C W 26 Education & knowledge through people & factsCoverStory 4 CANCERWORLD SEPTEMBER/OCTOBER2008 NadiaHarbeck: breakingwithconvention MarcBeishon Gynaecologistsdon’twintopawardsatASCO.Germanoncologistsdon’tmakeitonthe

� Nadia Harbeck: breaking with convention � Stopping trials early: sorting the rightdecisions from the wrong � Why ‘plenty of bed rest’ could be bad advice � Exploitingthe potential of top-quality surgery � Why is cancer more fatal in men than in women?

Nadia Harbeck

Education & knowledge through people & factsNumber 26, September-October 2008

CancerWorld

26SEPTEM

BER-OCTO

BER2008

CANCER WORLD � SEPTEMBER/OCTOBER 2008 � 1

Contents

3 EditorialECCO–ESMO: a powerful partnership

4 Cover StoryNadia Harbeck: breaking with convention

15 e-Grand RoundThe modern approach to managing locally advanced rectal cancer

22 Drug WatchStopping trials prematurely: sorting the right decisions from the wrong

28 MasterpieceBalancing cure and care: one surgeon’s multidisciplinary quest toraise standards across the board

35 Best Reporter AwardThe neglected magic bullet – UK health reporter asks: why the obsessionwith new cancer drugs?

40 Impact FactorAdjuvant EBRT improves survival in patients with lymph-node-negativepancreatic cancerLenalidomide plus dexamethasone is efficacious in patients with relapsed orrefractory multiple myelomaNewsround

52 Patient VoiceWhy ‘plenty of bed rest’ could be bad advice: survivors to be prescribed exercise ascancer care catches up with cardiology

58 Systems & ServicesWhy is cancer killing more men than women?

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantCorinne Hall

Editorial BoardFranco Cavalli (chair), Alberto CostaJacques Bernier, Vincent T. DeVitaLex Eggermont, Jan FoubertLynn Faulds Wood, Mike RichardsUmberto Veronesi

Contributing WritersKenneth Anderson, Marc BeishonSimon Crompton, Janet FrickerLisa Hazard, Sue MayorPeter McIntyre, Constantine MitsiadesNikhil Munshi, Paul RichardsonDennis Shrieve, Jonathan TwardAnna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonChatrina Melcher

Art EditorJason Harris

Layout DesignerMax Fuller

ProductionHarrisDPIwww.harrisdpi.co.uk

Printed byArti Grafiche Amilcare Pizzi

Cover photographTobias Hase/DPA

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 4545All correspondence should be sentto the Editor at [email protected]

Copyright ©2008 European School of Oncology.All rights reserved

Cancer World is published six times per year by the European School of Oncologywith an average print run of 10,000 copies. It is distributed at major conferences,mailed to subscribers and to European opinion leaders, and is available online atwww.cancerworld.org


Editorial

Bridging the bench-to-bedside gapand promoting multidisciplinarityare pivotal to advancing research

and improving patient treatment and care.The implementation and measurable out-

comes of both ideals in everyday practice gen-erally translate into increased dialogue anddebate between professional specialties andcommunities. In the battle to eliminate cancermuch more can – and will – be done.

The recently announced collaborationbetweenECCO, theEuropeanCanCerOrgan-isation, and ESMO, the European Society forMedical Oncology, was welcomed by the oncol-ogy community as a turning point in unitingforces, efforts and professionals across Europe.

ECCOexists touphold the rightof all Euro-pean cancer patients to the best possible treat-mentandcareandpromote interactionbetweenall organisations involved in cancer research,education, treatment and care. ESMO repre-sents one of the specialties most concerned insuch interaction, since medical oncologydemands a scientific and academic base, avision towards developing and evaluating noveltreatment methodologies andan involvement intotal cancer care.

To deliver on multidisciplinarity and provideequal access to quality care, neither ECCOnor ESMO can stand alone. ESMO’s decisionto join ECCO represents a further step forwardin shaping a united front – the convergence of

� Alexander MM Eggermont and José Baselga � GUEST EDITORS

specialty organisations that share a determina-tion to promote a coherent, concise and har-monisedapproach to tackling thesecond leadingcause of death in Europe.

One critical outcome of the collaborationis that the two leading educational opportu-nities in European oncology, the ECCO andESMOcongresses,havebeencombinedeveryother year. By fusing excellence and expertiseto create all-encompassing comprehensiveprogrammes of the highest calibre, the bien-nial joint multidisciplinary congresses are setto draw record attendances.

Setting thestandard for the future, the firstECCO–ESMO congress will take place inBerlin, Germany, 20–24 September 2009.Thereafter they will take place on uneven-numbered years, while ESMO will continueto organise its standalone congress in even-numbered years.

Unlike many other fields, cancer incorpo-rates multiple interrelated disciplines, whichnaturallyposesachallenge.Efforts to strengthenpolicies on cancer will succeed only by standingunited. Divided we will fail.

ESMO’s membership of ECCO will becrucial in the campaign to build awareness ofpatients’needsandencourageprogressive think-ing incancerpolicy, trainingandeducationat theEU level. The oncology community is now bet-ter positioned than ever to improve care andresearch interactivity across Europe.

ECCO–ESMO:a powerful partnership

Alexander Eggermont is the President of ECCO and José Baselga is the President of ESMO

CoverStory

4 � CANCER WORLD � SEPTEMBER/OCTOBER 2008

Nadia Harbeck:breaking with convention

� Marc Beishon

Gynaecologists don’t win top awards at ASCO. German oncologists don’t make it on the

international stage. Women who want large families can’t expect to be leaders in their field.

NadiaHarbeck’s high-flying career and relaxed leadership style demonstrate the great possibilities

that open up if you refuse to let conventional wisdom and prejudices stand in your way.

Thosewhowould like to see rigid careerstructures for oncologists and con-formity concerning the organisationof cancer centreswould dowell to paya visit to the department of obstetrics

and gynaecology at the Technical University Hos-pital inMunich.Not only is the department a lead-ing clinical trials centre for breast cancer – anunexpected finding for an ob/gynunit for thosewhodo not know theGerman system–but it is also partof a growing network of translational research andbreast care excellence in Germany, a country thathas the dual challenges of a fragmented public/private healthcare system and a pretty rigid hierar-chy in themedical professions.

One of the key agents of change in Munich isNadiaHarbeck, ostensibly an associate professor ofobstetrics and gynaecology, but actuallymore or lessfull time on one of her ‘subtitles’, namely head ofbreast cancer systemic therapy and the clinicaltrials unit in the department. “InGermany it is tra-ditional that gynaecologists have always treatedbreast cancer,” she says. “From the woman’s pointof view itmakes sense aswe see themwhen they are

healthy and then if they do contract breast cancerand other diseases we carry out all the diagnosis,treatment and follow-up care – it’s a continuum inone clinic.”

Harbeck, though, has gone much further thanmost gynaecologists inmaking the switch to oncol-ogy, including participating in research that hasbrought her to international attention on the largestpossible stage – at theAmerican Society of Oncol-ogy (ASCO) meeting in the US.What’s more, thework forwhich she is best known–aprognostic bio-marker for breast cancer – has beenmade possiblelargely because the continuumof care in her clinichas provided the opportunity to collect fresh tumoursamples and conduct translational research that ismore difficult at present in countries such as theUS, thanks to different medical practices. Andoverall she says Germany now has an advantage inbeing able to carry out neoadjuvant work, in par-ticular, because of this ‘all in one’structure. This bio-markerwork continues in her department, togetherwith other trials across the spectrum from preven-tion to metastatic treatment, while she also pro-motes holistic care for the cancer journey, with

CoverStory


strong interest in areas such as breast awareness andpsychosocial support for women with cancer.

But, as in other fields where specialists candominate, in particular urology, Harbeck recog-nises that there can be tension between the role ofgeneralmedical oncologists and specialists such asherself. The picture across Germany varies: at theTechnical University Hospital there is a separatemedical oncology department, while in other hos-pitalsmedical oncology leads on breast cancer, shenotes. Further,manyphysicians inGermany, includ-ing gynaecologists, work as private practitioners intheir own offices and clinics, and it can be chal-lenging to integrate themwith major centres.

Other specialists, in particular radiologists, arealso free to practise separately.Harbeck comments

on one group that recently set up its ownbreast unitinMunich, in part to carry out screening in linewithGermany’s recent rollout of a national programme.“But this means they are apart from the alreadyestablished multidisciplinary ‘all under one roof ’breast centres such as ours – and it is not clear if thiswill be to the benefit of the patient. This is a hotpolitical topic in Germany right now.”

Germany has only just announced a nationalcancer plan – health minister Ulla Schmidtannounced in June a programme for improvingearly detection, treatment and care, access to drugs,patient information and the communications skillsof doctors. Early announcements include the estab-lishment ofmore oncology ‘excellence centres’andfree skin cancer screening for those over 35. The

TOBIASHASE/DPA

country has also been late in establishing its breastscreening programme, and is still in the process ofensuring breast units conform to recent nationalguidelines and those from EUSOMA (the Euro-pean Society of Breast Cancer Specialists). Thecountry has a relatively low number of patientsrecruited into clinical trials; only a few regions, suchas Bavaria, maintain high-quality cancer registries(Harbeck regrets that agood registry inEastGermanywas allowed to run down after reunification); andmuch todo inprovidingbetterpalliativecare services.

Thismight seemsurprising given the perceptionofGermany as a high-qualitymedical provider, andindeed a high spender per head on cancer services,but healthcare is driven by a network of devolvedand expensive public andprivate insurance systemsthat more closely resemble the situation in theUSthanmost other nations.Meanwhile, addsHarbeck,there is still much to do in improving research net-works both among German centres and amongresearchers in the neighbouringGerman-speakingcountries ofAustria and Switzerland.

Indeed, as she says, because of lack of confi-dence in speaking English, fear of being out aloneas ‘one of the first’, and with so much to do athome, German cancer specialists have also notventured onto the international stage as much asthey could. That certainly does not apply toHarbeck– she is already a veteran of the conference circuit,attending all the key breast events such as the SanAntonio BreastCancer Symposium, theEuropeanBreast Cancer Conference, the St Gallen consen-sus event and also theASCOmeeting. It was at thelatter in 2001 that she received the fellowshipmeritaward as lead author for thehighest ranking abstract,which was for long-standing work on the prognos-tic breast cancer biomarker. “Thiswas really unusual– aEuropean, aGerman and a gynaecologist gettingthis award. It had never happened before andcreated a lot of publicity.”

Harbeck could also have added being awomento that list, for not only has she carved out an unof-

ficial specialism within gynaecology, one of Ger-many’s coremedical disciplines, she also started outat a timewhenmen dominated this and otherGer-man medical fields – and still do to a large extent,especially at the top. “My head of department inob/gyn here at theTechnicalUniversity is awoman,MarionKiechle, but shewas the onlywomandirec-tor of gynaecology in anyuniversity hospital in all theGerman speaking countries when she wasappointed in 2000, and this has not changed since,”she says.

Women, adds Harbeck, do have a differentleadership style, in her experience. “In my depart-ment, at least, hierarchies are not so rigid, and thatmakes it easier for me to travel and network, with-out which it would be very hard to progress withwork such as our trials portfolio.” Elsewhere inGermany, she says, department heads tend to runeverything and take all the credit, and also give lit-tle scope for younger staff to learn the administra-tive side of running a unit, which can be verydemotivating.

Harbeck left school with the qualifications tostudymedicine.Unsurewhat to do, she spent a yearinCanadawith a relative learning photography andfilm skills, but not wanting to end up as a weddingphotographer she returned to Munich to entermedical school, with a desire to specialise in ob/gynfirmly embedded. “I always wanted to work withwomen – you work with both healthy and sickwomen, carry out surgery, administer endocrinetreatments and so on – the many different disci-plinesmake you think. It also toucheswomen froma psychological point of view, as some diseasesaffect them very personally.”

She duly worked her way to a full ob/gyn quali-fication.Choosing to combine her careerwith hav-ing a sizeable family – she has four children – thistookher at least three years longer thanhermale col-leagues. “It is not surprising then that a lot ofwomen gynaecologists go off to private practicewhere they can work part time to accommodate

“This was really unusual – a European, a German

and a gynaecologist getting this award”

CoverStory


Her main achievements, then, fall into the twocamps of research and trial work, and building upthe department as one of Germany’s main cancercentres, especially for breast cancer.As trial workis a parameter for accreditation, the two reinforceone another. “In 2005wewere certified as a breastcentre by the German authorities – two organisa-tions have jointly drawn up specifications, namelythe German Cancer Society and the Societyof Senology, but they differ from EUSOMA’sguidelines. We do struggle with EUSOMAbecause it requires that med-ical oncologists be part of theunit and does not accept thatI have the expertise.” Harbeckherself sits on Germany’sAGO breast cancer gynaecol-ogy guidelines group.

The breast centre accredi-tation does, of course, includethe usual multidisciplinarystructures such as tumourboards – Harbeck and col-leagues run no fewer than fourearlymorningmeetings aweek,mostly for breast but also forother cancers such as ovarian,which a colleague specialisesin. Medical oncologists fromelsewhere, she says,would feelsuperfluous most of the time,“But we consult with them ondifficult cases, and in our phaseII trialswe alsoworkwith themclosely – I try to partner amed-ical oncologist with a gynae-cologist as investigators, to helpbridge the gap and avoidconfrontation.

“It is sometimeshard to explain to col-leagues abroad howwedo things here and that

family life,” she notes. “It is especially difficult forwomen with families to get to the top in surgicalspecialities.”

Needing an MD thesis, Harbeck chose anoncology topic involving monoclonal antibodiesthat could be carried out in the clinic. It was aboutdetecting tumour cells in the bonemarrowof breastcancer patients and was supervised by WolfgangEiermann at Munich’s other university hospital,Ludwig-Maximilians. This sparked her interest inbreast cancer research, especially in early spread ofthe disease, and she switched to the TechnicalUniversity as the then head of the ob/gyn depart-ment, Henner Graeff, was setting up a transla-tional researchunitwith a dedicated laboratory. Thelab is still run today by the same biochemist,Manfred Schmitt, who is one of Harbeck’s keymentors and colleagues.

“Henner Graeff had the vision of a role for aphysician/scientist, whichwas intriguing andwhy Icame here, and he likedmy background. But I wason a short-term contract – and when I left to havemy first child he kept a tenured position open forme, which was very unusual then. You can’t have afamily and plan research if you only have two-yearcontracts. This was a decisive point in my career –myhusband isAmerican and Iwas open to anythingthen, including going to work in the States.”

SoHarbeck’s research careerwas safeguarded –and has continued through three more children.About 10 years ago she also moved full time in theclinic away from surgery and day-to-day ob/gynwork to focus on systemic therapy and building upthe department as a top breast unit.

As she says, there can’t be too many interna-tionally known oncologists who have deliveredbabies and carried out breast cancer surgery andmany other procedures such as hysterectomies,and who are now investigating novel therapies.The experience, she feels, gives her a more pro-found insight into the needs of women, whichhelps in her work with breast cancer patients of allage-groups.

CoverStory


“You can’t have a family and plan

research if you only have two-year contracts”

TOBIASHASE/DPA

I don’twant to export our system–but I dowant therecognition that I aman equal in themedical oncol-ogy field in breast cancer, even though I did a dif-ferent specialist degree. I don’t think it is what youdid 10 years ago butwhat you specialise in now thatcounts.” In fact,Harbeck also faces someoppositionfrom within the ob/gyn world too – not all are tookeen to see their field extended and sub-specialisedso far in the direction of systemic treatment ofearly andmetastatic breast cancer.

Meanwhile, she considers the introduction ofcertified breast centres will radically change thelandscape of breast care in Germany. “The esti-mate is we need 200 centres to provide good care–we are at around 150 now. Smaller hospitals thatsee only a low number of cases should not carry onwith breast cancer work – but it will probably bethe insurance companies that decide the issue asthey won’t offer reimbursement to non-conform-ing places.”

It is important also, she adds, to implement astructurewhere the patients of private practitionersare referred to breast centres, but are then returnedto the care of the referring physician.

Harbeck’s department also carries out a gooddeal of secondopinionwork, seeing patients directly– but she feels that moves to implement a manda-tory second opinion system where only the paper-work is received,which is partly driven by insurancecompanies seeking to avoid expensive therapies, ispolitically controversial. “Who is going to takeresponsibility if the patient relapses – and can youreally give second opinions for individual patientsjust by following guidelines and published evi-dence?” That said, guidelines are critical: “Wehaveseen changes in treatment patterns and better out-comes in both breast and ovarian cancer for thosewho follow guidelines, and overall, despite whatsome of our journalists like to say, treatment inexperiencedGerman centres is not anyworse thanin the US. You do not have to go toAmerica to getthe best care.”

The research that has capturedHarbeck’s attentionis on the plasminogen activator system– a complexenzyme system where it has been found thatincreased levels of an activator, uPA, and also itsinhibitor, PAI-1, in primary breast cancers correlatewith aggressive tumours andpoor outcomes.As sheexplains, work on uPA goes back to the 1980s,where Joe Duffy, of St Vincent’s University Hospi-tal, Dublin, demonstrated the effect of high uPAactivity, while Manfred Schmitt in Munich devel-oped anELISA (EnzymeLinked ImmunoSorbentAssay) tomeasure the levels of uPAandPAI-1. TheuPA enzyme degrades the extracellular matrix andso tumour cells can escape and metastasise – andthe inhibitor also has a similar effect and helpstumour cellsmigrate,which is counter-intuitive, butwas shown to be true.

“Various groups around Europe, helped by thethen Receptor and Biomarker Group [now Patho-biologyGroup] of theEuropeanOrganisation for theResearch andTreatment ofCancer [EORTC], alsofound the same bad prognosis, and Fritz Janicke,then here in Munich, led the first clinical trial ofthese biomarkers, (Chemo N0). The results werepublished in 2001 in the Journal of the NationalCancer Institute.”

That trial should sound familiar in its aim toCancer World readers, as it concerns selectingwhich women with node-negative breast cancerwould best benefit from adjuvant chemotherapy,through risk stratification – the same aim of themuch discussed MINDACT and TAILORxtrials, which instead use gene signatures to helpdistinguish high- and low-risk groups. But theuPA/PAI-1work relies on a simpler andcheaper pro-tein measurement that Harbeck says is easier toreplicate and now has a robust quality controlmethodology.

