homo-geneous disease.

The take home message isthat the underlying biology ismuchmore heterogeneous thancurrentmarkersmight indicate,and an unsupervised approach isnecessary that does not sepa-rate patients into prespecifiedgroups. This has important ther-apeutic implications. For exam-ple, treating all KRAS mutantpatients with MAP kinaseinhibitors is not going to be suc-cessful, because of heterogene-ity between them.

A solution to this problem isillustrated by a study performedbyShirinKhambata-Ford atBris-tol Myers Squibb (the companythat markets cetuximab in theUS) in 2007 (JCO25:323037).This study was very open, andwas not just looking at EGFR

e-GrandRound


NOT ALL KRAS MUTATIONS ARE ALIKE

Different mutations in the KRAS gene affecttumour behaviour in different waysSource:N Normanno et al. (2009) Nat Rev Clin

Oncol 6: 519527, published with permission,

Nature 2009

RAS MUTATION PATHWAYS

Source:N Normanno et al. (2009) Nat Rev Clin Oncol 6: 519-527,

published with permission Nature 2009

copy number or KRAS. The trial biop-sied liver metastases in 80 patients justbefore treatment with cetuximab. FullAffymetrix profiling compared geneexpression in patients who did wellagainst thosewhodidbadly, revealing thebiomarkers for sensitivity to the drug(see figure above).

If we collect material in the manyongoing trials with targeted agents andanalyse it in an unprespecified way, wecan make a lot of progress in under-standing the biology of colorectal cancerover thenext fewyears (see figurebelow).

SUMMING UPIn terms of biomarker development incolorectal cancer, we have a good graspofwhat is going on inmetastatic disease.Therapies have been developed thathave known targets and the effect oftarget inhibition is known. It is essentialthat we keep an openmind on biomark-ers and critically evaluate the availableinformation, ensuring all findings arethoroughly validated.

Question: Looking at gene expressionprofiles do you think there are three orfour groups, or more?Answer: The published data mentionedpreviously show two big groups. I believe

the number is likely to be fewer than 10,but more than two. We are pleased withthis number, because it comes close tosomething that people can use in thefuture. It is important to note this group-ing was based only on gene expression. Ifyou add in copy number, mutation dataand microRNA, you can probably refinesubgroups further.

This is not the end of the story, but, in

a similar way to breast, it is a very goodstart. It puts us on track for planning aclinical trial, giving an idea of bench-marks, what to power for, and howmuchheterogeneity to expect within the popu-lation or within the drug effect.Question:Doyou think the futurewill bebased on these different groups distin-guished by gene expression, and then dig-ging deeper by knowing more about it?Answer: Yes, I hope that nature has notmade every colon tumour completelydifferent, but that there are recurringthemes. The assumption is that everytumour would fit into some category andwe are working hard towards getting thatclassification.Question:What is the general method-ology to adopt in biomarker studies?Answer: It is important to be aware of theshortcomings of whatever assay you areusing.Youneed large sample sizes, and youneed to be sure that effects are stable andthat there are no other variables thatchange the effect of themarker. Setting upboth a discovery and one or two validationsets is very important.


e-GrandRound

BIOMARKER DISCOVERY STUDY IN PATIENTS TREATED WITH CETUXIMAB

Studies like this one, which analysedhow gene expression profiles differbetween patients who did well oncetuximab and those who did not, willhelp identify markers of responseSource: S Khambata-Ford et al. (2007)

JCO 25:323037, published with

permission ASCO 2007

SUBGROUPING BASED ON GENE EXPRESSION

This analysis ofunprespecified geneexpression identifiedfour main subgroupsthat seem to be inagreement withother studies, butnot with currentlyused descriptors ofthe diseaseS Siena et al (2009)

JNCI 101:130824,

published with

permission Oxford

University Press 2009

Hope for me,and for others who come afterAward-winning article explores the impact of a new network of early trial centres

Death is a huge, viciousdog. We are trappedtogether in an alleyway,and every day I muststare him in the face,

and challenge him. I must attack himfirst, with all my strength, and everyweapon at my disposal. I have to ifI turned for one moment, if I lost mycourage, if I tried to run away instead,he would chaseme and he would leapon me, he would savage me and hewould kill me.