“When Fritz Janicke left, I took over as clinicallead on the project anddidmyprofessorial thesis onthe system,” saysHarbeck. “TheASCOmerit awardwas for a meta-analysis on behalf of the EORTC

CoverStory


“I don’t think it is what you did 10 years ago

but what you specialise in now that counts”

Receptor andBiomarkerGroup,wherewe showedthat uPAandPAI-1were ready for routine testing ofprimary breast cancer as level 1 evidence. No onehad ever done such an analysis of a prognostic fac-tor on over 8,000 patients – it was the first in anycancer I think – and theASCOorganisers emailedme twice to check thedetailswere true.” So far thesebiomarkers are the only ones proved in a prospec-tive trial in breast cancer. As an aside, she alsomentions the support she’s received fromMartinePiccart-Gebhart, current president of theEORTC,in developing her international work.

CoverStory


As she adds, the uPA/PAI-1 work is also an excel-lent example of translational research in action. “Wewent from bed to bench and back again. We hadthe clinical indication first, the scientist explainedhow it worked, and then we did the trial thatproved that high levels of these factors are bad forpatients.Wehave been a step ahead of the gene sig-nature work with level 1 evidence – i.e. ready foruse in the clinic – and we also have a second clin-ical trial (NNBC-3) now in train with 3,000patients in 150 centres that will be finished earlynext year.”

“So far these biomarkers are the only ones

proved in a prospective trial in breast cancer”

A familiar face on the international stage. Harbeck gavethe Emmanuel van der Schueren lecture at the opening

ceremony of the Sixth European Breast CancerConference in Berlin this April

FRANKNÜRNBERGER/EVENT-PHOTO.BIZ

“Some say, ‘If your biomarker isso good how come it’s not in StGallen?’But half of theStGallenpanel come from the US so it’snot surprising they don’t yet rec-ommend it. We had a big boostlast year, though – uPA/PAI-1 isnow in ASCO’s guidelines,which shows how scientificallyindependent they are. And thecompany making the ELISA islooking for approval from the

US Federal Drug Administration based on ourGerman data.”

The portfolio of trials inMunich – some15 cur-rently – is keeping Harbeck very busy; paperworkand organising and motivating junior doctors andremote participants in outlying clinics is an exhaust-ing business, even though she has the help of hercolleagues and a university trials centre.One of herkey achievements is turning the trials work in herdepartment froman informal, after-hours approachinto a fully fledged functional trials unit with studynurses and a growingportfolio. Shewould like to seemore clever trials that target subgroups such asthose with hard-to-treat triple-negative disease,and she is also an investigator for therapies such asAvastin (bevacizumab), which are starting to beusedmorewidely across several tumour types. “Butcompanies need to invest more in predictive bio-markers so we can see what compounds are bestused in which patient,” she says. She has recentlyapplied for a large grant for combining targetedtherapy with molecular imaging in line with thisneed to developmarkers for drugs such asAvastin.

“I try to be as patient-oriented as I can, but it is hard,

as we have to raise outside funds for much of this”

CoverStory


TheuPA/PAI-1 biomarker system is, saysHarbeck,now routinely used in clinics inGermany and else-where (about half of the current trial sites use thesystem in the clinic). As a consequence, about35%–40% of node-negative breast cancer patientsare spared adjuvant chemotherapy, butwider appli-cation is constrained by the need formedical oncol-ogists to access fresh tumour tissue and also haveavailable the ELISA. “TheAmericans don’t have it– after the surgeon takes out the tumour, samplesend up in formalin, and the company making theELISA test has not marketed it heavily.” The freshtissue constraint is shared with the MINDACTgene signature trial, but notwith TAILORx,whichis designed to work with formalin-fixed, paraffin-embedded tissue specimens.

Further, because it is deemed ‘impractical’, thebiomarker is acknowledged but not recommendedin the influential St Gallen breast cancer treat-ment consensus, nor is it used by the AdjuvantOnline resource (www.adjuvantonline.com),according to Harbeck, who is in discussion withAdjuvant Online on how to integrate her data.

Role model. Harbeck – pictured herewith children (from the left) Lara,Julian, Emma and Daniel, and husbandRonald – is living proof that, with a bitof give and take, it is perfectly possibleto combine family with a successfulcareer in oncology

gramme, feeling that its late introduction has costwomen’s lives inGermany, and comments that theold trials that have been criticised need to be inter-preted within the time they were initiated, andsome of their flaws may not be relevant any more,given the introduction of digital mammographyand a thorough double-reading procedure.

Harbeck has a close non-medical colleague inRenate Haidinger, a breast cancer survivor whofirst set up a support group inMunich and then co-founded Brustkrebs Deutschland (Breast CancerGermany).Haidinger gives counselling sessions atthe Munich clinic and has also worked with Har-beck on writing up patient experiences with treat-ments such as Femara (letrozole) (Breast Can ResTreat 105:91–103). There are other breast canceradvocacy groups inGermany, andHarbeck’swish isthat they would collaborate more closely and alsolook outside the country, in an echo of the situationon themedical side.

The pan-European advocacy group, EuropaDonna, does not have a big local presence in Ger-many, she says, despite German MEP Karin Jönsbeing a past Europa Donna president.

For her own part, Harbeck is determined to bea rolemodel for youngerwomenwanting to pursuea clinical research career. “Therewas no one likemewhen I was starting out – now I write at the top ofmyCV that I have four kids, so women can askmehow I did it.” Those children are aged 16, 14, 9 and4, and husband Ronald Kates, who was a relativityphysicist in the US, works now as freelancemath-ematician and indeed is a co-author onmanyofHar-beck’s papers. “He does my bio-maths,” she says.

Harbeck’s immediate plans are to continue todevelop the breast unit part of the clinic, and sheindicates she might move to head up her ownbreast centre if there was an opportunity to set upa genuinely holistic facility. Shewill of course be atevery major breast meeting in the next few years –and if you see her, somewords ofwarning: don’t askwho is looking after her children…

She adds that one other reason to travel somuch –especially to the US – is to meet top industry andacademic decisionmakers to discuss clinical trialsand biomarkers.

But a fewGerman oncologistsmaking interna-tional commitments is not sufficient to raise the bargenerally for German oncology, she feels. She ispleased to report that there is now a national trans-lational researchnetwork for gynaecological cancers(TRAFO), for which she is deputy chair, while sheis also the scientific co-chair of a new translationalresearch meeting for breast cancer, COMBAT,which has been deliberately set up as a German-speaking networking event (its inaugural event is inFrankfurt this November).

Naturally, though, she sits also on the scientificcommittee of the ASCO-NCI-EORTC AnnualMeeting on Molecular Markers in Cancer, whichwill be held in Florida this year, having had its firstmeeting inNyborg,Denmark, in 2000. She also toldthe uPA/PAI-1 story this year at the Breast CancerConference in Berlin as an invited lecturer at theopening ceremony. Harbeck is also one of the edi-tors in chief ofBreast Care, a journal set up in 2006that has both English and German contributions,and she seems tireless inwriting up treatment stan-dards and new developments.

Harbeck is keen to stress that she is not sin-gle-minded about treatment and survival. “I do tryto be as patient-oriented as I can, for example byintroducing counselling and a specialist breastcare nurse to the clinic, but it is a struggle, as wehave to raise outside funds for much of this. I’malso researching breast self-awareness – womenneed to learn about self-examination and we areevaluating what this brings to their awareness. Atechnique called MammaCare, which comesfrom the US, can help them do it better, and weare also doing this with breast cancer patients –they don’t like to touch themselves, but they needto feel a new lump.

She is firmly on the side of the screening pro-

CoverStory


“Now I write at the top of my CV that I have

four kids, so women can ask me how I did it”

e-GrandRound


The modern approachto managing locallyadvanced rectal cancer

The last few years have seensome major changes in themanagement of rectal can-cer. Theold standardsdevel-oped by the US National

Institutes for Health in 1990 have nowlargely been left behind. The classicalapproach was to carry out surgical resec-tion, followedbyapathologyassessmentofpenetration of the tumour into the bowelwall, and the involvementof lymphnodes.This allowed us to estimate the stage andrisk. Treatment was based on classicalTNM factors, as recommended by theNIH consensus conference (Adjuvanttherapy for patients with colon and rectalcancer. JAMA 1990, 264:1444–1450).Surgery would be followed by postopera-tive concurrent chemoradiation, whichhad been shown to improve survival.

THE MODERN APPROACHMRI stagingThefirstmajorchange in theapproachcur-rently taken to rectal cancer isMRI stag-ingbefore surgery.Themesorectum– the

The traditional approach tomanaging locally advanced rectal cancer has shifted to the concept

of total mesorectal excision and the use of MRI for local staging and selecting patients for

multimodal therapy. This case report highlights the key role of the pathologist, the benefits of

preoperative concurrent chemoradiation and the importance of multidisciplinary discussion.

The European School of Oncology now pres-ents fortnightly e-grandrounds which offerparticipants the opportunity to discuss arange of cutting-edge issues with leadingEuropean experts in the field, from contro-versial areas and the latest scientific devel-opments to challenging clinical cases. Oneof these will be selected for publication ineach issue of Cancer World.In this e-grandround, Andrés Cervantes,associate professor ofmedicine at the Hos-pital Clinico Universitario, Valencia, Spain,reviews a challenging case of locallyadvanced rectal cancer. His presentationwas summarised by Sue Mayor.

The recorded version of this e-grandround, together with 25 minutes of discussion,is available at http://tiny.cc/rectalcancer

fascia surrounding the rectum – can bevisualised clearly byMRI (see p17).

TheMRI scans show this patient hasa bulky rectal tumour above the levatorsand located at 10 cm from the anal verge.There are several lymph nodes with sus-pected neoplastic involvement above thetumour.There is invasion of thepresacralspace and of the mesorectal fascia (cir-cumferential resectionmargin) at the lat-eral left side. There was also suspectedinvolvement of the right ureter and anextramural invasionofmore than10mm,but no vascular invasion.

Multidisciplinary team discussionThe next step afterMRI staging is multi-disciplinary team(MDT)discussion.Oneof themain tasks for theMDT is to selectpatients for preoperative therapy. Thisincludes systemic staging, which wouldusually include CT of the thorax andabdomen. However, the patient did nothavemetastaticdisease.Local stagingwasperformed using rectoscopy, endorectalultrasoundanddigital rectal examination.

After local staging, MRI has a keyrole in defining:� the circumferential resection margin

(CRM) involvement – if it is T3-4 oris arisingat, orbelow, the level of originof the levatormuscles. This ismore orless the lower third of rectum andshould be considered high risk

� extramural spreadofmore than5mm� extramural vein invasion

� peritoneal involvement. If this is inthe upper third of rectum, patientsare at risk of theCRMbeing involved,and we would recommend preopera-tive treatment.

Thereareessentially threedifferent groupsof patients in terms of preoperative treat-ment strategies (see table below).

For groupA, the risk is very low. Thisincludes patientswith T1, T2 or evenT3tumours, but less than 5mm in diameterand no affected lymph nodes, or verysmall ones. For this group,we predict theCRMwill be negative, so the patient cango to surgery. In contrast, for patients ingroup C, we predict that the CRM isgoing to be involved, so preoperativechemoradiation is indicated. In themid-dle group, it is safer for patients to havepreoperative chemoradiation.

The impact of MDTs on surgeryoutcomesThe importance of MRI data being dis-cussed with the MDT is illustrated bydata published byRoyalMarsdenHospi-tal in the UK (Burton et al. Br J Cancer2006, 94:391–397). From a total of 298patients with rectal cancer, 76% of the259 patients considered to be potentiallycurative were discussed in a MDT. Ofthese,81 (41%)wereconsidered to requirepreoperative therapy. Of those going tosurgery alone, 97% had negative marginsindicating that decisionmaking was gen-erally correct.


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Presenting symptomsA 55-year-old man presented with: consti-pation and rectal bleeding; false diarrhoea;increased urinary frequency; 20 kg weightloss in the last threemonths; performancestatus of 1.

Diagnostic testsPhysical examination detected no peri-pheral lymphnodesandnosignsof ascitis orpleural effusion.Adigital rectal examdetecteda tumour at10cm from theanal edgewith fix-ity of the surrounding tissues from 5 cm.Rigid rectoscopy confirmed a fixed tumourat 10 cm from the anal verge completelyobstructing the rectum.Biopsy showed poorly differentiated invasiveadenocarcinoma of the rectum.Colonoscopy detected a tumour at 15 cm.The flexible colonoscope was not able topass the rectal mass.Endoscopic ultrasonographywas not per-formed because it was not possible to gothrough the rectal mass.Blood tests showed no anaemia or leuco-cytosis.Biochemistrywaswithin normal range, andthere were no liver alterations.Carcinoembryonic antigen was 2.9 ng/ml.Chest and abdominal CT scans showed noevidence of metastatic disease.Barium enema showed the tumour starting10 cm from anal verge. It was extensive,going up the colon for a considerable length.

THE CASE

Treatment group MRI features Treatment strategy

A T1-2, T3 <5 mm, TME surgeryN0-1,Predicted CRM–

B T3>5 mm, T4 Pre-op chemoradiationN2Predicted CRM–

C Predicted CRM+ Pre-op chemoradiation

SELECTION OF PATIENTS FOR PREOPERATIVE THERAPY

� each case considered from the varietyof perspectives provided by theMDT

� patients more likely to be offered arange of types of treatment at appro-priate times

� a supportive environment where pro-fessionals can share their concerns

� feedback to the surgeons fromhistopathologists and other teammembers on the results of their work

However, in the62patientsnot discussedbyanMDT,wheredecisionswere reachedonan individual basis, 100%were sent onto surgery alone.A very high proportion –26% – were found to have histologicalinvolvement of the margin, posing a highrisk of local and systemic relapse.

Thesedata support aMDTdiscussionbefore takingdecisions.Benefits include:� improved coordination of care

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1. In this patient, MRI shows a very extensive tumour almostinvading the sacrum, which is also pressing on the urinarybladder. This explains the urinary frequency that the patientwasexperiencing 2. The axial views depict the circumferential fascia as a straight

line.The fact that the left part of this line is notwell depicted indi-cates that the tumour is invading the pelvic wall

3.On the left side, the tumour can be seen completely invadingthe mesorectal fascia

4 .Thediagramdrawnby the surgeon in the surgical report indi-cates that the tumour couldnot be resectedbecause itwas firmlyadherent to structures in the pelvic wall

Magnetic resonance imaging

� anoptimal setting for clinical research.

Preoperative chemoradiationThe MDT agreed that chemoradiationwas indicated in thepatient being consid-ered in this e-grandround. The treatmentplan was capecitabine (1,300 mg/m2

per day from day 1 to the end of radio-therapy.Radiotherapywas6MeVphotonsat a dose of 45 Gy (180 cGy/day for

5days/week),which took fiveweeks. Sur-gery was indicated 5–6weeks after.

Side-effects included grade 1 diar-rhoea and grade 1 cystitis with someurinary symptoms. There were nodelays in dose due to toxicity, and radio-therapy was given as planned, over afive-week period.

TME surgical resectionMRI was performed before proceedingto total mesorectal excision (TME) sur-gical resection. This showed clearshrinkage of the tumour, with the blad-der no longer being constricted by thetumour. However, despite this shrink-age, the tumour was still in contactwith the presacral area towards thespine. The margin on the lateral rightside was involved. We had to discussthe case very carefully with the sur-geons, who, because of a lack of previ-ous experience in operating on whathad been considered a completelyunresectable tumour, were reluctantto go ahead with surgery, but we con-sidered that it was justified.

Surgery was performed six weeksafter radiotherapy ended. A TME wasperformedwith a sphincter-saving pro-cedure (anterior resection); the levatorswere not involved. The patient alsounderwent a temporary ileostomy.

Pathology and risk assessmentafter surgeryThe next step is a pathological assess-ment and estimation of risk. The classi-cal pathology approach would be toassess bowel wall invasion, regionallymph node involvement and distantmetastasis. The current pathologicalapproach includes three further impor-tant assessments:� the macroscopic integrity of the

mesorectum� the distance to CRM� staging after preoperative chemo-

radiation.Thepathologist alsoauditsthe surgical skills applied,assessing themacroscopicof the excised mesorec-tum. Pathologists should


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define planes of surgery as follows:Mesorectal plane: intactmesorectum

with only minor irregularities of asmooth mesorectal surface; no defectdeeper than 5 mm; no coning; smoothCRM on slicing.

Intramesorectal plane: moderatebulk to mesorectum, but irregularity ofthe surface; moderate distal coning;muscularis propria not visible; mod-erate irregularity of the CRM.

Muscularis propria plane: little bulk tomesorectum with defects down ontomuscularis propria and or very irregularCRM (Quirke et al,ASCO 2006).

Macroscopic assessment of theresected mesorectum showed an irreg-ular area in the front section, in front ofthe sacrum, close to the presacral space.Ink staining showed that themesorectal

surfacewas smooth, withno mesorectum in thepelvic wall.

The pathology reportshowed that the rectosig-moidectomyspecimenwas16cm in length.Thequal-ity of theanteriormesorec-tumwascomplete, but theposteriormesorectumwaspartially complete.Macroscopic assessment of the resected specimen

MRI assessment after chemoradiation. Shrinkage is clear, and the bladder is no longer pressed by thetumour. However, at the back, the tumour is still in contact with the presacral area

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Robert Glynne-Jones (RG-J), of the Mount Vernon Centre for Cancer Treatment,Northwood, UK, put questions toAndrés Cervantes (AC) about the case.

RG-J: You must have been delightedthat you started off with a bulky tumourand got such a fantastic response. Is theremore risk of an anastomotic leak withadvanced tumours?AC: Not with our surgical team. Theyalways proceed to protective ileostomyand then close the ileostomy 4–6months after treatment is complete toavoid leaks.RG-J: In terms of the regression grades,a complete pathological response is veryclear. How reproducible are the otherregression grades?AC: This requires some experience.We have gained experience discussing

all our cases and we try to reproducethe recommendation of Philip Quirkein having at least 20 slides of the spec-imen revised. If the pathologist is notcareful, the probability of regressionmay be higher.I think that sometimes it may be com-plicated to have the five grades, as pro-posed by Dvorak. However, goodregression grades are related to betteroutcome – this is the best validity of thegrading system.RG-J:What about the standardisation ofpreoperative chemoradiation for allpatients, even T1 and local excision?You would not usually give preoperative

chemoradiation forall patients?AC: No. I do notlike the approachof ignoring thepatient in front of you and goingstraight to preoperative chemoradia-tion, because there are long-term toxi-cities, including sexual problems,urinary problems and problems withthe sphincters after radiation. I preferto select patients with MRI, becausethis reveals tumours that are involved orclose to the margin, making it clearwhen we should give preoperativechemoradiation. �

therapy show this rate has fallen to 5%.In contrast, theproportion of patients

presenting with distal metastases hasshown almost no change from the early1980s to today.

There is currently no consensus onthe use of adjuvant chemotherapy inpatientswith resected rectal cancer, butits use is widespread. Recent data fromthe UK QUASAR study (Lancet 2007,370:2020–2029) for patients with anuncertain indication showed significantimprovement in five-year survival withchemotherapy (P=0.02). In the sub-group of patients with rectal cancers,the benefit was marginal but almostsignificant (P=0.06).

Follow upThe patient had an intraoperativecolonoscopy,which showed the absenceof metachronic tumour or polyps. Hewas not given postoperative chemother-apy because he had a presacral abscessand slow recovery after surgery. The

The tumour was located at 7cm fromone of the borders. The distal and cir-cumferential margins were free, withthe circumferentialmargin (macroscopi-cally) at 7mm from the tumour edge.

Microscopic assessment showedthat there was extensive fibrosis. Thetumour had completely regressed. Therewas some indication of postradiationangeitis. None of the 23 lymph nodesexaminedwere involved (ypT0 ypN0) –thiswas a goodnumber to analyse as it isnot easy to obtain a large number in sur-gical resection after radiation. Overall,the specimen indicated pathologicallycomplete remission.

Postoperative chemotherapyThepatient should receive postoperativechemotherapy if this is indicated. Ran-domised trials over the last 28 years haveshownmajor achievements in control oflocal relapse. In the early 1980s, 25%–30% of patients had local relapse, butrecent trials with TME plus chemo-

ileostomywas reversed after sixmonths.At two-year follow-up, his CEA was1.9 ng/ml, whichwaswithin normal lev-els. Thoracic, abdominal and pelvicCTscans showedno evidence ofmetastaticdisease and no local relapse.

ConclusionsIn this patient,whopresentedwithunre-sectable rectal cancer but nometastaticdisease,multidisciplinary discussionwasessential in optimising the treatmentstrategy, as for all rectal cancer cases.Successfulmultimodality treatmentwasgiven, with an R0 resection (completeresection with no microscopic residualtumour), and therewas no relapse at twoyears. This case was the first I have hadin which a patient underwent acolostomy in order to avoid obstructionduring chemoradiation.

In conclusion, unresectable rectalcancer should be treated with concur-rent chemoradiation using amultidisci-plinary team approach.


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Even if people do not feel that surgeryis safe, I would consider preoperativechemoradiation, because with amesorectal margin involved, it is diffi-cult to put things back in the right way.I think people should think about it,but I would not consider preoperativetherapy for all.RG-J: The original surgeon defunc-tioned the patient because of fear ofobstruction. Right at beginning youcould not introduce ultrasound becauseit was a very bulky tumour. Do youhave a policy of when you defunctionpatients routinely?AC: In our series of 120 patients overthe last seven years, we have defunc-tioned only two or three patients –those presenting with impendingobstruction. It is important that thesurgeon should not remove thetumour in these patients, which arelocally advanced cases. Instead, adefunctioning colostomy should beperformed. This takes one week –then you can start preoperativechemoradiation. However, this prob-lem is very infrequent.RG-J: We saw the value of MRI inrelation to the circumferential margin.What about lower down, below the lev-ator? Does your MDT feel as confidentin that?AC: In T3 and T4, we go directly topreoperative chemoradiation. How-ever, the surgical team tries to con-firm if the levators are involved withthe tumour. If they are, and MRI isvery clear on that, then a sphincter-preserving procedure may not beindicated.RG-J: You routinely operate 5–6 weeksafter completion of chemoradiation. Doyou restage patients with another CT tomake sure they haven’t developed diseaseoutside the pelvis?AC: Yes, especially in trials, we always

do. When we give preoperativechemoradiation this adds 5–6 weeks,making 12 weeks in all. This is not along time. But we do MRI just beforesurgery. Sometimes, we recommendrestaging the liver or lung.RG-J.What about giving chemotherapyafter surgery? This is an area where it canbe difficult to make decisions. In apatient with a pathological completeresponse, are you going to give morechemotherapy?AC: Treating patients with locallyadvanced disease, there is no level 1evidence, but I consider that adjuvantpostoperative therapy may be benefi-cial. It is difficult to differentiatepatients with colon cancers from thosewith rectal cancers. We have achievedmajor improvements in colon cancer.But if the control of systemic disease inpatients with rectal cancer is not good,the situation is more difficult. In ourprogramme, we favour postoperativechemotherapy for these patients. Butthe patient presented in our case studyhad mild chemotherapy – justcapecitabine and radiation, and nooxaliplatin. It would be useful to haverandomised controlled trials showingthe effect of adding oxaliplatin.RG-J: What happens when patientsdon’t respond to chemoradiation?AC:Assessment has to be done in thepathology report. If the pathology reportafter surgery indicates a bulky tumour,positive lymph nodes and vascular inva-sion, these are very negative signs indi-cating a high risk of relapse. There areseveral options. If the patient has hadchemotherapy with 5-FU or an oralfluoropyrimidine, I would go aheadwith oxaliplatin plus 5-FU. If thepatient has had an R0 resection but isresistant to chemotherapy, they areprobably OK and we would followthem up and give chemotherapy when

they relapse. I am not sure of the role ofchemotherapy in patients who areresistant to chemoradiation.RG-J: In the UK, we give a short courseof chemoradiation. Is there any role forshort-course radiotherapy? We argueabout this a lot, with concerns aboutmorbidity for early tumours which MRIsuggests are resectable.AC: The evidence is there, with threerandomised controlled trials showingbetter local control. Before the use ofMRI, I think it had a definite role. Inpatients who cannot tolerate chemo-radiation, short-course radiation isa possibility. The problem is that itdoesn’t downsize tumours, so I amreluctant to give it for locally advancedtumours by MRI.RG-J: On another issue, how much dosurgeons like having the quality of themesorectum documented?AC: In our team, the surgical group isquite sensitive about this point. Theyhave performed a lot of studies on thisissue. Especially in the lower third, theresults show they should check care-fully. Reporting gives them feedback,improving the final result. It has beengood to see the quality of surgeryimproving over the years. Now, we have100% data on sphincters in pathologyreports, which were almost absent fiveyears ago. So we are sure the levatorsare in the specimen and analysed by thepathologist. These are points of quality.The way forward is for the surgicalgroup to understand that feedbackfrom pathology improves quality.RG-J: It’s also a way of validating theMRI decision – you need the report onquality to validate this. If after surgerythere is 20% involvement of the cir-cumferential resection margin, youknow that the decision was not wellfounded. Pathology helps us to move inthe right direction.

asmore results come in.However, if theanalysis coincideswith a spike that exag-gerates the benefit, the question of stop-pingearlymaybe raised–hence thebias.

The more interim analysesdone ina single trial, thegreater thelikelihood of hitting a randombene-fit spike, leaving trial sponsors open toaccusations of looking for the rightmoment to ‘quitwhile they’re ahead’.

WHY STOP EARLY?There are of course very good rea-sons for stopping a trial thatshows benefit early – particu-larly where lives are at stake andthere are no therapeutic alterna-tives. An interim analysis mayreveal evidence so strong that itwould be unethical to continue torandomise patients to the controlarmof the trial and to delay accessto the new therapy among thewider patient population.

StuartPocock, professor ofmedical statistics at theLondonSchool ofHygieneandTropicalMedicine, has written exten-sively on this subject. “Goodpractice should be that you stop

Stopping trials prematurely: sortingthe right decisions from the wrong� Anna Wagstaff

Arecommercial pressuresprompt-ingpharmaceutical companies tostop trials prematurely? A group

from the Italian drug regulatory agency,AIFA, and the Mario Negri Institute inMilan, suggest that this may be the caseinanarticlewidely reportedonboth sidesof theAtlantic.Theydrawattention to thesharp increase in the number of cancertrials stopped early on the basis of bene-fit shown in interimanalyses,pointingoutthat the vast majority were registrationtrials, aimedat gettingmarketingapprovalfor a new drug or a new indication.

Their article in theAnnals ofOncology(2008, 19:1347–1353) surveyed all clin-ical trials of anti-cancer drugs publishedfrom January 1997 toOctober 2007 thatwerestoppedearly ‘forbenefit’(i.e. exclud-ing those stopped due to lack of efficacyor unacceptable toxicity). Therewere 25trials in this category.

The survey, say the authors, high-lights, “a consistent increase (>50%) inprematurely stopped trials in oncologyduring the last 3 years in comparison tothe whole period analysed.” They pointout that, of those stoppedprematurely inthe last three years,more than78%wereused for registrationpurposes. “This sug-

gests a commercial component in stop-ping trials prematurely.”

Senior figures from the industrystrongly deny the allegations and areunhappy about the tone of the mediacoveragepromptedby theAnnals article,which, they feel, fuelled a climate of sus-picion and failed to spell out how com-panies insulatedecisionsonclinical trialsfrom inappropriate influence.

Stopping a trial early is generally con-sidered undesirable. It is likely to result inlosing informationof relevance in evaluat-ing efficacy in the longer term, deprivingphysicians, patients and researchers ofimportant knowledge. The chance togather statistical data on disease recur-renceandprogress, drug resistance,metas-tasis or adverse eventsmaybe lost forever.

An early halt has also been shown tolead to a systematic exaggeration of ben-efit because, in any randomised trial, thesmaller the number of outcomes orevents, the greater the likelihood that thedifferencebetween thearmsof the trial ata givenmomentwill represent a ‘randomspike’. If the interim analysis shows lowbenefit, researchers have an incentive tocontinue the trial as planned to seewhether theearly results readjustupwards


DrugWatch

Allegations that commercial pressures may be leading to cancer drug trials being halted

prematurely hit the news on both sides of theAtlantic lastApril. Industry leaders are pleading

‘not guilty’. But how can we judge when calling an early halt to a trial is the right thing to do?

for benefitwhere there reallyis very strong evidence – wesometimes use the phrase‘proof beyond reasonabledoubt’ – that the new treat-ment is superior.That is, tak-ing into account not just thepatients in the trial now, butif you are going to recom-mend a new treatment forfuture patients, you reallywant to make sure you areright. Otherwise, you runthe risk of inflicting anapparently superior buttoxic treatment on lots andlots of future patients. Itwould be very unfortunate

if you happened to

have stoppedon lesser evidence,when intruth the treatment is not superior.”

Establishing sensible statistical stop-ping boundaries before the trial startsadds objectivity to any subsequent deci-sion to stopearly, but the final judgementneeds tobebasedonawise interpretationof the total evidence available, saysPocock. For example, the leaders of theHERAtrial into trastuzumab (Herceptin)as an adjuvant – oneof the trials listed inthe Annals article – justified sacrificingdata on side-effects when they stoppedthe trial early by pointing to the strongdata already available from widespreaduse of the drug in themetastatic setting.

Wise judgement is also needed inbalancing the interests of future patientsand the patients on the trial. RogerWil-son, a patient advocate who works withtheUKnational cancer researchnetwork(NCRN)expresses the dilemma. “I feeltrappedbetween the two sides, becauseI really dowant to see unequivocal evi-dence that patients will benefit.At thesame time, as a patient, I want to ben-efit at the earliest possible opportunityshould that present itself.”

Wilson regrets the loss of potentiallyimportant information about develop-ment of resistance that resulted from arecent decision to halt prematurely theACOSOGtrial into imatinib (Glivec) asan adjuvant in GIST patients. He alsobelieves that stopping early the sunitinib(Sutent) trial for GIST patients whodon’t respond to imatinib sacrificedimportant data on overall survival,mak-ing it very difficult for some patients toget the treatment reimbursed.

“In termsof treatingpatientsnow–2006 when they did it – it was

DrugWatch

“You risk inflicting an apparently superior but toxic

treatment on lots and lots of future patients”


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“The authors point to a number of factors they say

might indicate that commercial concerns played a role”

absolutely the right thing todo.Butwearegoing to have to live with the conse-quences. All we’ve got at the moment isabout amedian of eightmonths progres-sion-free survival on Sutent for patientswho relapsed on imatinib. We haven’tgot anydata to say thatpatients goingontoSutent live for anextra two to three years.It’s just not possible to produce it.”

“Patientsdobenefit in the short term,and that is somethingwemustn’t ignore,”says Wilson, adding that crossover trialdesigns can help resolve the conflict,although they tooentail some lossofdata.In the end, he says, researchers have tobalance thepotential short-termbenefitstocurrentpatientsof stoppinga trial early,against the long-termdisservice to futurepatients fromthe lossofdata. “Youhave tooperate somesort ofbalancemechanism,whereby you put the evidence into a potand come upwith a view.”

FOR PATIENTS OR PROFIT?Given the complexity of the issues indeciding to stop early, the seven-pageoverviewof 25 trials in the Annals articleis not sufficient to show whether thedecisionwas justified on ethical groundsin each case. The authors nonethelesspoint to a number of factors they saymight indicate that commercial con-cerns played a role – possibly to save thecosts of continuing the trial or to steal amarch on companies with rival prod-ucts in the pipeline.� More than 78% of all trials stopped

early for benefit in the last threeyears were used to support an appli-cation for marketing authorisationat the European Medicines Agency(EMEA) and theUSFood andDrugAdministration (FDA).

� The average time to publicationwasaround two years, suggesting thatdisseminating information for thebenefit of a wider patient popu-lation was not the drivingforce.

� In all, only around 3,300patients/events out of aplanned8,000were stud-ied.Theauthors accept thatthis couldbeaccounted forbyethical considerations, “How-ever, the relation betweensparing patients [frompoten-tially unnecessary randomi-sation] and saving time andtrial costs is also unquestion-able, and indicates that there is also amarket-driven intent.”

Alan Barge, head of Clinical Oncologyat AstraZeneca, strongly denies thatcommercial pressures play any role inhis company’s decisions about how totake a trial forward, and he says it is alsohighly unlikely that this happens inother major pharmaceutical firms.“There is not a shred of evidence toshow this is the case.”

Like most pharmaceutical compa-nies,AstraZenecauses independent datamonitoring committees (DMCs – alsoknown as data safety monitoring com-mittees) to ensure that decisions onstopping early are independent of inap-propriate influence–whether fromcom-mercial pressures, from enthusiasticprincipal investigators or from anxiouspatients.DMCmembers are appointedaccording to strict criteria. “Theymust becompletely independent of the study,and independent of any pecuniary inter-ests ofAstraZeneca. Second, theDMCmust be an independently scientifically

credible group of people. Third, theymust be accepted by the principal inves-tigators as an appropriately qualified

group to monitor the study. Wethenmake everyone involvedaware of the names, includ-ing the regulatory agencies.”

The DMC then becomesinvolved in the study design,includingdefining the efficacy andsafety criteria and the statisticalstopping boundaries. Once thestudy has started, no-one outsidethe DMC has access tounblinded data (without whichno comparisons can be madebetween treatment arms).

Barge says that this insulates the trialfromcommercial pressure. “Knowing as Ido the degree to which DMCs jealouslyguard their independence, and also theview that regulatory agencies take of clin-ical trials stopping early, I cannot envisagea situation where my commercial col-leagues would try to put me or, moreimportantly, the independent physiciansconducting thestudyand theDMCunderpressure to stop a trial early, or in anywayinfluence their view about the medicalrationale or ethics for continuing.”

Barge argues that thepharmaceuticalindustry is second only to the nuclearindustry in its level of regulation. “If acompany were to decide to stop a trialbased on commercial considerations orotherwise conduct a trial in a way thatwould not be considered appropriate,those actions are discoverablewhen thedossier is filed with the regulatoryagency. Any company that were to dothat runs the risk of being found out,which would fundamentally damagetheir credibility.”


DrugWatch

Academic trials, he adds, are subject tofar less scrutiny.

DianeYoung, head of globalmedicalaffairs at Novartis Oncology, says sheandher colleagueswere disappointed bythepress coverage, given theweaknessesof the Annals article. “In order to do thetype of analysis they are trying to do, theywouldhave to look at all the protocols foreach study, and understand the statisti-cal model, and why an interim analysiswas built in…You can’t just look at it ona surface level and say they did or did notdo the right thing.”

She accepts that pharmaceuticalcompanies could improve the way theyreport decision-making processeswhenthey publish trial results. “Maybe thereis an educational opportunity here, thatpeople need to understand that there aresignificant safeguards built into thedesign of these trials.Wedo it in collab-orationwith a lot of independent peopleas well as the regulators.”

One of the 25 trials listed in theAnnals articlewas the letrozole (Femara)trial, stopped after one-third of theplanned events. Young points out that,although thiswas a registration trial for aNovartis therapy, itwas initiated,designedand conducted entirely by an independ-ent trials group, led by theClinical TrialsGroupof theNationalCancer InstituteofCanada and including theNorthAmeri-can Breast Intergroup and the BreastInternational Group.

The trial was studying the therapy inan adjuvant setting in a population ofwomen who had already received fiveyears of tamoxifen, so that ‘events’regard-ing the primary outcome measure ofdisease-free survival, took a long time to

accrue.Carrying that trial to its plannedconclusion, Young argues, would havedelayed access to a beneficial treatmentfor years. She also denies that the deci-sion to stop early saved money; thewomen are still being followed up, eventhough the trial has stopped.

The ACOSOG trial, she adds, wasalso entirely in the hands of a cooperativegroupof investigators,whohave their ownprocedures. “Wegot thephonecall thedaybefore they were going to announce theywere going to stop the study”.

Both Barge and Youngbelieve that the increasingnumber of trialsbeing stopped earlymay simply reflectthe surge in the num-ber of cancer trials beingcarried out in recent years.They also suggest it couldbe linked to the movetowards novel targetedtherapies. “Because weare using targeted agentswe are often able to pickpopulationswhere therearen’t other therapies available. In thesepopulations, if you have solid data atthe interim analysis that the drug is ben-eficial to patients, because you havepatients on the trial and out in theworldtoo who don’t have any alternative, it isimportant to make that informationavailable,” says Young.

Interim analyses also have a muchmore important role to play in develop-ing drugs aimed at specific targets, saysBarge. “In the past youmight have beentaking forward a cytotoxic drug that wasslightly different to a previous version of

the same drug, where you already hadphase II data showing that it shranktumours. The same is true of hormonalagents developed in the ’70s and ’80s.Proof of conceptwas already established.There was no need to look for early evi-dence of efficacy in a large trial. Theissue was all about safety.”

By contrast, when developing a drugbased on a new concept, and trying tofind theappropriatedoseandpatientpop-ulation, the rationale for interim analysesismuchgreater.However, it is not aneasy

option, says Barge, because themere fact of conductinganinterim analysis incurs apenalty–youhave ineffectto show a higher level ofsignificance in your finalresults than would other-wise have been the case.

Young takes issuewiththe assumption thatbecause a trial ends early,research comes to a halt.“It simply isn’t possible to

answer every ques-tion anddo itwell inone study. But it’s

important to have a programme ofresearch that answers the questions.”