Julie-AnnGallagher is 45 years old;she has spent the past 14 years in anear daily battle with cancer. Her frag-ile beauty masks an internal conflictbetween her body where tumoursravage her lungs, breast, throat (onewraps around her windpipe), and clogher bones and her mind, which is

still sharp, decisive and brave.She has fought onmany fronts: not

only has she been determined to stay

alive, but she has also found thestrength to survive the loss of her hus-band, Alan, an infantry soldier, whocommitted suicide six weeks beforeher first cancer appeared, and to bringup two children. Somewhere along theway she found a deep faith inGod; shealso found an equally profound trust inmedicine. So much so that she hasnow been given a desperate lastchance, taking part in a clinical trial ofan experimental treatment that maygrant her more time but equallymight not help her and might haveside-effects. The trial results, however,will contribute to the development ofbetter treatments for the cancerpatients who will come after her.

Gallagher is a vital human element


BestReporter

Delays in getting promising new treatments into trials are slowing progress in cancer care and

failing patientswhohave run out of options and are running out of time. This article, which earned

freelance journalistVictoria Lambert a BestCancer ReporterAward, looks at whatUK efforts

to cut these delays has meant for three patients with advanced cancer.

Victoria LambertELLENNOLAN

effects; phase II, testing for efficacyand safety on a larger scale; and phaseIII a definitive assessment of howeffective the drug is, in comparisonwith current gold standardtreatment ina large population group. No wonderthat with new cancer treatments theaverage development time is about 10years from bench to bedside.

Thework of the ECMCs covers alltypes of cancer, from breast, colonand prostate to the 10,000 Britonswhose primary tumour location isimpossible to find; and all manner oftherapies from those home-grown intheCancer ResearchUK labs, such asParp (Poly ADP ribose polymerase)inhibitors, which cleverly target nat-ural faults in certain cancer cells andexploit them, increasing the chance ofcell suicide, to those created by thehuge pharmaceutical companies suchas GlaxoSmithKline.

Cancer patients taking part in phase Itrials have already received all stan-dard treatments, such as conventionalradiotherapy and chemotherapy, avail-able to them.As a result they have lim-ited treatment options, and onlymonths orweeks to live.Other trials arecarried out to test medicines alreadylicensed by the National Institute forClinical Excellence (NICE) for a spe-cific purpose but combining themwith other drugs or radiotherapy, orsimply to assess them in other cancers.

For example,Avastin is licensed bythe NHS [National Health Service]for advanced bowel cancer that hasspread; scientists have been looking atways it could help treat bowel cancer atan earlier stage or even different typesof cancer. Until those treatments havealso been approved by NICE, how-ever, the drug remains available only intrials or at an oncologists discretion

BestReporter


in a clinical trial programme, theExper-imental Cancer Medicine Centres(ECMCs), created in April 2007 byCancer Research UK. Together withthe departments of health of England,Scotland,Wales andNorthern Ireland,the charity is jointly funding a networkof 19 centres of excellence acrossBritain, at a cost of 35million over fiveyears until 2011.

The centres run clinical trials tobridge the gap between treatments thatlook promising in the lab and therapythat can be given to patients. Theyspeed upwhat can often be a slow andexpensive process. Before human trials,drugs are tested in the lab to obtain pre-liminary information on efficacy, toxic-ity and pharmacokinetics (whathappens to a drugwhen it is applied toa living organism). Then they passthrough three stages of trials in patients:phase I, assessment for safety and side-

The patients voice.Given that fearsabout safety andexploitation form theframework for manydrug developmentstories, this articlewas important inproviding analternativeperspective: thatof patients withadvanced cancer,for whom accessto drug trials offerstheir only hope

BestReporter


(the practice of giving a patient alicensedmedicine for a condition otherthan that approved byNICE is knownas prescribing off-licence).

In either case the common threadof ethics remains if there is an estab-lished treatment for their conditionalready in existence, patients musttry that first. Experimental treatmentsstill come second.

Dr Sally Burtles, the director ofcancer centres at Cancer ResearchUK and who oversees the ECMCprogramme, explains that the impetusto set up the scheme came from arecognition that while superb cancercentres already existed in Britain, anetwork was needed to draw themtogether and to encourage collabora-tion: We wanted to speed up thedevelopment of new drugs, and weknew that by providing specialistresources we could improve the sys-tem we had. The programme is alsoan excellent way to ensure that eachcentre can concentrate on its ownoncological specialty, while ensuringthat patients get themost appropriatenew therapy for them. Patients can bereferred between centres dependingon their ability to travel, or receivetheir treatment close to home.