Barge agrees.Hehas spent years try-ing to figure out why dramatic phase IIresponses to AstraZeneca’s non-small-cell lung cancer (NSCLC) drug gefi-tinib (Iressa) were not replicated in thephase III trial. “It’s a rather simplisticview to say you will never know thosethings if you stop clinical trials early.Youset out on a series of clinical trials toanswer different questions.”

He points out that clinical trials are

“People need to understand that there are significant

safeguards built into the design of these trials”

DrugWatch


designed to muchmore robust standardsthan used to be the case. “The initialapproval for taxotere inNSCLCwasbasedononly around100patients. Inoneof ourdrugs recently,wehavedoneadirectheadtoheadcomparisonwith taxotere, andwestudied 1,400 patients, just to demon-strate that our drug, which is a well-toleratedoral drug, is as good as taxotere.”

AN IMPORTANT ISSUEPocock,whohasbeen following the issuefor many years, says: “Practice is betterthan itwas in termsof sensible choices asto when to stop trials, but there is still aproblemandweneed to improve.Certaintrials do stop too soon – it’s a question ofeducating investigators and sponsors.”

Pocock feels that the Annals survey“went slightly beyond what we canconclude” in singling outcommercial interests. “Ithink it’s probably amix ofindustrymotivation of get-ting to profit fast, over-enthu-siasm of investigators andover-enthusiasmofDMCs to stoptrials too quickly.”

Hesuggests thatpseudo-ethical arguments canoften lead to decisionsto call a premature halt.“Many will stop becausethey think it is ethical tostop, but their judgement may not bethewisest one on that paticular issue. Ifyou have some evidence, and you arepassionate about your treatment anyway,whether as an investigator or as a spon-sor, you may feel, ‘Ooh it’s heading inthat direction, I always knew it would,therefore I should stop early.’

“One can speculate, but it is dangerousground to think you can tell what thespecific motives are in a particular cir-cumstance.”

However, the underlying concernraised by theAnnals article – that a trendtowards stopping trials early is resultingin unclear and poorly defined risk/benefits – stands regardless of themoti-vation. It is a concern that urgently needsto be addressed, as physicians struggle touse appropriately a stream of new ther-apies about which too little is known.

Francesco Trotta, lead author of theAnnals article, says he and his co-authorswould like to see action on threefronts. They want DMCs used in allclinical trials (there were no DMCs inalmost a quarter of the trials in the

Annals survey) and greater trans-parency over who sits on

them. Names should bemade publicly availableeither in the clinical trial

registers (when the trial isongoing) or in the published arti-cles (when the trial terminates).

They want trial patients to bemade fully aware when they signconsent forms that theprimarypur-pose of research is to reach robust

conclusions. “Before the trialstarts, investigators should informpatients that interim results

should be considered as partial, and thatonly completing the trial allows theachievement of the study objectives.”Wilson, with his experience as a patientadvocate, points out that consent formsusually do make this point. “The troubleis that people who have never beenexposed to theclinical trials environment

don’t ever actually get thatmessage.”Above all, they want to exploreways

of improving themethodology governingthe early truncation of trials to ensurethat trials only stop early when this isdemonstrably appropriate, and that theyare followed upwith confirmatory trialswherever possible.

This is one of the big challenges ofcurrent drug development. Finding solu-tions will require constructive dialogueinvolving not just academic researchersand statisticians, but the regulators,patient advocates… and the industry –commercial interests and all.


DrugWatch

“With targeted agents we are often able to pick

populations where no other therapies are available”

TRIALS STOPPED EARLY

The Annals article listed 25 trials into anti-cancer therapies that were halted earlybetween 1997 and 2007. Among themwere registration trials for:� sunitinib (Sutent) in (i) metastatic renal

cell carcinoma, and (ii) advanced gas-trointestinal stromal tumour (GIST)

� sorafenib (Nexavar) in advanced clear-cell renal cell carcinoma

� bevacizumab (Avastin) in (i) a combi-nation regimen for non-small-celllung cancer; (ii) various combinationsfor metastatic colorectal cancer; and(iii) metastatic renal cell cancer

� lapatinib (Tykerb) + capecitabine forHER2+ metastatic breast cancer

� trastuzumab (Herceptin) for earlyHER2+ breast cancer

� letrozole (Femara) for receptor-positive early breast cancer

� irinotecan (Camptosar) + cisplatin formetastatic small-cell lung cancer

Balancing cure and careOne surgeon’s multidisciplinary quest to raise standards across the board

� Janet Fricker

Cornelis van de Veldewent into cancer because he loved the complexity. Throughout his career

he has grasped each newdevelopment across the disciplines to see how it could help resolve the

difficult balance between curing a patient and preserving their quality of life. Spreading excel-

lence in surgery, he says, is the singlemost important thing Europe can do to improve outcomes.

When Cornelis van de Velde’s youthfulambition of becoming a fighter pilotwasthwarted by aDutch air force’s freeze on

recruitment, he was forced to turn to his secondcareer choice–medicine. From theoutset therewasnoquestionhewoulddo anything other than surgery– it required the samemacho ‘action hero’ outlookon life, love of gadgets and gizmos, and hand–eyecoordination skills as flying.Throughout his career as a surgical oncologist,

flying has been a recurring theme, helping himtransfer the disciplines of quality assurance to theoperating theatre. “If yourCaptain tells you that yourflight to Heathrow had a 10% chance of crashinginto the North Sea, you don’t accept that level ofrisk.Yet in cancer surgery, every day patients acceptmuch higher levels of risk without question,” saysvan deVelde, who has dedicated his career tomin-imising those risks and raising standards of care par-ticularly in breast, gastric and colorectal cancer.“By conductingwell-controlled clinical trials in

surgerywehave been able tomake simple improve-ments that dramatically change outcomes andmakea real difference to patients’quality of life,” he says.

It has often been an uphill battle, however, as sur-geons – surgical oncologists in particular – havebeen slow to accept the feasibility of conductingclinical trials in their specialty. “Therewas a real feel-ing that you could not compare different surgicalprocedures, since surgerywasmore of an art than ascience, and impossible to control… But we havefound that by introducing a rigid system of check-lists it is possible to control for the individual skillsof different surgeons and introduce proper clinicaltrials,” he says, adding thatwidespread introductionof good evidence-based surgical techniques hasgreater potential to improve cancer care acrossEurope than any new pharmaceutical agent.Van de Velde appreciates the historical irony

that it was a French surgeon barber,Ambroise Paré(1510–1590),whoperformed the first clinical trialsinmedicine.Cauterising thewounds of amputees atthe siege of Villaine, in 1537, Paré ‘randomised’patientsbetween tar andanointmentcombinedwithligatures– the latter proving tobebetter for both sur-vival rate and comfort. It’s an example vandeVelde,who was appointed professor of surgery at Leiden(Netherlands) in 1987, and has headed the


Masterpiece

justmetres fromher. The experiencewas somethingshe never spoke of.”As a teenager, van deVelde describes himself as

a real ‘dare-devil’, not in the least interested in any-thing academic. “I started flying at 14, and did myfirst solo flight at 16, and remember literally scream-ing with delight. Flying gave me such a wonderfulsense of freedomandpower, and also opportunitiesfor travel.Onesummer Idida student exchangewiththe Israeli air force,” he remembers. There was,however, amore artistic side – in his spare time theyoung Cornelis also enjoyed playing the piano andpainting landscapes in the style of the impressionists.In 1968 he started his medical studies at the

University of Leiden, not far fromAmsterdam.As a

Department of Surgical Oncology at Leiden Uni-versityMedical Center since 1999, is proud to fol-low. Indeed it was van de Velde who developed theprotocol for the first clinical trial ever in theNether-lands for breast cancer, as part of his PhD.Cornelis van de Velde was born in 1951 in

Zevenbergen, a rural community in the south of theNetherlands. The family settled in the area at theend of the SecondWorldWar, when his father, Jo,moved to a dental practice. The quiet environmentparticularly suited hismother, Lien, who had beenbadly injured in the allied bombing, and lost mostof her immediate family. “My mother was the solesurvivor when her family home was bombed – herparents and brother, after whom Iwas named, died

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KATHALIJNVANDEVELDE

student he enjoyed rowing, and back-packing around Europe and North andSouth America, and he met his wifeKathalijn, who was studying law.A job administering anaesthetics, in

his fourth year of studies, exposedhim tomany different types of surgery, and hepicked up on the challenge of cancer.“The complexity of oncology reallyappealed tome, particularly the balanceyou need to strike between doing exten-sive surgery to enhance cure and limitingprocedures to offer patients the bestquality of life. Thedifferent facets of can-cer surgery offered access to somanydif-ferent areas of medicine,” he says.The year he turned 25, Van deVelde

married, startedhis residency andgainedhis PhD. His thesis in breast cancer,looking at the role of lymph nodes, theextent of their removal and the value ofadjuvant chemotherapy, set the tone fora career in which investigating the con-cept of preoperative chemotherapy, hormone ther-apy and radiotherapy has been a dominant theme.

THE FUTURE IS NEOADJUVANTLastMay, he published the 10-year survival resultsof theEORTCstudy of preoperative chemotherapyinprimary operablebreast cancer.The studydemon-strated no survival differences (for either overall ordisease-free survival) betweenbreast cancer patientswho received chemotherapy preoperatively andthose receiving it postoperatively. Theuse of preop-erative chemotherapy, however,was accompaniedbyan increase in the rate of breast conserving surgery.Chemotherapy and hormone therapy prior to

surgerymakes ‘intuitive sense’, he says, as it permitsless extensive surgery and helps to prevent tumourspread. “Tumourmanipulation can lead to a showerof tumour cells, and animal studies have also shownthat, following surgery,metastatic cells divide fasterand have a higher labelling index.”

The general theme is one he has taken beyondbreast cancer into gastric and rectal cancer. Hehasn’t always found it easy to convincehis fellow sur-geons, however.At times, says van deVelde, he hasfelt like a ‘failed comedian’ when he has done thelecture circuits trying unsuccessfully to persuadeother clinicians to change their practice. “Breast andgastric cancer surgeons still find it really difficult todelay surgery,” he says.In gastric cancer he was a co-investigator of

theMAGIC trial (Medical research councilAdju-vantGastric InfusionalChemotherapy), publishedin 2006,which showed that chemotherapy prior tosurgery improved the resectability of stomach


Masterpiece

Action hero. Van de Velde, seen here on a student exchangewith the Israeli air force (front row, second from left), is sobusy nowadays that he cannot clock up sufficient hours tomaintain either his flying licence or his right to performcertain tricky surgical procedures

“Striking that balance between enhancing the cure

and preserving quality of life really appealed to me”

tumours by 10% and improved five-year survival by13%, making it the new standard of care.In rectal cancer he showed that, although total

mesorectal excision (TME) combinedwith preop-erative radiotherapy resulted in increased local con-trol, therewasmore long-termbowel dysfunction inirradiated patients. “But I’m increasingly hopefulthat the advent of more tailored therapy will soonallow us to select the patients who’ll benefit mostfrom treatment,” he says.Most recently he has been advocating preoper-

ative chemotherapy and hormone therapy in breastcancer prior to sentinel node biopsy, since it leadsto significantly less lymph node dissection andmorbidity for patients.In 1980 van de Velde and his wife spent six

months in the US, where he worked at the MDAnderson (Houston, Texas), and theNationalCan-cer Centre (Bethesda, Maryland). This proved aparticularly creativeperiod,mostnotablypursuinghisidea fordeveloping the techniqueof isolated liverper-fusion for patientswithmetastatic colorectalcancer. He got the idea from hearingabout isolated limb perfusion inmalignantmelanoma.Isolated liver perfusion is a

procedure in which acatheter is placed into theartery providing blood tothe liver, and a second isplaced in the vein takingblood away from the liver,thereby temporarily sepa-rating the liver’s blood sup-ply from theblood circulatingthroughout the rest of the body.The technique allows four timesthe maximum tolerated dose ofchemotherapy to be directed to the liver.Van de Velde also developed a safety valve, givinglabelled erythrocycteswith the treatment to spot anyleaks. If a problem developed, the chemotherapy

could immediately be flushed from the body.First he performed the procedure on pigs, often

sleeping in the lab with his animals, until finallymoving on to trials in patients. Results showed thatsurvival could be increased from seven monthsbefore isolated perfusion to 24months for patientsexposed to prior chemotherapy and 34months forchemotherapy naïve patients. But therewas disap-pointment that the technique did not have morepotential for cure, as can sometimes be achieved insurgery for liver metastases.“The logistics of the procedure were extremely

complex, since in addition to surgical teams weneeded separate teams to monitor for leakage,”says van de Velde, adding that with improvedchemotherapy now allowing survival with metas-tases to 20months, it is likely that thehey day of iso-lated liver perfusion has passed.

A TRIAL OF TECHNIQUESIn themid-1980s, van deVelde became aware that

Japanese surgeons were producing dramat-ically better outcomes in gastric cancersurgery than surgeons in theWest.After surgery, the five-year sur-vival for stage II disease was29% in theWest, comparedto 72% in Japan, and thefive-year survival for stageIII disease was 13% in theWest compared to 44% inJapan. The difference, hefound, was that Japanesesurgeons undertook moreextensive removal of lymphnodes and used wider surgicalmargins than the standard of care

employed in the West. “It seemed

The five-year survival for stage III disease

was 13% in theWest compared to 44% in Japan

Masterpiece

Who says clinical trials don’t work in surgery? Van de Velde,age 25, with his PhD thesis, which included the protocol forthe first breast cancer trial ever conducted in the Netherlands


obvious that we needed to teach our surgeons tooperate like the Japanese, but we needed to showthat survival differences were due to techniqueand not some fundamental racial difference in dis-ease,” he says.In 1985 van de Velde visited the National

Cancer Centre in Tokyo, working with KeiichiMaruyama, and theSeoulNationalUniversityHos-pital, SouthKorea,workingwith JinPokKim, to learnfor himself the Japanese way of performing thetechnique.With a better understanding of the pro-cedure, he initiated a project to bring Japanese sur-geons to theNetherlands, to teachDutch surgeonshow toperform the operation. In a randomised con-trolled trial – where the surgeons were randomisedto thedifferenthospitals – theywere able to compareoutcomes for the Japanese andDutchapproaches toperforming the surgery in the same racial population.But toundertake the trial they firstneededtostan-

dardise the Dutch approach to surgery. “Studiesshowed that patients died from recurrent diseasewhen the tumourmarginswere not big enough, butthatmore extensive surgery increased the likelihoodof theirdying fromcomplications,” says vandeVelde,whoover thepast 20 yearshas organisedmanyaddi-tional trials to define the optimumextent of surgery.One notable feature of the Japanese–Dutch

randomised trial was that the investigators bankedthe tissue– a very uncommonpractice in thosedays.Thismeans they are now able to look for candidatemarkers for selecting patients most likely to bene-fit frommore aggressive surgery.Despite hiswealth of experience, new ideas still

have the potential to excite vandeVelde.One of hisPhDstudentshas just discovered that damage to thelevator ani nerve – responsible formotor innervationto the levator ani muscle – explains why faecalincontinence often occurs following surgery forrectal cancer. The nerve was isolated when theresearcher correlated common areas of damage inpatients who developed incontinence after surgery,and mapped these directly to intact nerves in dis-sectionsof cadaverswhohaddied fromother causes.

“It’s so inspiring that in anolddiscipline like anatomywecan still bemaking discoveries in 2008 that havethe potential to make a real difference to patients’quality of life,” he says.Van de Velde is also involvedwith an innovative

project using a special camera system that can iden-tify light emitted by injected dyes capable of specif-ically targeting tumour cells. “This project has twopotential applications: it allows the visualisation oftumourmargins, thereby promotingmore accuratesurgery, and it also allows clinicians to see whethersentinel nodes have been invaded by cancer cellswithout having to open patients up,” he says.

A STRATEGIC SURGEONToday van de Velde leads a packed life, sitting onnumerous national advisory and clinical boards,teaching, lecturing, andpursuing his research activ-ities.He still operates one day aweek and sees out-patients on another day, although he no longertakes the lead onmore complex surgery.One of theironies of his quest for improving surgical stan-dards is that he cannot himself always undertakeenough annual procedures for quality control pur-poses. But he is happy to take more of a back seatin surgery, aware that through his internationalcommittee work and coordination of trials he canmake amore strategic contribution.He also exerts an influence in supervising PhD

students – to date he has supervisedmore than 50theses, ranging from surgery to immunology. “Mystudents are the potential surgery leaders of thefuture, and educating them well is one of the bestways of improving standards,” he says, adding thathe is achieving an evenwider sphere of influence onthenext generation through editing theDutch stan-dard textbook on oncology Leerboek Oncologie.On the national scene, he has been president of

the medical section of the Royal Academy of Sci-ences of theNetherlands, where he chairs a groupof 23 medical leaders from the Netherlands whocome together to prioritise medical developmentsand inform theMinister ofHealth.Hehas also been


Masterpiece

They can now look for markers for selecting patients

most likely to benefit frommore aggressive surgery

largely responsible for initiating national groups forbreast, gastric and colorectal cancer, that help totranslate the results fromclinical trials into nationalstandards of care, and has played a key role in therecent creation of the virtual Centre forMolecularMedicine – a joint initiative between academiaand industry that allows the sharing of resourcessuch as tumour banks.In Europe, he is set to become president of the

European Society of Surgical Oncology (ESSO) inSeptember, and is in theprocess of settingupaqual-ity assurance programme for Europe. The scheme,starting first with colorectal cancer, aims to ensurethat all patients get access to thebest treatments. “Inthe past protocols have just stated ‘surgery’, withoutappreciating that surgery is not all the same.For colo-rectal cancer, for example, there is a 10%differencein survival according to the country inwhich people are operated,” he says.At the EuropeanCanCerOrganisa-

tion (ECCO),where he is a boardmem-ber, he has been promoting interactiveworkshops, involving internationalexperts. “Oncologists attending theseworkshops canbe really inspired to intro-duce significant improvements in theirday-to-day care of patients,” he says.Life is undoubtedly hectic. “I don’t

have any time for a golf handicap, but Ikeep fit by walking my Labrador andcycling towork,” says van deVelde, whounwinds at weekends by tinkering withhis old Ferrari. Solo flying is no longerfeasible, he sayswith regret, as in recent

years he has not had time to put in the requirednumber of flying hours to guarantee his safety.Holiday time is particularly precious, though far

from relaxing. Van deVelde uses his annual leave toindulge his love of travel and try experiences that areas removed fromhis daily existence as possible. Lastyear hewas ship’s doctor on aRussian cruise ship totheNorth Pole, and next January he plans to repeatthe experience on a trip toAntarctica.Other recenttrips have included skiing in Canada with his wifeand their two adult sons, JanWillem, aged 27,whoworkswith an oil company andMichiel, aged 26, alawyer, and they have just returned from a trip toBotswana, where they hired a four-wheel drive toview elephants.His flying daysmay be over, but vande Velde remains above all an action man, both inhis professional and personal life.

“Colorectal cancer survival differs by 10% according

to the country in which people are operated”

Masterpiece


Family time. With holidays like this one,watching elephants in Botswana, it’s

little wonder that sons Jan Willem andMichiel opt to come along (the holidayhe spent as ship’s doctor on a Russiancruise to the North Pole, however, was

just him and wife Kathalijn)

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The neglected magic bulletUK health reporter asks: why the obsession with new cancer drugs?

The operating theatre isdimly lit andcompletelysilent apart from the

gentlebeepof theheartmonitor.Thepatient lies strangely angledwith his feet in the air, his headnear the ground. Around himare seven nursing and medicalstaff and three raised videoscreens, revealing the intima-cies of his organs. And abovehim looms a large spider-likeobject wrapped in transparentplastic, its arms passing intosmall holes in his abdomen.

I’mwitnessing surgery con-ducted by the amazing Da Vinci robotic surgeon atAddenbrookesHospital,Cambridge.Despite its for-bidding appearance, it is themost advancedpieceofsurgical equipment in the UK, offering the man onthe table a chance of recovery from prostate cancerthathewouldneverhavehadfiveyearsago.He ishav-ing his prostate gland removed because of a cancer-ous growth.But there is noneed for thepatient tobe‘opened up’. The three abdominal holes accommo-dateDaVinci’s camera armand twooperating arms.To the sideof them, twomoreabdominalholes allownurses to drain fluids, feed in clips to stembleedingand push organs out of theway.

Controlling the robot at a console four metres

from the patient is the cancersurgeonProfessorDavidNeal,his headpressed against stereo-scopic eyepieces conveying3-D pictures of the abdomen’scontents from the central cam-era leg of Da Vinci: the robot’seyes are his eyes throughoutthe surgery. ProfessorNeal tellsme it’s like having your headinside the patient. His handsare swivelling, tweaking andpinching joystick-style controls,controlling the tiny robotic

hands at the end of Da Vinci’s two other arms. Helooks more like a seamstress than a surgeon.

Everymovement hemakes is scaled down intothe far smaller, shakeless,movementsmade by the7-mm, multijointed pincers, deep inside thepatient’s abdomen. You can see everything in highmagnification on those screens above, though to theuntrained eye it’s hard to tell bladder frombowel, abit of fatty tissue from amajor vein.

ProfessorNeal, aCancerResearchUKprofessorof surgical oncology, isworkinghiswaydownfromthemiddleof theabdomen,past thebladder, to its deep-est recesses in the pelvis, where the prostate islocated.Gravityhaspushed theupside-downpatient’s

Surgery still offers by far the best hope of a cure in solid tumours.Yet patients are being let down

by too great a focus on drugs at the expense of investment in surgical equipment and training,

argues Simon Crompton, in an article for the The Times that won him a Best Cancer

ReporterAward, and is reprinted below.

Simon Crompton

BestReporter


bowels out of theway, up under the ribcage.There’s the occasionalmagnifiedwhoosh of red

asProfessorNeal nicks a blood vessel and,more sur-prisingly, little puffs of smoke. The little robotichands have super-heated edges, which mean theyburn through tissue (rather than actually cutting it)and cauterise veins as they go. It’s quite over-whelming on the senses. The burning tissue lookslike pork crackling and there’s a whiff of burntmeat. My vision starts to bleach and my headbegins to whirl. I have to sit down for a minute.

Eventually, an hour into the operation, the

prostate is revealed, a crimson globe sitting behinda deflated bladder. Now comes the tricky bit. Tra-ditionally, one of the great problems of removing aprostate gland affected by cancer is that the nervescontrolling urination and penile erection are tightlyand intricately wrapped around it. Removing theprostate the conventionalwaymeans cuttingnerves,often resulting in impotence or incontinence.

But so dextrous areDaVinci’s cuttinghands, andso clearly visible is the noodle-like mesh of nervesattaching to the prostate, that it can be detachedintact before the prostate is removed. “Outcomesaren’t greatwhen you remove theprostate using con-ventional open surgery,” says ProfessorNeal. “Afterfour years, half of men will have lost erections, orcontinence, or their cancerwill have returned. Butwith this type of surgery, 90% of patients are com-pletely dry. The finer dissection that robotic surgeryallows means that patients are more comfortableafter the operation, there are fewer complicationsand they get better more quickly.”

Professor Neal has conducted 230 radicalprostatectomies at Addenbrookes using Da Vincisince itwas bought three years ago.Remarkably, halfof Professor Neal’s prostate operation patients gohome the next day. “My star patientwas back onhistractor in a week.”

This is one of only six Da Vinci machines in theNHS [UK National Health Service], comparedwith350operating in theUnitedStates. If such sur-gery were to become more widely available, the

THE MAN ON THE OPERATING TABLE WAS...

...Michael Mills, 65, a building contractor from Cambridge.“The prostate cancer was picked up after a routine health check. Thespecialists said I might be OK for 15 years and there didn’t seem tobe any spread outside the prostate, but I didn’t want it hanging overme. When I was told that recovery was quicker with robotic surgery,I thought that was a good reason to go for it.“I went in to hospital on Monday, had the operation on Tuesday, andwent home on Wednesday lunchtime. I’ve had no pain at all and nota single painkiller. It was a little uncomfortable where the holes inmy abdomen were. The only problem I’ve had is controlling my urine,but that seems to be getting better.“I was back to work in three weeks. To be honest, I feel as if noth-ing has happened.”

Discussion point: Articles like this one helppromote public debate and politicalaccountability around the best use of limitedhealth resources. Video footage of the operationgave readers the chance to see the operation forthemselves http://www.timesonline.co.uk/tol/life_and_style/health/article3728811.ece


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implications for men with prostate cancer could beprofound. On diagnosis, only 20% of men opt forprostate removal. Because many tumours are slowgrowing, specialists often recommendwatching andwaiting, andnot risking thepermanent sexual anduri-naryproblems that surgery canbring.But this causesuneasiness inmanymen,who simplywant to be ridof thecancer.DaVinci changes theodds, andmakesprostate removal amore feasible ‘play it safe’option.

Now Professor Neal is pushing, dabbing andstroking the prostate as he cuts it away, detaching itfrom theurethra (whichpasses through it), pushingit away from thebig veins comingup from thepenis.Finally, it’s released. “Just pop it upunder the ribs fornow,” he tells the nurses, andusing keyhole probes,theymanipulate it into a plastic bag, and push it up

out of sight of the camera. (After the operation,they will pull it out, through one of the keyholes.)

Meanwhile, Professor Neal has more intricatework to do. He has to remove lymph tissue in casethere are any cancer cells there and, finally, stitch thebladder back to the urethra. It’s incredibly fiddlywork, but the tiny robotic hands, holding a needleandwinding thread into loops and knots, work fast.Robotic surgery minimises blood loss and transfu-sions are rarely required. The patient lying in frontofmehas lost less than100ml of fluids – just a smallwine glass full – during the operation.

After an intense two hours, the operation over,Professor Neal takes me for a cup of tea and a bis-cuit – his lunch before the nextDaVinci operationbegins in just over an hour.

Why arewe so obsessedwith new can-cer drugs? Surgery is the real and unac-knowledged hero in the battle againstcancer, according to an increasing num-ber of experts, including the [UK]HealthMinister LordDarzi. They pointout that only 10% of cancers are curedby drugs, while surgery cures half.

Currently, the £700 million [€885million] spent annually by theNationalHealth Service on cancer drugs dwarfsthe amount spent on surgery. Yet inno-vative techniques such as robotic sur-gery not only improve survival andquality of life for peoplewith cancer butgive more bang to the NHS buck thanexpensive drugs.

“Local therapies such as surgeryand radiotherapy cure ten times asmany people as chemical means,” saysProfessor Gordon McVie, a seniorconsultant at the European Instituteof Oncology in Milan and formerdirector of the Cancer ResearchCam-paign. “Medical oncologists get all themoney spent on them, but the sur-geons are the unsung heroes. Surgery

is more cost-effective and, if donewell, it has a significant effect onimproved quality of life.”

In the past decade there have beenvast improvements in surgery. Increas-ing expertise in cancer surgeons, thedevelopment of keyhole (lapara-scopic) surgery and, perhaps mostspectacularly, the rise of the robothave meant that cancers can beremoved far more cleanly, with lesstrauma, than ever before. There’s evi-dence that this is having an impactnot just on how long people are livingbut, arguably more importantly, onthe quality of the rest of their life.

In prostate cancer, for example, thepinpoint accuracy of theDaVinci robotin removing the prostate glandwithoutdamaging surrounding veins, nervesand tissuemeans that patients are freeto get onwith their liveswithin days andare considerably less likely to suffer thedisabling side-effects that often accom-panied traditional surgery, such asincontinence and impotence. The suc-cess of this, and other newkeyhole sur-

gery techniques, has contributed to a335% rise in prostate cancer surgeryrates in the past ten years. Recent trialshave also indicated the efficacy of DaVinci at performing radical hysterec-tomies for gynaecological cancers.

In bladder cancer there has been adrop in mortality rates of about 10% inthe past 15 years, partly as a result ofmore advanced surgical techniquesbeing used to remove lymphnodes thatmay carry cancer cells.

And the fact thatmore surgeons arechoosing to specialise in operating onparticular types of cancer has also had awide effect on cancer mortality andcomplication rates. The number ofpatients dying in hospital after removalof oesophageal cancer halved between1997 and 2005, largely because thesurgery was increasingly performed byspecialists rather than generalists,according to theDepartment ofHealth.

Yet the money allocated to advanc-ing surgical practice can pale intoinsignificance comparedwith newcan-cer drugs. The NHS spent about

Cancer drugs or surgery? There really is no contest

�

£100 million [€125 million] on thebreast cancer drugHerceptin in 2006,but some estimates say that only about500 patients actually benefited. Thatkind ofmoney could train hundreds ofsurgeons to specialise in the latesttechniques, or transform research intonew surgical techniques each benefit-ing thousands of people. OneDaVincimachine costs £1 million [€1.25 mil-lion] to buy and maintain over fiveyears, helping hundreds of cancerpatients in that time.

“The thing that is improving cancercure rates is specialised surgeons focus-ing on particular operations, doingthem more often and getting better atthem,” says David Neal, the CancerResearch UK Professor of SurgicalOncology at Addenbrookes Hospital,which houses one of the six Da Vincirobots in the UK. “But until five yearsago there weren’t the surgeons heretrained to do prostate removal properly.Surgery needs an investment of timefor training in the latest techniques.

“I get fed up with the currentemphasis on cancer drugs. It gets for-gotten that surgery is the single mosteffective treatment for cancer. TheNHShas fallen behind on equipment.In the US, 65% of radical prostatec-tomies are done using a robot. InEurope it’s one in three. But here it’sjust 1% or 2%.”

Professor Neal has high-level sup-port. Cancer experts such as ProfessorMcVie and Karol Sikora, a professor ofcancer medicine and honorary con-sultant oncologist at HammersmithHospital, in West London, point outthat the days of discovering block-buster drugs helpingmillions of people

are gone, and drug development isbecoming increasingly focused on spe-cialist drugs that will help ever-smallergroups of people.

There are signs that the contributionof surgery to curing cancer may finallybe acknowledged. LordDarzi, the con-sultant surgeon at St Mary’s Hospital,London, who introduced the Da Vincirobot to the UK, is a Health Minister.His input is clear in the Government’snew Cancer Plan, with proposals toestablish a new programme to trainmore surgeons in laparascopic surgery.The Department of Health has prom-ised a £250 million [€315 million]investment in ‘capital equipment’ forcancer over the next three years, buthowmuch of that will be spent on sur-gery is as yet unclear.

As both aminister and a director ofthe new Hamlyn Centre for robotic

surgery research at Imperial CollegeLondon, Lord Darzi has to tread acareful line. But he says he agrees thatthe amount invested in surgery is“minuscule”.

He would like to see much moremoney going into research into theeffectiveness of new surgical tech-niques, then the case for investing inrobotic and laparascopic techniqueswould be unanswerable.

“People don’t realise that their onlychance of a cure from cancer isthrough an operation that removes itcompletely,” he says. “There has alwaysbeenmore emphasis on drugs becausethe pharmaceutical lobby is so strong.We’ve got to remember that in phar-maceuticals we have yet to find amagic bullet that has the potential tocure most cancers. But in surgery wealready have that.”


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This article was first published in Body&Soul, The Times (www.timesonline.co.uk) on 12 April 2008, and is reprinted with permission

©2008

INTUITIVESU

RGICAL,INC

ImpactFactor

Adjuvant EBRT improves survival inpatients with lymph-node-negativepancreatic cancer� Lisa Hazard, Jonathan Tward and Dennis Shrieve

Though the role of radiation therapy in the adjuvant treatment of pancreatic cancer remains

controversial, a recent large retrospective study indicates that radiation is associated with

improved survival.

Therole of adjuvant external-beamradiotherapy (EBRT) for thetreatment of pancreatic adeno-

carcinoma remains controversial.A ran-domised trial by the GastrointestinalStudy Group demonstrated a survivalbenefit with the addition of chemora-diotherapy to surgery, and a randomisedtrial by the European Organisation forResearch andTreatment ofCancer alsoshowed a trend towards improved sur-vivalwith adjuvant chemoradiotherapy.1,2

On the other hand, a randomised trial bythe European Study Group for Pancre-aticCancer (ESPAC),which comprisedfour adjuvant treatment arms (observa-tion, chemotherapy alone, radiother-apy with concurrent chemotherapy,and radiotherapy with concurrentchemotherapy followedbymaintenance

chemotherapy),3 revealed that the sur-vival of patientswho received radiother-apy (with or without maintenancechemotherapy) was inferior to that ofpatients who did not receive radiother-apy. The authors of this report concludedthat radiotherapy haddeleterious effectson survival.

The reasons for the decrease in sur-vival in patients receiving radiotherapyon the ESPAC trial remain unclear.Radiation was not reported to increasetreatment-relatedmortality, but late radi-ation toxicity is difficult to report accu-rately because it can be difficult todifferentiate from symptoms of a pro-gressive tumour, andpatientsmaybe lostto follow-up. The ESPAC trial did notdescribe radiation field size and tech-nique, and central review of radiation

plans was not required. The RadiationTherapy Oncology Group (RTOG) hasreported that amajor deviation from theprotocol-defined radiation therapy planwas associated with inferior survival forpatientswith pancreatic cancer enrolledon the RTOG 97-04 trial, suggestingthat radiation technique is important.4

The current study based on theSEER registry by Artinyan et al. (seeopposite) demonstrates that the addi-tion of radiotherapy to surgery inpatients with T1–3N0M0 pancreaticadenocarcinoma is associated withimproved survival. Limitations of theSEER registry include its retrospectivenature and lack of information regard-ing surgical-margin status and the useof chemotherapy. In addition, it is notpossible to determine any bias in the

Lisa Hazard is an assistant professor, Jonathan Tward is a resident, and Dennis Shrieve is professor and chair of the Department of Radiation Oncology at the Huntsman CancerHospital, University of Utah School of Medicine, Salt Lake City, Utah, USA. This article was first published online in Nature Clinical Practice Oncology on 24 June 2008, and isreproduced with permission. www.nature.com/clinical practice, doi:10.1038/ncponc1163, © 2008 Nature Publishing Group


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selection of patients for radiotherapy.For example, patients who do not havemajor health problems could be morelikely to receive radiation, thereby bias-ing survival rates in favour of patientswho receive radiation. Alternatively,patients who have high-risk featuresnot assessed in the SEER studymay bemore likely to receive radiation, biasingresults against radiation.

Given the limitations of the SEERregistry, the results of this study do notanswer thequestion ofwhether the addi-tion of radiotherapy to chemotherapyimproves survival.

The study does, however, suggest

that, at a minimum, radiation is notdetrimental to survival, as suggested bythe ESPAC study.

In the current study, improvement insurvival with radiotherapywas observedregardless of T stage on multivariateanalysis, although improvement in sur-vival was limited to patients with T3disease onunivariate analysis.Using theSEER registry data, Hazard and co-authors did not detect a survival benefitof radiotherapy and surgery in patientswith T1–2N0M0.5

It is possible that T3 disease is asso-ciated with a higher probability of mar-gin positivity, and the benefits of

radiotherapy are, therefore, greater. Itis also possible that patients with T1–2N0 disease who receive radiotherapyare more likely to have high-risk fea-tures, thereby limiting the potential sur-vival benefit of radiotherapy.

In summary, this study indicates thatadjuvant radiotherapy is an acceptabletreatment for pancreatic adenocarci-noma that warrants continued investi-gation; only a randomised trial candetermine whether or not the use ofradiotherapy improves survival.

Details of the references cited in this article can

be accessed at www.cancerworld.org/magazine


SynopsisAvoArtinyan,MiniaHellan, PabloMojica-Manosa et al. (2008) Improved survival with adjuvant external-beam radiation ther-apy in lymph node-negative pancreatic cancer: a United States population-based assessment.Cancer 112:34–42Background.Theprognosis for patientswith lymph-node negative (N0) pancreatic cancer is very poor, with low survival rates aftercurative resection.Adjuvant treatment regimens consisting of chemotherapy, radiotherapy or a combination of both have beenusedto improve survival; however, the role of adjuvant radiation therapy is unclear.Objective.To assess the benefit of adjuvant external-beam radiation therapy (EBRT) in patientswith locally confined lymph-node-negative pancreatic cancer.Design and intervention.This study used the Surveillance, Epidemiology andEndResults (SEER) registry to identify patientswho had undergone surgery for histologically confirmed, node-negative, invasive pancreatic cancer during the period 1988–2003.Patients whose tumourswere excised orwho had extensive pancreatic andmultiorgan resectionswere included. Patients who hadundergone biopsies, exploratory surgeries or lymph-node dissections alone and patientswith no lymphnodeswere excluded.A totalof 1,930patientswere included in the analysis. Kaplan–Meier analysiswasused to compare the survival rates of patientswho receivedEBRTwith those of patients who did not.MultivariateCox regression analysis was used to determine the prognostic significanceof adjuvant EBRT.Outcome measures.The primary end point was overall survival (OS). The administration of adjuvant EBRTwas themain prog-nostic factor of interest.Results.ThemedianOS for thewhole study population was 17months. Patients who received adjuvant EBRThad significantlybetter survival than patients who did not (medianOS20months vs 15months;P<0.001). Univariate regression analysis revealedthat adjuvant EBRTwas significantly associatedwith survival (hazard ratio [HR] 0.75, 95%CI 0.67–0.84;P<0.001).Age at diag-nosis, and tumour location, grade and classificationwere all associatedwith survival.Multivariate analysis revealed that EBRTwasassociated with an approximately 30% reduction in the risk of death (HR 0.72, 95% CI 0.63–0.82; P<0.001). With each year ofincreasing age therewas an approximate 1% increase in the risk of death (HR1.01, 95%CI 1.004–1.016;P<0.001). Kaplan–Meiersurvival curves showed that after the exclusion of patientswith less than 3months survival, therewas no difference inOSbetweenpatientswhodid andpatientswhodid not receive adjuvantEBRT (median 20months vs 19months;P=0.14); however,multivariateanalysis showed that adjuvant EBRT was an independent predictor of improved OS (HR 0.87, 95% CI 0.75–1.00; P=0.044).Conclusion.Adjuvant EBRT provided a survival benefit to patients with operable, node-negative pancreatic cancer and shouldbe considered as adjuvant treatment in this group of patients.Acknowledgement: The synopsis was written by Mandy Aujla, Associate Editor, Nature Clinical Practice.