Cancer ResearchUK facilitates theECMC programme, and in 2011 itsresults will be peer-reviewed, the offi-cial test of whether it has been a suc-cess. Prof Ruth Plummer, the clinicalprofessor of experimental cancermed-icine based at Newcastle University,believes that the network has beenenormously positive in the first year,400 trials took place, by year three(2008) that number had doubled, andby the end of this year it will no doubthave expanded exponentially again. Ithas really made the UK research situ-ation attractive to the global pharma-ceutical companies; one recentlycontactedme to ask if we had the facil-

ities to take on amajor trial. If not, theywould take it to Europe. A few emailslater, I was able to inform the companythat we were more than set up to takeon thework. Plummer also points outthat Britain is the only country to havesuch a network, although other coun-tries are watching closely and a sim-ilar EU-wide scheme is in the processof being set up.

Agreeing to go on to a trial was asurprisingly easy choice for 21-year-oldCalum Elliot, because it seemed abonus both for him and others. Iwasmore than happy, he says, what-ever the side-effects or results. It wasgood to think that my experiencemight make it easier for other youngpeople who are diagnosed like me.Two years ago, Elliot, a plasterer,started having episodes when hewould become mentally absent for afew moments; his family mother,Jane, 40; stepfather, Craig Watson, a43-year-old driver; and his 17-year-old sister, Danielle, with whomhe stilllives in a flat close to Glasgow airport and his friends spotted that he sim-ply didnt respond to anything con-versation or action for two to threeminutes at a time. These momentsmight occur in the pub or playing foot-ball, or even when watching his team,GlasgowRangers. Concerned, in 2008his mother took him to the GP, whoreferred him to a specialist. An MRIscan revealed a tiny abnormality on theleft side of his brain and epilepsy wasdiagnosed. For the next year and ahalf, Elliot took anti-epileptic drugsbut the drugs did not stop the seizures,which had become weekly.

For Elliot the toughest news wasbeing told that his driving licencewould be suspended (as it is with allepilepsy sufferers on safety grounds).Not long after, he suffered an episodeat work and was let go four weekslater. Yet he still didnt feel ill and

played football with an understandingteam and leaguemates (who took himto the side when a seizure struck andallowed him back on to the pitchwhen he came round). Then, in Sep-tember this year, Elliots doctors senthim for a routine MRI scan; he wascalled in for an appointment to dis-cuss it the next day. The night before,he suffered a terrible headache andbegan vomiting. His mother drovehim straight to the hospital. I wasgiven a CT scan that showed therewas bleeding on the brain, he says.The doctor who I had been due to seethe next day showed up to seeme. Heexplained hewas a surgeon; I guess hemust have known already he wouldneed to operate on me.

Elliot underwent a five-hour oper-ation: the small spot on the originalMRI scan from 2008 had grown intoa 2 cm tumour, and after 90% wasremoved, leaving a small horseshoe-shaped scar on the left side of hishead, it was provedmalignant. Of thediagnosis itself, Elliot says now,Thats something you dont want tohear. But you have to deal with it andbe strong. His stepfather says, Wetold everyone that first day friendsand family and especially Calumsgranny; theyre very close and thatwas the hardest bit, I think.

Elliot was warned that his was oneof the worst cases the surgeon hadseen a grade 4 glioblastoma (one ofthe most aggressive brain tumours atits most advanced state cancers aregraded 1 to 4 in severity). But Elliotwas immediately offered the chanceto go on a trial organised by an ECMClocally as incredibly a blood sam-ple showed that his DNA matchedthe exact requirements of a new drug.He would be the first person in theworld to try a vaccine created in aGlasgow lab that aims to boost thebodys own defences.


Prof JimCassidy, who runs theECMCat the University of Glasgow with hisfellow oncologist Prof Jeff Evans,believes that there are tremendousbenefits to the scheme. We havealways been good at research and atclinical care here; establishing theECMC helps us bring the twotogether, so not only does bench getclose to bedside, but we can also workthe otherway round.We can take sam-ples frompatients who are undergoingexperimental medicine andseewhat the drug is doing tothe tissue or tumour, to seehow it succeeds or fails. Itsnot trial and error, it is trialand understanding.

Calum Elliot needs tohave 13 injections in thecourse of the trial and hasalready had nine. He isundergoing a course ofradiotherapy that will beover before Christmas, andchemotherapy, which willlast until April.