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Lenalidomide plus dexamethasoneis efficacious in patients with relapsedor refractory multiple myeloma� Nikhil Munshi, Constantine Mitsiades, Paul Richardson and Kenneth Anderson

Two recent studies have shown that lenalidomide in combination with high-dose dexametha-

sone is significantly more effective than high-dose dexamethasone alone in patients with

relapsed multiple myeloma.

Lenalidomide is a more potentanalogue of thalidomide thatdirectly induces apoptosis of

multiple myeloma (MM) cells andinhibits interactions between MMcells and bone-marrow-stromal cells.In addition, lenalidomide blocksboth the constitutive productionof cytokines and the production ofcytokines induced by the binding ofMM cells to bone-marrow-stromalcells. In blocking cytokine produc-tion, lenalidomide mediates MM-cellgrowth and survival, inhibits angio-genesis, and upregulates natural killerand T-cell responses against MMcells.1 On the basis of preclinical effi-cacy, phase I and II clinical trials havedemonstrated that 25 mg lenalido-mide given for 21 days of a 28-daycycle is well-tolerated and inducesresponses in over 30% of patients withrelapsed MM. Moreover, these

responses are enhanced by the addi-tion of dexamethasone.2 On the basisof these exciting results, two ran-domised phase III trials were con-ducted that compared lenalidomideplus high-dose dexamethasone withhigh-dose dexamethasone plus placeboin patients with relapsed or refractoryMM. Both the NorthAmerican studybyWeber et al. (n=353)3 and the inter-national study by Dimopoulos et al.(n=351; see opposite) confirmed thatthe combination regimen was signifi-cantly superior to dexamethasone interms of response rate, time to pro-gression and overall survival.

In the North American study,3

those receiving lenalidomide had sig-nificantly improved partial and com-plete response rates (61% and 14.1%,respectively) and time to progres-sion and overall survival were signifi-cantly prolonged (11.1 months and

29.6 months, respectively). The cor-responding partial and completeresponse rates in those receiving dexa-methasone were 19.9% and 0.6%,respectively, and time to progressionand overall survival were 4.7 monthsand 20.2 months. The results of theDimopoulos study were very similar.Oral lenalidomide plus dexametha-sone was active in patients who hadpreviously received bortezomib, high-dose therapy and stem-cell transplan-tation, or thalidomide. A tolerabletoxicity profile was observed in bothstudies. These studies provided thebasis for the rapid approval of lenalido-mide plus dexamethasone by the FDAand the European MedicinesAgencyfor the treatment of patients withrelapsed MM following initial induc-tion therapy.

Notably, the study by Dimopouloset al. confirmed that deep vein

Nikhil Munshi is the associate director and Paul Richardson is the clinical director of the Jerome Lipper Multiple Myeloma Center, and Constantine Mitsiades is an instructor inmedicine at the Department of Medical Oncology, all at the Dana-Farber Cancer Institute, and Kenneth Anderson is the chief of the Division of Hematologic Neoplasia and the KraftFamily Professor of Medicine at Harvard Medical School, Boston, Massachusetts. For a declaration of competing interests, please see www.cancerworld.org/magazineThis article was first published in Nature Clinical Practice Oncology vol. 5 no. 7, and is reproduced with permission. www.nature.com/clinical practice, doi:10.1038/ncponc1151,© 2008 Nature Publishing Group


SynopsisM Dimopoulos, A Spencer, MAttal et al. (2007) Lenalidomide plus dexamethasone for relapsed or refractory multiplemyeloma.NEngl JMed 357:2123–2132Background. Lenalidomide is a more-potent and less toxic derivative of thalidomide. When lenalidomide is combined withdexamethasone this combination is more effective than either agent alone in the treatment of refractory myeloma.Objective. To investigate the efficacy of lenalidomide plus dexamethasone in patients with relapsed or refractory myeloma.Design.Thismulticentre, randomised, placebo-controlled phase III trial recruited 351patientswithmultiplemyeloma (MM) fromcentres in Europe, Israel and Australia between September 2003 and September 2004. All patients had received at least oneprevious antimyeloma treatment.Other eligibility criteria included age at least 18 years, anEasternCooperativeOncologyGroupperformance status of 2 or less and an absolute neutrophil count of at least 1,000mm3. Patientswho experienceddisease progressionwhile being treated with high-dose dexamethasone or who had hypersensitivity to previous treatment with thalidomide or dex-amethasone were excluded.Intervention. Patients were randomly assigned to receive either 25mg oral lenalidomide (n=176) or placebo (n=175) on days1 to 21 of a 28-day cycle.All patients received 40mg oral dexamethasone on days 1 to 4, 9 to 12, and 17 to 20 for four cycles; afterthe fourth cycle, dexamethasone was administered on days 1 to 4 only. Patients continued to receive the assigned regimen untildisease progression or the development of unacceptable toxic effects.Outcome measures. Time to disease progression was the primary endpoint of this trial. Secondary endpoints included overallsurvival, rate of response and safety.Results.Themedian time to progressionwas significantly longer in patients treatedwith lenalidomide plus dexamethasone thanin patients treated with placebo plus dexamethasone (11.3 months vs 4.7 months; P<0.001; hazard ratio for time to progression2.85). In total, 106 patients in the lenalidomide group achieved at least a partial response, comparedwith 42 patients in the placebogroup (P<0.001). A complete response was achieved in 28 patients receiving lenalidomide and in 6 patients receivingplacebo (P<0.001). The median duration of response in the lenalidomide group was 16.5 months compared with 7.9 months inthe placebo group (P=0.02). Patientswho received lenalidomide had significantly improved overall survival (hazard ratio for death0.66;P=0.03).Ahigher incidence of grade3neutropenia, grade 3 or 4 thrombocytopenia and venous thromboembolismwas reportedin the lenalidomide group than in the placebo group.Conclusion.The combination of lenalidomide plus dexamethasone ismore effective than high-dose dexamethasone alone in thetreatment of relapsed or refractory MM.Acknowledgement: The synopsis was written by Mandy Aujla, Associate Editor, Nature Clinical Practice.

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thrombosis is an important side-effectof lenalidomide and that optimumprophylactic anticoagulation is req-uired.4 In this study, high-dose dex-amethasone was used at 40 mg ondays 1–4, 9–12 and 17–20 for the firstfour cycles of treatment. A recentEastern Cooperative Oncology Groupstudy in patients with newly diagnosedMM has shown a survival advantagewith the combination of lenalidomideplus low-dose dexamethasone (40 mgonce a week) versus lenalidomide plushigh-dose dexamethasone.5 This find-ing raises the question as to whether aweekly dose of dexamethasone could

be used in combination with lenalido-mide to treat relapsed MM.

Ongoing studies are evaluating theuse of lenalidomide as maintenancetherapy after induction therapy ortransplantation. Moreover, it is nowbeing combined with melphalan andprednisone to treat newly diagnosedpatients who are not transplantationcandidates.6 Lenalidomide is alsobeing combinedwithmonoclonal anti-body therapy to enhance antibody-dependent cellular cytotoxicity.Finally, preclinical studies showinginduction of dual apoptotic signalingand synergistic cytotoxicity have led to

investigations into the combinationof lenalidomide with bortezomib. Thecurrent study provides further clinicalvalidation of the novel treatment par-adigm – targeting the MM cell in itsbone marrow microenvironment toovercome drug resistance to conven-tional therapy. These studies repre-sent a key advance in the treatment ofMM and an extraordinary exampleof rapid, collaborative bench-to-bedside research to improve patientoutcome in MM.

Details of the references cited in this article can

be accessed at www.cancerworld.org/magazine


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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

Prognostic scores canguide treatment insome pancreatic cancers� Annals of Surgery

Prognostic scores can be used to predictoutcomes and guide adjuvant treatment in

pancreatic neuroendocrine tumours (PNETS),concludes a US study.

PNETs – also known as neuroendocrinecarcinomas or islet cell neoplasms – have apoorly defined natural history. In contrast topancreatic adenocarcinoma, PNETs (whichaccount for just 3% of all pancreatic neo-plasms) have a more indolent tumour biology,aremore amenable to resection, and showbet-ter long-termsurvival. However, the relative rar-ity of the disease has limited the identificationof factors affecting survival after resection.Single-institution studies have identified con-flicting factors associatedwith outcomes afterresection,with the result that awidely acceptedstaging system to provide prognostic informa-tion does not currently exist for PNETS.

In the current study, Karl Bilimoria and col-leagues fromNorthwesternUniversity (Chicago,Illinois), identified 3,851 patients from theNational Cancer Data Basewhohadundergoneresectionof PNETs between1985and2004. Theobjective of the studywas to assess the clinico-pathologic features of resected patients, deter-mine long-termsurvival andexaminethepatient,tumour, treatment and hospital characteristicspredicting outcome after resection. Ultimately,

� Prognostic score predicting survival after

resection of pancreatic neuroendocrine tumors.

Analysis of 3851 patients. KY Bilimoria, MS

Talamonti, JS Tomlinson et al. Ann Surg March

2008, 247:490–500

Percutaneous radiofrequencyablation shows promisein lung tumours� Lancet Oncology

Percutaneous radiofrequency ablation – aminimally invasive treatment technique that

heats anddestroys cancer cells – achieves ahighrate of sustained complete response in selectedpatientswith lung tumours, according to resultsfrom the first prospective study of patientstreatedwith the technique.

Surgical resection, the standard of care forearly-stagenon-small-cell lungcancer, achievesfive-year survival ratesgreater than50%.Patientsunfit for surgerymaybe treatedwith radiother-apy, with five-year survival rates of up to 27%.

Surgical resection of pulmonary metas-tases has been shown to improve survival inselected patients. However, only a fewpatientscan undergo resection because of the extentand location of tumours in the lungs, tumourselsewhere in the body or concurrent medicalconditions. The high risk of cancer recurrenceand theneed to remove functioning lung tissuetogether with the cancerous tissue furtherrestricts the use of surgery for lung cancers,

the team looked to develop prognostic scoresbased on these predictive factors.

Results showedthat the five-yearoverall sur-vival for the3,851patientswhounderwentpan-createctomy for PNETs was 59.3% and that the10-year survival was 37.7%. Five-year survivalvaried according to histologic subtype – 58.3%forneuroendocrine carcinoma,67.3%for insuli-noma, and51.4%forglucagonoma. In thePNETpost-resectionprognostic score, the teamfoundthat age, tumour grade and distant metastaseswere the most powerful prognostic factors forpatients undergoing resection.

Tumour functionality and the typeof resec-tionwere also found to be independent predic-tors of survival after resection, but gender, race,socioeconomic status, tumour size, nodal status,margins, adjuvant chemotherapy and hospitalpancreatic surgery volumewerenot found tobeassociated with survival. From these data theteam developed a PNET post-resection prog-nostic score taking into account age, grade anddistantmetastases.

For patients with complete information onage, tumour grade and distant metastases, aprognostic score was calculated, with five-year survivals for three score groups. The five-year observed survival was 76.7%, 50.9% and35.7 % for each of the three groups; this pro-duced a P-value of <0.0001 for each pair-wise comparison.

“The prognostic scorewill provide informa-tion regarding expected survival, assist in adju-vant treatment decisions and allow for patientstratification for clinical trials,”write theauthors.

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so new treatment techniques are needed.Percutaneous radiofrequency ablation uses

imaging techniques such as ultrasound or CT toguide a needle electrode into a tumour. High-frequency electrical currents are then passedthrough the electrode, generating heat thatdestroys the abnormal cells.

Researchers assessed the effects of percu-taneous radiofrequency ablation in a seriesof 106 patients with 183 small lung tumours.The tumours included non-small-cell lungcancers in 33 patients, metastases from co-lorectal carcinoma in 53 patients and metas-tases from other types of cancers in 20patients. All of the patients were considered bytheir doctors to be unsuitable for surgery,radiotherapy or chemotherapy.

The patients were treated with radiofre-quency ablation and followed up for two years.A complete response in target tumours lastingatleast one year was achieved in 75 of the 85assessablepatients (88%).Overall survival at oneyear was 70% (95% CI 51%–83%) and at twoyears was 48% (95%CI 30%–65%) in patientswith non-small-cell lung cancer. Cancer-specific survival was higher – 92% at one yearand 73% at two years, meaning that mostpeople who died during the study died due tocauses other than cancer.

Survival was similar in the patients withcolorectal metastases (89% at one year and66%at twoyears) and in thosewithothermetas-tases (92% at one year and 73% at two years).Cancer-specific survival at two years was 68%and 67% for these two groups, respectively.

The safety profile of the procedure wasconsidered acceptable, with no deaths or life-threatening complications associated withradiofrequencyablation. Themajorcomplicationsincludedpneumothorax in27patients andpleu-ral effusion needing drainage in four patients.None of the patients suffered significant wors-ening of lung function.

The researchers, led by Riccardo Lencioni,associate professor of radiology in the Divisionof Diagnostic and Interventional Radiology attheUniversity of Pisa, Italy, said: “Percutaneousradiofrequency ablation yields high propor-tions of sustained complete responses in prop-

erly selected patients with pulmonary malig-nancies and is associatedwith acceptablemor-bidity.” They commented that the92%two-yearcancer-specific survival achieved in patientswith stage I non-small-cell lung cancer waspromising, and comparable with the rateachievedwith radiotherapy. “A randomised con-trolled trial comparing radiofrequency abla-tion with standard non-surgical treatmentoptions is now warranted to prove the clinicalbenefit of this approach,” they conclude.

� Response to radiofrequency ablation of

pulmonary tumours: a prospective, intention-to-

treat, multicentre clinical trial (the RAPTURE

study). R Lencioni, L Crocetti, R Cioni et al. Lancet

Oncology July 2008, 9:621–628

Physiotherapy-guided pelvicfloor training aids continenceafter prostate surgery� European Urology

Pelvic floormuscle training helps regain uri-nary incontinence significantly betterwhen

guided by a physiotherapist thanwhenpatientstrain on their own, concludes a Norwegianstudy in men who had undergone radicalprostatectomy.

Postprostatectomy urinary incontinence,which occurs in between 7% and 87%ofmenundergoing prostatectomy, is most oftencaused by dysfunction of the urethral sphinc-ter from injury of either the striated musclefibres or the innervating nerve fibres. Increas-ing the strength of the pelvic floormuscles cansupport the voluntary sphincter muscle andincrease blood supply.

An earlier study showed that 88% of menwith postprostatectomy urinary incontinenceparticipating in a pelvic floor re-education pro-gramme (involving active pelvic floor muscleexercises, biofeedback and additional electricalstimulation)were continent threemonths aftersurgery, comparedto56%inacontrolgroupwhodidnotundergo treatment. This raised theques-tion of whether the same results could have

beenachieved from interventionswith less time-consuming follow-up by physiotherapists.

In the current study, Mari Overgard andcolleagues from St Olav’s Hospital and Trond-heimUniversity Hospital (Trondheim, Norway),set out to assess the effects of intensive andfrequent pelvic floor muscle training, bothwith andwithout follow-up instructions froma physiotherapist.

In the study, 85menwith clinically localisedprostate cancer, operated on between Septem-ber 2005 and December 2006 at St Olav’sHospital, were randomly allocated to two inter-vention groups.

The 42 patients randomised to group Afollowed a pelvic floor muscle exercise courseconsisting of intensive pelvic floor muscletraining guided by a physiotherapist for 45minutes once aweek. Patients were instructedto perform three sets of 10 contractions dailyat home.

The 43 patients randomised to group Breceived oral and written descriptions of thepostoperative trainingprogramme,withencour-agement toperform three sets of 10pelvic floormuscle contractionsdaily. Theprimaryoutcomemeasure of the study was self-reported conti-nence/incontinence at three months after sur-gery, with continence defined as the absence ofuse of continence pads.

Results at sixmonths showedaclinically rel-evant difference in continence status – 79% ofpatients ingroupAwere continent compared to58% ingroupB (P=0.061). At 12months92%ofpatients in group A were continent, comparedwith 72% in group B (P=0.028).

“Our findings suggest that in patients withpostoperative incontinence, follow-up instruc-tions by a physiotherapist increase long-termadherence to pelvic floor muscle training andthereby improvecontinence ratesover timemorethan informationprovided topatients for train-ing on their own,” conclude the authors.

� Does physiotherapist-guided pelvic floor muscle

training reduce urinary incontinence after radical

prostatectomy? A randomised controlled trial.

MOvergard,AAngelsen, S Lydersen et al.European

UrologyAugust 2008, 54:438–448

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Five biomarkers bestat identifying basal-like breast cancer� Clinical Cancer Research

Includingmarkers for epidermal growth factorreceptor (EGFR) andcytokeratin5/6 (CK5/6) inaddition to the ‘triple-negative phenotype’ inmicroarraypanels results in a significantly betteridentification of basal-like breast cancer, con-cludes a Canadian study.

Basal-likebreast cancer–whichaccounts forapproximately 15% of all breast cancers – isassociated with mitotically active high-gradeinvasive tumours,whichaffect youngerpatientsand have a poor prognosis. Identifying thesetumours would help target a cohort of breastcancer patients who require more aggressivesystemic therapy.

Clinically, a triple-negativephenotype (TNP)– i.e. testing negative for oestrogen receptor(ER), progesterone receptor (PR), and HER2 –has been used to identify basal-like breastcancer.While the TNP is convenient, since it usesbiomarkers routinely ordered during the clinicalwork-upofbreast cancerbiopsies, theadditionofEGFR and CK5/6 has been shown to identifybasal-like tumours from gene microarrays with100%specificityand76%sensitivity. Thecurrentstudy by Maggie Cheang and colleagues, fromtheVancouverCoastalHealthResearch Institute(BritishColumbia, Canada) and theUniversity ofNorthCarolina (ChapelHill,NorthCarolina,USA),set out to compare the prognostic value of thethree and five biomarker panels in identifyingbasal-like breast cancer.

In the study, tumours from 4,046 womenreferred to the British Columbia Cancer Agencybetween1986and1992wereassembled into tis-suemicroarrays. Allwere accompaniedby infor-mation on staging, pathology, treatment andoutcome,withamedian follow-upof12.5 years.

Among3,744 interpretable cases, 17%werefound to be basal using the triple-negative def-inition (with a 10-year breast cancer death spe-cific survival of 67%) while the five markerdefinition found 9% to be basal (with a 10-yearbreast cancer death specific survival of 62%).

sponsive to amedian of two classes of laxatives– were randomised to methylnaltrexone (at adoseof0.15mg/kgbodyweight)oranequal vol-ume of placebo administered subcutaneouslyonalternatedays for twoweeks. Cancerwas theprimary diagnosis in 58%of patients studied.

Results show that, within four hours of thefirst dose, 48% of methylnaltrexone-treatedpatientshadabowelmovement, comparedwith15%ofpatientsgiven theplacebo (P<0.001). Thecorresponding rates within four hours of thesecond, third or fourth doses were 52% formethylnaltrexone-treated patients and 8% forplacebo-treatedpatients (P<0.001). The responsetomethylnaltrexonewas rapid; amongpatientswho had a response within four hours afterreceiving a dose, half experienced defaecationwithin one hour. Overall methylnaltrexone waswell tolerated, with the most frequent adverseevents being abdominal pain and flatulence.

“Our study showed that in this populationmethylnaltrexone rapidly induced laxationwith-out compromising analgesia.Methylnaltrexonemay represent an important therapeutic optionfor patients with advanced illness who are suf-fering from opioid-induced constipation,” con-clude the authors.

In anaccompanyingeditorial, CharlesBerdeand Samuel Nurko, from the Children’s HospitalBoston and Harvard, write that althoughmethylnaltrexone was more effective thanplacebo, “itwas somewhatdisappointing that inboth phases of the study, the drug producedrescue-free laxation [i.e. laxationswithout theuseof a rescue laxative such as an enema or sup-pository] in only about half of patients.” Theexplanation, they suggest, is that constipationcould have been caused by the effects of otherdrugs or disease processes, or that the centralactions of opioids – not the peripheral ones,whichwould be blocked bymethylnaltrexone –might have caused the constipation.

� Methylnaltrexone for opioid-induced consti-

pation in advanced illness. J Thomas, S Karver,

GA Cooney et al. N Engl J Med 29 May 2008,

358:2332–2343

� Opioid side effects – mechanism based therapy.

C Berde and S Nurko. ibid pp2400–2402

Likelihood ratio tests ofmultivariateCoxmodelsincludingstandardclinical variables showthat thefive marker panel was significantly more prog-nostic than the threemarker panel.

“Our results provide strongevidence to sup-port the use of a five-biomarker surrogate todefine thebasal-like subtype, a findingof imme-diate relevance to prognostication and clinicaltrial design,” write the authors. “Drawing onreadily available inexpensive diagnostic toolsalready inclinicaluse, this immunopanelprovidesamore specific definitionof this aggressive formof breast cancer for which there is a particularneed to improve therapeutic options.”

� Basal-like breast cancer defined by five

biomarkers has superior prognostic value than

triple-negative phenotype. MCUCheang, D Voduc,

C Bajdik et al. Clin Cancer Res 1 March 2008,

14:1368–1376

Relief for opioid-induced constipation� New England Journal of Medicine

Subcutaneous methylnaltrexone is safe andeffective at relievingopioid-induced consti-

pation, concludes amulticentre phase III trial ofpatients with advanced illness.

Clinicians oftenuse opioids to treatmoder-ate to severepain, but inadvanced illness, opioid-induced constipation often rivals the distresscaused bypain. Treatingopioid-induced consti-pationcanprovechallenging, sinceopiumantag-onists (such as naloxone) cross the blood–brainbarrier, resulting inopioidwithdrawal. Incontrast,methylnaltrexone is a peripherally actingµ-opioid-receptor antagonist thathas restrictedability to cross the blood–brain barrier.

In the study, Jay Thomas and colleaguesfrom San Diego Hospice and the Institute forPalliativeMedicine (SanDiego,California) deter-mined the safety andefficacyofmethylnaltrex-one in133chronically ill patients from27USandCanadiannursinghomes, hospices andpalliativecare centres. The patients – all of whom hadopioid-induced constipation that was unre-

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Stellate-ganglion blockaderelieves hot flushes inbreast cancer survivors� Lancet Oncology

Stellate-ganglion blockade significantlydecreases the number and intensity of hot

flushesanddecreasesnightawakenings inbreastcancer survivors, aUSpilot studyhas concluded.

Hot flushes and sleep dysfunction are a fre-quent side-effect of pharmacological breast can-cer treatments, including oestrogen-synthesisinhibitors, oestrogen antagonists and aromataseinhibitors. “Hot flushes can have a debilitatingeffectondaily living, bydisrupting sleepandcaus-ing fatigue and irritability during the day,” writestudy authors, Eugene Lipov and colleagues fromtheAdvanced Pain Centers (Hoffman Estates, Illi-nois, USA). In severe cases they can substantiallyincrease the risk of sleep deprivation, depression,sexual dysfunction, andothermedical conditions.

Earlier studieshave suggested that the stellateganglion interactswith several key structures in thebrain known tomodulate core body temperature.One study using functional MRI on post-menopausal women experiencing hot flushesshowedthe stellateganglionprovidedneural inputinto the insular cortex, an areaof thebrain knownto be activated during a hot flush. The studiessuggested toLipovandcolleagues thepossibilityofrelieving hot flushes by interrupting the stellateganglion’s input to the sympathetic system.

In the study, 13 women in remission frombreast cancer,whowereexperiencing severehotflushes and night awakenings, underwent stel-late-ganglionblockat theanterolateral aspectofthe C6 vertebra on the right side. For one weekprior to the procedure, and 12weeks after, sub-jects kept a daily record of the number of nightawakenings and the frequency and severity ofhot flushes. Thedecision to repeat theblockwasmadebythepatient if she thoughther symptomswere returning.

Fivepatientshadonestellate-ganglionblockand eight had two blocks.

Results show that the total number of hotflushes decreased from a mean of 79.4 per weekprior to theprocedure to49.0perweekduring the

first twoweeksafter theprocedure (P=0.0002).Overthe remaining 3–12 weeks, the number of hotflushescontinued todecrease, stabilisingatameanof 8.1 per week (P<0.0001). Severe hot flushesdecreased from26.5perweekat theoutset to5perweek by the end of the study (P<0.0001).

Night awakenings also decreased, from ameanof 19.5 perweekprior to theprocedure to7.3perweekduring the first fewweeks after theprocedure (P<0.0001), stabilisingatameanof1.4perweek by the end of the study (P<0.0001).

“The findings of this pilot study suggest thataproperlydone stellate-ganglionblockademightbe a highly effective treatment for both hotflushes and night awakenings in survivors ofbreast cancer, butmore studies areneeded,” con-clude theauthors, adding that somecontinued toexperience relief from hot flushes for more thantwo years after a single block.

� Effects of stellate-ganglion block on hot flushes

and night awakening in survivors of breast cancer: a

pilot study. EG Lipov, JR Joshi, S Sanders et al.

Lancet Oncology June 2008, 9:523–532

Treatment groupsdefined in locallyadvanced breast cancer� British Journal of Cancer

Locally advanced breast cancer (LABC)patients with tumours testing negative for

oestrogen receptor (ER), progesterone receptor(PgR) andHER2 show the lowest levels of recur-rence-free survival (RFS), an Italian study hasconcluded. The investigators, who also foundthat a high Ki-67 labelling index and the pres-ence of peritumoral vascular invasion (PVI) cor-relates with poor RFS, hope that their findingswill help todefinedistinct biological entities thatrequire a differentiated approach.

LABCdefines aheterogeneousgroupofdis-eases, includingtumourswith locoregional lymphnode metastases, primary breast carcinomasinfiltrating skin or chest wall – known asnon-inflammatory breast cancer (NIBC) – andinflammatory breast carcinoma (IBC). Limited

information is available, however, onprognosticandpredictiveparameters forboth IBCandNIBC.

In thecurrentprospective study, EmiliaMon-tagnaandcolleagues fromtheEuropean Instituteof Oncology (Milan, Italy), evaluated the clinicaland pathological features of 504 consecutivepatients with NIBC and IBC operated on at theInstitutebetween1999and2006. Thedatawerecollected from patients who were treated withmultimodal treatments, including neoadjuvantchemotherapy followed by radical surgery andradiotherapy. Tumour samples obtained at sur-gery were evaluated using standard immuno-histochemicalmethods. Patients with recurrenttumours,metastaticdiseaseatpresentation, pre-vious tumours, no primary chemotherapy, malebreast cancer and those who received tras-tuzumab therapywere excluded fromthe study.

Altogether, 248patientsweredeemedeligi-ble, ofwhom107 (43%)werediagnosedwith IBCand 141 (57%) with NIBC. The investigators didnotobserveanydifferences inRFS (P=0.72), dis-ease-free survival (P=0.98) and overall survival(P=0.35) between patients with IBC andNIBC.

In amultivariate analysis, patientswith ER-andPgR-negative disease showed significantlyworse RFS than patients with ER- and PgR-positive disease (HR 2.47, 95%CI 1.33–4.59,P<0.001). The worst RFS was found in the sub-group of patients with endocrine non-respon-sive breast cancer and HER2-negative breastcancer. Here the two-year RFSwas 57% in bothNIBCand IBC. In addition, a highKi-67 labellingindex (>20% of the invasive tumour cells) andthe presence of peritumoral vascular invasion(PVI) significantly correlated with poorer RFS.Tumourswith a Ki-67 >20%had a hazard ratiofor RFS of 2.69 (95%CI 1.61–4.50, P<0.001),while presenceof PVI gave ahazard ratio of 2.27(95%CI: 1.42–3.62, P=<0.001).

“This study confirms thevalueofprognosticparametersassessedat final surgery, includingERand PgR expression, Ki-67 expression and pres-enceof vascular invasion,” conclude theauthors.

� Factors that predict early treatment failure for

patients with locally advanced (T4) breast cancer.

E Montagna, V Bagnardi, N Rotmensz et al. BJC

27 May 2008, 98:1745–1752

Why ‘plenty of bed rest’could be bad advice

Survivors to be prescribed exercise as cancer care ‘catches up’ with cardiology

� Peter McIntyre

Evidence from a growing number of robust studies points incontrovertibly towards the

benefits of regular, moderate activity not just in preventing cancer, but in rehabilitation for

survivors and protection against recurrence. The question, as ever, is how to help thosewho need

it most to get the message and act on it.

Not everyone can be like LanceArmstrong. Following treatment fortesticular cancer with lung andbrainmetastases, he famouslywenton to win the Tour de France seven

times, and now he has retired from competitivecycling, he runs marathons.

“I view running as a hobby and a necessity,” hesaid inApril 2008, just before completing theBostonmarathon in 2 hours 50minutes and 58 seconds.

Nor can all cancer patients be like Jane Tomlin-son fromLeeds inEngland,who, given sixmonths tolive at the age of 36, swam, ranmarathons, cycled toRome and back, and cycled across America raising£1.75million (€2.2million) for cancer care.

Jane died in September 2007, having outlivedher six-month prognosis by nearly seven years, andhaving achieved her ambition to see her childrenthrough their early childhood–her youngestwas 12when Jane died.

These are exceptional people. One is still aliveand the other is not, but in both cases exercise rep-resented a focus of thewill towin and thewill to live.

However, a growing tide of research shows that

the benefits of exercise for cancer patients do notdependon runningmarathons.Even ‘moderate’dailyexercise – such as briskwalking or energetic house-work – is important in the rehabilitation of cancerpatients. Doctors are increasingly advising theirpatients to takemoderate exercise five times aweek,to speed their recovery, improve their quality of lifeand help prevent the return of the cancer.

Fernando Dimeo runs a specialist referral cen-tre for cancer patients with fatigue at the CharitéUniversitätsmedizin in Berlin. He says simply, “Ifthere is no clear contraindication for exercise, allcancer patients should exercise. Thatmeans thatweare putting the argument on its head. Usually doc-tors recommend their patients not to exercise,unless they have a good reason to do so.”

Anna Campbell has researched the effects ofexercise on patients with cancer in Scotland andnow runs cancer rehabilitation training coursesacross theUK (www.canrehab.co.uk). She is focus-ing on how to introduce into cancer care packagesevidence-based practice on exercise.

“There is somethingprotective aboutbeingactivepost diagnosis. For people who have already had a


PatientVoice

Rowing back to health. Dragon boat racing is becominga very popular form of exercise among breast cancersurvivors. Pictured here is the UK Pool of Life team(www.pooloflife.net) from Liverpool, on a 42-km paddlealong the Leeds/Liverpool Canal this May, to raiseawareness about the importance of early detection

Exercise is now becoming an issue wherever

the number of cancer survivors is increasing

PatientVoice


cancer diagnosis, 30 minutes of moderate exercisefive days aweekwill cut byhalf the risk of colorectalor breast cancer comparedwith someonewhohas avery sedentary lifestyle. There is no patient whocouldnot incorporate somekindof physical activity,whether home-based or in a group setting or a one-to-one programme into their daily life.”

Both specialists say that exercise improves qualityof life and can often begin during treatment, thoughthere are caveats for patients who suffer exercise-related pain, poorly controlled hypertension or dia-betes, unstable heart disease, or other comorbidity.

Cancer care is taking time to catch upwith car-diovascularmedicine in understanding the benefi-cial role of exercise, saysDimeo. “For 20 years now,we have recommended patients with cardiovascu-lar disorders or lung disorders to start exercising orincrease physical activity. But for cancer patients,somedoctors recommend that patients do not exer-cise during anaemia or immunosuppression. If youask themwhy, they cannot give you a reason.”

Exercise is nowbecoming an issuewherever thenumber of cancer survivors is increasing, such as incolorectal or prostate cancer. There is increasinginterest in encouraging children with leukaemia toexercise and there are studies showing benefits forpatients with myeloma and non-Hodgkin’s lym-phoma.There is alsoevidence that exercise improvesquality of life for patients receiving palliative care.

THE EVIDENCE IS STACKING UPTheevidence showing thebenefits of exercisebeforeandafter diagnosis is stackingup fast. It is estimatedthat inactive lifestyles could account for up to 5%ofall cancer deaths, 13–14%of all bowel cancer cases

“Racing dragon boats is physically and mentallydemanding, which makes you focus and forget your

problems momentarily. Every woman rises to the chal-lenge. You gain your confidence back and are able toface life again, head-on. Perhaps the most importantthing is the fun – whether it is sunny, raining, hail orsnow, we go out on the water and have a laugh!”

Wendy de Corte, Pool of Life

WILFHOLDEN


PatientVoice

“Inactive lifestyles could account for up to 13–14%

of colorectal cancers and 11% of breast cancers”

The studiesExamples of the growing body of literature testifying tothe importance of exercise in survivor quality of life, pri-mary prevention and preventing recurrence include:� Adulthood lifetime physical activity and breast cancer.B Peplonska, J Lissowska, TJ Hartman et al. Epidemiology,March 2008� Benefits of supervised group exercise programme for womenbeing treated for early stage breast cancer: pragmatic randomisedcontrolled trial. NMutrie,A Campbell, FWhyte et al. BMJ,16 February 2007� Effects of an endurance and resistance exercise program onpersistent cancer-related fatigue after treatment. F Dimeo,S Schwartz, N Wesel et al. Ann Oncol published online1April 2008� Exercise for the management of cancer-related fatigue inadults.FCramp and JDaniel,Cochrane Database of System-atic Reviews 2008 Issue 2Art. No. CD006145,April 2008� Exercise for women receiving adjuvant therapy for breastcancer. M Markes et al. Cochrane Database of SystematicReviews 2006 Issue 4Art. No. CD005001, October 2006� Impact of physical activity on cancer recurrence and survivalin patients with stage III colon cancer: findings from CALGB89803. JA Meyerhardt, D Heseltine, D Niedzwieckiet al.JCO, 1August 2006� Physical activity and survival after colorectal cancer diagnosis,JAMeyerhardt, ELGiovannucci,MDHolmes et al. JCO, 1August 2006

and11%ofbreast cancer cases.A recent study fromPoland, where 9,000 women are diagnosed withbreast cancer every year, showed that women whowere in themost active groupwere20% less likely todevelopbreastcancer thanwomenin the lowestactiv-ity group. Beata Peplonska and colleagues at theNofer Institute of OccupationalMedicine in Łódz,found particularly strong benefits for women whoincreased activity levels in their 50s.

The benefits of exercise post diagnosis is alsobecomingclear.Oneof themostdramatic resultswas

shown inastudybyMeyerhardt andcolleagues in theJournal of Clinical Oncology. They followed 573womenwith stage 1–3 colorectal cancer, and foundthat cancer-specific deathwas60% lower inwomenwho exercised six or more hours a week (walking ataverage pace) than in those who exercised for lessthanonehour aweek.The reduction indeaths fromall causeswasalmost as large.Asecondstudyofmorethan800patientswith stage 3 colon cancer showedthatmortality was reduced by half in the group thathad exercised six hours a week ormore.

Exercise canalsohelpwith the fatigue thatmanypatients suffer long after treatment. A Cochranereviewpublished inApril found that “exercise canberegarded as beneficial for individuals with cancer-related fatigue during and post cancer therapy”. Itcalled for further research to decide the best type,intensity and timing of exercise.

Dimeo’s group in Berlin enrolled 32 cancerpatients withmild-to-severe persistent fatigue in aresearch programme that involved 30-minute ses-sions on a treadmill with resistance exercises for themajormuscle groups.After threeweeks, thepatientsshowed a significant increase in physical perform-ance and reduced overall fatigue scores by a meanaverage of 25%.

However,whenDimeoanalyseddetailed fatiguescores, he found no significant effect on cognitivefatigue, depression or anxiety.

“I have had patients here working out for six oreightweeks, andweobserveaveryclear improvementin their physical performance, but at the end, somegoon feelingmentally tired.Whydo theycontinue tofeel lackofmotivation andhave cognitiveproblems?The first idea was exercise – we were very ecstaticabout exercise and the improvement inphysical per-formance. Now we are certain that the problem offatigue ismuchmorecomplex than that, and that thepatient also has problems in other areas.”