I was warned to expectside-effects but Im fine,he says. The injectionswhich go into my upperthigh sting for 10 minutesbut thats it. I havent evenlost much hair from theother treatments. Overallhe feels fit, eats well, andhas had no episodes sincethe operation. He goesclubbing with his friends,drinks in moderation andis planning a four-dayweekend in Butlins Skeg-ness to celebrate the end of

the radiotherapy. It will be a fewmonths before Elliot knows whetherthe experimental treatment hasworked when he is scanned a fewweeks after the end of radiotherapy. Itwill not be until a second MRIanother six weeks later that an accu-rate result will emerge but he seemsto be focused less on getting throughthe course and more on countingdown the days until he regains hisdriving licence.

In the South Yorkshire town of Penis-tone, 72-year-old Terry Windle is alsowaiting to see if his experimental can-cer treatment has worked. Slim andhealthy-looking, he could easily pass fora decade younger. The homehe shareswith hiswife, Kathy, 58, a retired phar-macist, is decoratedwith paintings andphotographs of motorsport he hasspent his life designing, building andracing motorbikes. Next year Windleplans to cross the US on a Harley-

Davidson (Itll beme and acouple of other fellows:ones 70-odd and the others84. We cant wait). Butbefore he can buy the planeticket, he has to have acheck-up with his oncolo-gist at St JamessHospital inLeeds, anECMCwhere hereceived treatment for hisocular melanoma anincredibly rare cancer thatfirst appeared in his eye 29years ago.

I shouldhavedied then,Windle says, enormouslycheerful. But I didnt evenknow it was cancer. Id hadproblemswithmy sight play-ing squash, and Iwas sent tohospital, where they found atumour on the back of theright eyeball, which theyremoved. No one said thetumourmightbemalignant.

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Calum Elliot, 21, has beentaking part in a trial that aimsto limit the aggressive tumourin his brain by boosting hisbodys natural defences

It was good to think that my experience might

make it easier for other young people

ELLENNOLAN

Then 23 years later, in 2004, Windlestarted experiencing unusual stom-ach pains; that August he was sentfor anMRI.A specialist told him theyhad found a tumour on his liver, whichthey intended to remove within a fort-night. I wasnt that surprised. A fewyears before, a friend had undergonethe same eye experience an extraor-dinary coincidence. He had beenwarned it was cancer and that it mightspread to his liver, which it duly did,and he died. So I had begun askingquestions and learnt that ocularmelanoma usually kills youwithin fiveyears. By my own reckoning I shouldhave been dead by 1986. However, aseries of regular monthly, three-monthly, and six-monthly CT scansshowed no recurrence. I just got onwith life, he says. But the cancer didrecur in 2006, first in his navel in theform of an inoperable tumour, andthen a lump on the back of his neck.They sat me down in 2007, and said,its months, not years now. Youre 69,pack in your work and enjoy what time

you have left we can do nothing.But they did suggest that Windle

could join the ECMC at St JamessHospital, and in the summer of 2008hewas invited to join a phase I trial forgene therapy for ocular melanomawhich had spread to the liver. Thetrial was of a new treatment called aPolyMEL DNA vaccine. It works byteaching immune cells to recognisecertain proteins (antigens) made bymelanoma cells. Theoretically, theimmune cells will then kill themelanoma cells.

I had three jabs over a few weeks thats all just like any other vaccinein my arm. While he waited to see ifit would work, Windle spent the nextyear building a shining Lotus racingcar from a kit.

The results appear to be good hisoncologist has told him the cancerhas stalled.And despite his tumours,which all appeared in the two yearspreceding the trial (one in themuscleof his shoulder, one in his breast, oneon his side, two in the lungs and one

by the navel), he looks fit and well,and is planning another skiing trip.Fromwhat I can gather this has com-pletely stalled them; I cant be cured,but my condition can be managed.That will do for me. It is extraordinary.Im not even considered terminallyill any more.

Julie-Ann Gallagher, who lives inBishops Waltham, Hampshire, can-not make the same bold statement.LikeWindle, her experience has beenextraordinary, her endurance inexpli-cable. But unlike Windle and Elliot,she has also undergone lengthy boutsof pain and discomfort and she looksas ill as she is. We talk in her sitting-room family photographs of herdaughter, Sarah, now 20, a fitnessinstructor, and son, Carl, 15, whointends to take up an apprenticeship inplumbing after school, are proudly dis-played on a table.

Gallagher is wrapped inmyriad lay-ers, furry boots and a fleecy blanket.The temperature is nearly as cold insideher small council house as it is out.Gal-lagher has spent most of her adult lifefighting cancer and raising her chil-dren alone; she hasnt been able todevelop a career or save for infirmity. Icant afford to put the heating on yet,she says. I told Carl, we must waituntil it is really necessary. We simplycant afford it. She looks blue-greywith cold.Advancedcancer patients arenot allocated winter heating supportas pensioners are an issue that thecancer support charity Macmillan iscampaigning on strongly. It is the onlyoccasion thatGallagher showsher frus-tration at her lot. Imneverwarm the


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Terry Windle, 72,with his wife, Kathy,at their home inPenistone, SouthYorkshire. Terry hashad a successfuloutcome to hisclinical trial treatmentat St JamessHospital in Leeds,which teachesimmune cells to killmelanoma cells

ELLENNOLAN

My condition can be managed. Its extraordinary.

Im not even considered terminally ill any more

tumours in my lungs feel like icicles,and the only time I know the sensationof heat is when Im in hospital under-going an iodine transfusion.

Gallagher first developed cancer atthe age of 31, inAugust 1996,when sixweeks after her husbands death (hesuffered, she believes, from manicdepression) she found a lump in herleft breast the size of a piece of coal;one day there was nothing, the nextthis thing. It felt like it had smallertumours, like grapes, hanging off it. Ihave no doubt it was due to theextreme shock and stress of my situa-tion. I was thewidowedmother of six-year-old Sarah andCarl, then aged 18months. Her GP took one look andsent her the same day to a specialist.The breast sister appearedwith dreadin her eyes I thought, I am going tofollowmy husband. That was the firstand last moment of self-pity sheallowed herself. I thought, I mustfight this for my children they dontdeserve this.

Moreover, she wanted them tounderstand that, despite their fatherssuicide, life is worth choosing. Sheunderwent a mastectomy and recon-structive breast surgery, but thetumour, which was a grade 2/3, hadalready spread to her lymph glands.She underwent six months ofchemotherapy, and began takingtamoxifen to prevent it recurring. Ilost my hair but I didnt care; I evenstopped wearing the wig I was given,when Carl pulled it off in the super-market. Nothing mattered but surviv-ing. Her breast sister warned her, Itwill come back, youmay get 10 years ifyoure lucky.

Gallagher shakes her head. Thatwasnt enough time forme, but itmademe start planning. I promised mydaughter I would be at her wedding,which, last year, I was.

She began to feel well, fit and

strong, and launched a business, sell-ing decorative gold and silver nipplejewellery for mastectomy sufferers.Life was briefly good. And then, in2004, I came last in the parents race onsports day I had no puff. A few dayslater, I raced a parking warden back tomy car, and lost, feeling breathless.Her doctor ordered an X-ray, and Gal-lagher admitted that she had felt alump on her neck, too.

A tumour had appeared, wrappingitself around her jugular vein and thewindpipe next to it. A tiny patch ofcancer cells had somehow survived,undetectably hidden behind the recon-structed breast, and had spread notonly to her windpipe, but also pittingboth lungs.

The tumour on her side was cutout, but although she was offeredchemotherapy,Gallagherwas told thatthere was no hope of recovery. WhenI said, Dont you bet on it, they toldme, Thats what all the patients say.

Gallagher refused to give in. Sheunderwent a year of very gruellingchemo. Then, in 2006, her oncologistannounced there was no more shecould do for Gallagher and told herfirmly that she should not expect tocollect her pension. I think if youget secondary cancer you become anuisance; they know what to do withprimary and they know how to sup-port you, but once you get tomy stage,its so different.

Gallagher was not prepared to giveup shemoved to SouthamptonUni-versity Hospital, and after demandingto try something, was given hormonetherapy, which had to be injectedpainfully into her stomach to slowdown her ovaries, which seemed to befuelling the growth of the cancer. By2008 she was becoming more breath-less. I could smell death on myself my lungswere filling upwith fluid andI was drowning.An operation to drain

her lungs worked but left her ill; shelost a stone in weight.

A scan revealed the cancer wasnow in her spine and hips, and herbodywas clearly tooweak for chemo tobe considered. It was time to stop theagonising injections too Gallaghersimply couldnt stand them. I was soclose to death last Christmas, I knowthat, she says. But then a small mira-cle happened. I was asked to join theECMC trial at Southampton Univer-sity Hospital for a drug called zole-dronate, which is given intravenouslyonce a month.

Her consultant oncologist, JenniferMarshall of Southampton UniversityHospital Trust, explains this is a trial ofa bisphosphonate therapy, principallyused in osteoporosis patients as itstrengthens bones and helps to reducebone pain. We have learnt that it pos-sibly also has an anticancer effect, too,she explains, hence the idea for a ran-domised trial.

And in Julie-Anns case, while wecouldnt cure the bone cancer, Mar-shall says, we could at least put her onthe trial and do something about thepain shewas suffering while hopefullyprotecting her from fractures.

Gallagher recalls, After the firstinfusion I felt relief. I just felt better,somehow. But after six months, herveins collapsed to the extent that injec-tions were no longer an option. Shewas taken off the trial as she couldnot carry on, but prescribed off-licenceanother form of bisphosphonate ther-apy called ibandronate, which shetakes in tablet form once a day.

Although Julie-Ann was not onthe trial for the full period of two years,it did reduce her pain and continues to nor has she suffered any breaks, so Ithink for her you could say it has beensuccessful, Marshall says.

Gallagher is now busy planningChristmas and looking forward to her

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sons 16th birthday, and thenher daughters 21st. JenniferMarshall is happy to keeplooking out for new trialsbecause, she explains, Julie-Anns defied the odds; wejust want to give her as gooda quality of life as possibleand keep her well.

Part of the problem withany cancer is its mutability.Tumours changeandbecomeresistant, Dr Sally Burtlesexplains, which iswhy singledrugs, however good theymaybe when they get passed byNICE, are often more effec-tivewhenwe start trying themin combinations with otherdrugs or radiotherapy. Plusmuch of the work done inECMCs is the search for bio-markers: these are the factorsin our DNA that mean oncewe understand them we canstart to anticipatewhowill dobest from which drug beforetreatment even begins.

Highly personalised treat-ment is the future, sheconfirms. We call it stratifi-cation: ultimately the aim is that everyindividual will be treated according tothe exact genetic code of their cancer.Obviously there is still much work tobe done, but I have no doubt this willcome.As for the ECMCs, she admitsthat it is too early to talk of generalsuccess rates; that will be decidedafter peer review in 2011, but sheanticipates that the project will bedeemed a success.

Prof Ruth Plummer admits she issometimes in awe of the patients whojoin the ECMCs nationwide trials. Itis very humbling tomeet these peoplewho want to join our studies; theyknow they are often incurable andmany are running out of options. Wehave to be really honest about whatthey are doing but they accept thatthis is unknown territory. They say Iknow this may not helpme butmaybe

it will help someone in thefuture. It makes our centresvery positive places to be.And there is a very lowrefusal or dropout rate onthe trials. It is unusual foranyone to decide not to joinin if they physically can.

None of the three peo-ple interviewed knows forcertain if their treatmenthas been a magic bulleteither, yet all would take upthe offer to do another trial.Even Gallagher, for whomthe future does not look sohopeful, feels blessed. Iam grateful for the 14 yearsI have had. I am grateful Ihave seen my daughterswedding. But you have tohelp yourself and makeyour own luck. Last Christ-mas I felt I didnt have long

but I am still here and I have nodoubt that getting the bisphospho-nate therapy has helped.

Without these new drugs, can-cer would have takenme, but I am notready to go yet. I love life. And I stillhold out hope for a miracle cure.


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Without these new drugs, cancer would have

taken me. But Im not ready to go yet. I love life

Julie-Ann Gallagher, 45, motherto 15-year-old Carl and 20-year-old Sarah, has lived with cancerfor the past 14 years. Gallagherhas been involved in a clinicaltrial during the past year

ELLENNOLAN

This article was first published in the Telegraph

Magazine on 4 December 2010, and is republished

with permission Victoria Lambert 2010

Redefining the roleof pathologyHow Giuseppe Viale embraced the new responsibilities of the molecular era

Simon Crompton

In the era of personalised therapies, complete and accurate pathology reports are vital. Helping

pathologists rise to their new responsibilities, and ensuring they are given the opportunity to play

a full role, has been amission for Giuseppe Viale, a leading Italian pathologist whose career has

spanned the transition frommicroscope to molecular imaging.

Pathologists are meant to be retiringtypes, locked away in white roomspoised above their microscopes, feed-ing their findings through to physi-cians but rarely involved with patients.

Cancer World 45

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