Dimeo says that we need better definitions ofmental fatigue to distinguish, for example, betweenpatientswho feel rundownand lacking inmotivationand those who become forgetful and unable to

Long-term benefit. These survivorsare part of the 203-strongrandomised clinical trial thatdemonstrated a significant impactof the CATS (Cancer and TirednessSupport) exercise programme onquality of life. Lead researcher,Anna Campbell is pictured leadingthe class, in Renfrew, Scotland

Even patients who do not seem to have made progress

exercising during treatment often feel the benefits later

PatientVoice


concentratewhen reading abookorwatching a film.“The instrumentswehave are veryunspecific.We

have toask thepatient:whatexactlydoyoumeanwhenyou feelmentally tired?Youcannot concentrate or youare forgetful or what? The next step is to define thelimitations of the patient, and after that we can startto evaluate different therapeutic approaches.”

LATE EFFECTSHowever, Campbell says that even patients who donot seem to havemade progress during the exerciseprogrammeduring treatment often feel thebenefitslater. Shewas involved in research inGlasgow,Scot-land, that randomised 203 women with early-stagebreast cancer to a12-weekexerciseprogrammedur-ing their treatment or a control group, and then fol-lowed themup sixmonths later.

The women attended two 45-minute exerciseclasses aweek andwere encouraged todooneotherexercise sessionathome.After12weeks theyshowed

physical andpsychological benefits compared to thecontrol group. However, the difference in generalquality of life first emerged at the six-month follow-up.Ofcost–benefit interest is that theexercise groupspent fewer nights in hospital andmade fewer visitsto their doctor, comparedwith the control group.

This was the first randomised controlled trial ofexercise inbreast cancerpatients in theUK,and, likeDimeo, Campbell thinks there is a complex storyunderneath the figures.

“When you look at any group studies post-treat-ment, when you give them a physical exercise pro-gramme they not only get fitter, able to be moreactive and stronger, but their quality of life improves.We found that when you are doing an interventionwithphysical activity during chemo- or radiotherapy,it is much more difficult to see an overall improve-ment in quality of life. We think that during thetreatment there are other issues and side-effects oftreatment,whichperhapsmask theoverall improve-

ment. The interesting thingis that when we followed upthe women six months later,when they finished their treat-ment, surprise, surprise, thewomenwho have been givenexercise, their quality of lifehas improved, comparedwiththewomenwhohaven’t beengiven the exercise.”

Group exercise appearsto have some extra benefits

CATHYMCINTYRE

over exercising alone, according toCampbell. “Def-initely the group dynamics did have some effect, sotherewere twoplusses. But it cameout very stronglythat the women were not interested in just sittingaround the table talking about their cancer. Thephysical functioning improved and they showedreduced fatigue and a greater range ofmovement.”

One manifestation of this group effect is thesuccess of dragonboat racing amongst breast cancersurvivors, as awayofcombiningexercisewith funandgroupsupport.This is ahuge sport inCanada,NorthAmerica and Australia, and has spread to Europe,with teams in the Czech Republic, Germany, Italy,Poland and theUK. This September, the EuropeanDragon Boat Racing championships, hosted inSabaude, Italy,will feature for the first timea race forbreast cancer survivor teams.

LEARNING FROM CARDIAC CARECampbell is involved in trying to get physicalexercise into routine cancer rehabilitation careas part of NHS treatment in the UK, workingwith healthcare and exercise professionals todevelop properly validated training and educa-tional courses. She too believes that cancer careprofessionals should learn from cardiac care.

“Cardiac rehab is a fantasticexampleofwhere thepatients, after a triple bypass orwhatever, have a12-week structured programme with exercise and arealsogiven informationonhealth lifestyle suchasdiet,smoking andalcohol consumption.At theendof the12weeks theyare straight intocommunity-basedpro-

grammes near them in the local gym. That is what Iwould love to see takeplace forcancer rehabilitation.”

Makingexercisepart of rehabilitationcarewouldbe a great help in gettingpeople started.But as everyhealthclubknows, it is one thing to start exercise andanother thing to make it a part of your daily life. Astudy in Alaska showed that breast cancer patientswhoweregivenstepcountersandencouraged towalk“like theywere late for an appointment”were takingmore exercise after three months than those whowere simplygivenverbal encouragement,but after sixmonths the differencewas no longer significant.

Campbell says that those settingupexercisepro-grammeshave topaycloseattention to themotivatorsand thebarriers to takingpart, especially to attract thepatients whomay be the least likely to attend.

“You may find that younger women weren’tcoming in after a diagnosis of breast cancer com-pared to older women. The main factors may bethings like childcare, or they are keen to get backto work and the timing does not suit them, or thetreatment they are getting is slightly more aggres-sive and they are finding it harder to cope. I amlooking at how to overcome the barriers so you canincorporate people who maybe cannot travel to alocal gym or who have comorbidities. Like every-thing else, the first to take it up are the moresocially and educationally advantaged people. Youreally want to target the people who are not com-ing along, but need it the most. But many healthprofessionals would like more training in helpingpatients to change behaviour.”


PatientVoice

“Many health professionals would like more training

in helping patients to change behaviour”

Group dynamics. The CzechDracice team (www.dracice.org) isone of the more recent additionsto the European breast cancersurvivor dragon boat racing scene.They are pictured here (centre)taking part in the Prague DragonBoat Festival this June

FRANTISEKHONZAC

Why is cancer killingmore men than women?� Marc Beishon

A rising focus on men’s health issues, more sophisticated registry data and new techniques for

investigating the biology of cancers are fuelling interest in unravelling what lies behind

gender differences in cancer incidence and mortality. Getting answers could boost prevention

and early detection and could even lead to better targeted therapies.

When it comes to thedifferences betweenmen and women,publicity about can-cer tends to focus on

the tumours specific to each sex – in themain, prostate and testicular for menand cervical, ovarian and breast forwomen (althoughof coursemenalso getbreast cancer – and there is rising inci-dence in some countries). But there arestriking differences between adult menandwomen in somecancers common toboth sexes, which are starting to receivemore attention – andwhich raise awiderange of biological, social and environ-mental issues concerning cancer inci-dence, survival and mortality.

As JanWillemCoebergh, professor ofcancer surveillance at theDepartment ofPublicHealth,ErasmusMedicalCentrein Rotterdam, points out, there are twocancer siteswhich currently standout assignificantly different in cancer survivalandwhicharehard toexplain.Melanoma

has a higher incidence in women, butmore men proportionately die from thedisease.But the reverse is true inbladdercancer,where theprognosis forwomen ispoorer despite a lower incidence. Tryingtounpick the reasons for thesedisparitiescan involve everything on the ‘gender’side, fromwhenmenandwomenpresentto health services, to what doctors dothat may be different, to lifestyle riskfactors such as smoking andobesity, andalso the ‘sex’ factors – possible differ-ences in male and female biology.

However, for some cancers commonto men and women the big differences,in incidence at least, are relativelystraightforward to explain, according toCoebergh. “Tobacco exposure in partic-ular and also alcohol explain the higherrates in men in many countries intumour sites such as lung, larynx, blad-der and to someextent pancreas, andwehave of course seen a decline in thesecancers in northern Europe as smokingrates have decreased, although there is a

lag of 0–25 years in the data.” As maleand female smoking rates have becomemore equal acrossEurope, so toohas thecancer incidence differencenarrowed inthose tumourswhere tobacco is amajorrisk factor.

“We are also seeing the rates of colo-rectal cancer in older men going up insome countries – this could be theresult of a longer latency time of 30–40years for smoking, but the data is muchless robust,” he adds. He points outthat survival andmortality rates in olderage groups are also heavily influencedby comorbidity with other diseases,especially cardiovascular conditionsand chronic obstructive pulmonarydisease – again where smokingmakes amajor impact.

But asCoebergh adds, thewider sta-tistical picture of male and female dif-ferences around Europe is very mixedand complex. An analysis of the latestEurocare-4 data shows that, for Europeas awhole, the regionallyweightedmean


Systems&Services


five-year cancer survival is about 55%for women, but just 45% for men for alltumours, and those countries that spendthe least on healthcare per head havenotably lower scores.

It isnotable too that theUShasmuchhigher survival figures than Europe andmen actually do better – about 66% formen and 63% forwomen. But as FrancoBerrino and Riccardo Capocaccia pointout, inResponding to the challenge of can-cer in Europe (available from WHOEurope),men in theUShavea lower inci-dence of lethal cancers such as lung andstomach, and an exceptionally high inci-dence and survival for prostate cancer,thanks to widespread screening.

Thosewanting to delve deeper into gen-der patterns could look at a recent paperin theEuropean Journal ofCancer (Hen-rikeKarim-Koset al, 2008,44:1345–89),inwhichEurocare and other sources aremined for17cancer types acrossEurope.This lengthy report gives detailed figuresfor men and women on incidence, sur-vival and mortality for several cancers,includingcolorectal, pancreatic and lung,andsummariesof trends in various coun-tries. There is also some discussion onpossible reasons for the gender patterns.Amoredetailed gender paper, byAndreaMicheli and colleagues at the Eurochiphealth indicator project in Milan, willbe published in theEJC this year .

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DIFFERENCE IN RELATIVE SURVIVAL (%) BETWEEN WOMEN AND MEN UNRAVELLING THE CAUSESIt has been ten years since Micheli et alpublished their last gender paper, whichlooked at earlier Eurocare data. In‘The prognostic role of gender in survivalof adult cancer patients’ (EJC 1998,34:2271–78), which was put forward asthe first suchexaminationofgender incan-cer survival, they suggested that “womenmaybe intrinsicallymore robust thanmenin copingwith cancer.” The better overallsurvival inwomen, theynoted, could resultfromoneormore factors –womenpayingmoreattention to their bodies, resulting inearlier diagnosis; the impact of differentrisk factors on the cancer case mix; and a“biological superiority in women inresponding todisease, treatment or both”.They alsonote the figuresmaybe skewedby different corrections for comorbiditybetweenmen andwomen.

For Alan White, probably the firstprofessor ofmen’s health in any country,basedatLeedsMetropolitanUniversity intheUK, thedata onworse incidence andoutcomes for many male cancers is ahuge issue that absolutely requiresmoredetailed analysis. “In2003 theEuropeanMen’s Health Forum commissioned astudy ofmen’s health acrossEurope, thefirst timewehad looked across all healthissues formen, and it emerged thatmenseemed to be developing and dying fromall sorts of conditionsat agreater rate thanwe thought.Weassumed that cardiovas-cular disease would be the major condi-tion – but cancer emerged as a highercause thanwe anticipated.”

White has also assembled data fromvarious sources. Looking for example atthe differences in England and Walesbetween the sexeshe finds that, althoughcancer accounts for a greater proportionof female deaths in younger age groups,removing breast and genital cancersreveals that “63% more men in Englandand Wales in the 15–64 age group suc-cumb to cancers that shouldbe affectingmen andwomen equally”.

Age-standardised data for adults diagnosed in the period 1990–1994.Source: MP Coleman et al, Eurocare-3 Summary, Ann Oncol 2003, vol 14 (suppl 5), v135

He has since spent a good deal of timeanalysing the causes for the excess malecancer mortality, including organising anexpert symposium on the issue (‘Tacklingthe excess incidence of cancer in men’),held in2006 inLeeds.At this event,DavidForman, of the Centre for EpidemiologyandBiostatistics at theUniversity ofLeeds,noted that the received wisdom of menpresenting later is not sufficient to explainthe discrepancy inmortality rates.He alsocommented that the drop in smokingamongmenandthe lower ratesof lungcan-cer, while cutting overall male rates couldstillmaskdifferences inother cancers, andindeed in most other tumour sites theredoesn’t appear tobe any single explanationfor the higher incidence in men, though asimplecombinationof smokingandalcoholis associatedwithmale oral cancers.

White considers thatwhile laterpres-entation is a factor, it has to be added inwith a wide range of lifestyle factorsincludingsmoking,diet, physical exercise,body fat and obesity. Socioeconomicinequality also plays a part – in England,social disadvantage worsens outcomesfor men more than for women. (TheEurocadet project –www.eurocadet.org– iscurrentlyexamining themajor lifestyleand socioeconomic factors affecting theincidence of cancer aroundEurope.)

Melanoma stands out, as Coeberghand White comment, because of theworse outcome for men coupled withlower incidence–oneof the fewcancers,in fact, where incidence is higher inwomen. Identifying the reasonsmayhelppoint researchers inpromisingdirections.At theLeeds expert symposium,Formanpresented data that showed that evenafter controlling for stage at presentation

and the location of the tumour, there isstill a 31%survival advantage forwomen,which can partly but not wholly beexplained by factors such as age andsocioeconomicstatus.Similar resultshavebeen written up by colleagues ofCoebergh in the Netherlands, led byEsther de Vries at the Erasmus MedicalCentre, where again an unexplained gapin male/female survival was found in asample of more than 10,000 Dutchmelanoma patients.

“Hypotheses about the differenceinclude looking at the roleof the immunesystem,”commentsCoebergh. “Andthereis also evidence about obesity as a cancerrisk for men and melanoma – we do notsee thesamerisk inobesewomen–so theunderlying factors that determineobesityin men may also determine the progres-sionofmelanoma.”Hepoints to a recentmeta-analysis in the Lancet that re-inforced theobesity link.Headds thathisgroup is cooperating with the EuropeanOrganisation for theResearchandTreat-ment of Cancer (EORTC) in looking atmelanoma trial data,where there ismoredetailedpathology, in the search forprog-nostic factors formenandwomen.Otherresearchhementions is ledbyAlanSpatz,chair of theEORTCmelanomagroup,onthe role of the X and Y chromosomes inprotection and tumour progression. “Aninteresting point is if we can explain themale/female difference it might lead tonew therapeutic approaches, as nothingseems towork so far withmelanoma.”

Meanwhile, inbladder cancer,whichstands out as a cancer in which womenfaceaworseprognosis,Coebergh saysheis not aware of systematic efforts toexplain the reasons, but there are various

explanations, including underlying bio-logical causes, while urologists have, hesays, traditionally investigatedmenearlierandmore thoroughly thanwomen,wherein any case the tumour has been rare.

CULTURAL FACTORSDifferences in treatment and wider cul-tural factors areof great interest toWhite.“My concern is that we start seeing amarked rise in incidenceofdiseases suchas cancer and heart disease after the ageof35 inmen,which is also the timewhenthey are least likely to be seen by healthservices. We need to target men moreeffectively in theworkplaceso thatwecanidentify those men who are reluctant tocome forward and aremissing the bene-fits of early diagnosis.”

The European Men’s Health Forum(EMHF) leads on many activities likethis around the region, and this yearmadetheworkplace the theme for the Interna-tional Men’s Health Week. It issued a‘Lungcancer in theworkplace’documentin June, which highlights the need forhealth policies formigrant workers.

TheEMHF’s president, IanBanks, isa pioneer of men’s health in Europe, andnow a visiting professor at Alan White’sdepartment. The site www.emhf.org hascopious resources, includingadownloadofthe proceedings of theLeeds expert sym-posium – this event, White is pleased toreport, is referenced in England’s recentreformof its national cancer strategy. “It isclear thatmore research isneeded ifweareto fullyunderstandhowgender impactsoncancer,” the strategy notes.

Indeed, theEMHFandprofessionalssuch asBanks andWhite are also callingfor far more research about men and


Systems&Services

“For Europe as a whole, five-year cancer survival

is about 55% for women, but just 45% for men”

cancer. As White says, “No systematicstudyofmen’s increased riskofcancerhasyet been undertaken.” There could, headds,bemajor implications forhealthcarepolicy makers in the sex and gender dif-ferences. Take colorectal cancer, wherescreening programmesare now startingtobe implemen-ted in severalcountries: if thereis evidence thatmen are develop-inganddyingfromthe tumour earlierthan women –which indeedthereis – does it makesense to start every-one at the sameage? Itmaybemoreeffective and cost-effective tobring for-ward the age of firstscreening formen, orput back the first female screen.

Coebergh points to another factorwithcolorectal cancer, this time in favourof men. “Men tend to have spouses tolook after them and so are more likely toreceive adjuvant chemotherapy thanwomen,manyofwhomarewidowswhentheyarediagnosedwithdisease.”Anotherintriguing difference in treatment appli-cations,whichwas reported at theexpertsymposium,concernedoesophageal can-cer, where data from one region in Eng-land show that radiotherapy is thefavoured treatment for women withoesophageal cancer but chemotherapyfor men. Marked differences have alsobeenreported insurgery forcolonandrec-tal cancers, and treatments offered for

lung cancer. These differences arenot easy to explain, although other pat-terns are, such as more aggressive treat-ments for youngermen.

Response to treatment and funda-mental differences in biology add furtherlayersofcomplexity.Trialsofnewtherapieswill increasingly look for differences inhow men and women respond as knowl-edge of genetic factors increases. Hor-mones, notes Coebergh, could also beplaying a role in somecancers.Oestrogen,for example, while a risk factor in post-menopausal women for breast cancer,may be protective in sites such as thebowel and stomach where there are alsooestrogen receptors. Studies have shownthatexposingmentooestrogencan reducetheir risk of gastric cancer, for example.

Researchers in the US have recently car-ried out one of the first studies on miceshowing that male animals suffer moreskin damage and worse tumours when

exposed to harmful ultra-violet radiation.

But it is only relativelyrecently that a massivegender bias – in men’sfavour – has started to beaddressed in developingtherapies. Many cancerdrugswere initially testedonlyonmen, and there iscontinuing bias in clini-cal trials and researchtowardsmennot just forcancerbut formost dis-eases. Safety and com-parability with otherstudies are among thereasons for women’sexclusion. In1994, the

US National Institutes of Health issuedguidelines that allowedAmericanwomento enter phase I, II and III trials, but asAnitaHoldcroft, of ImperialCollege,Lon-don,writes, “therehasnotbeenadramaticrecruitment of women’s data into trialresults,” and many drugs are withdrawnfrom the market because of women’shealth issues (see J R Soc Med 2007,vol 100).

There is a good dealmore to come inthe sex and gender story in cancer, asthere is in the development of ‘gendermedicine’ as a specialty in its own right.Just where the biggest impacts are likelyto come from – underlying biology, orcultural and treatment factors – and forwhichcancers, shouldoccupy researchersfor some time,provided thewill andpres-sures are there to carry out the studies.

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“We need to target men more effectively in the

workplace to identify those reluctant to come forward”

Targeted message. To catch the attention of anadult male audience, the UK Men’s HealthForum published this information and advice oncancer in the form of a ‘Haynes manual’ –familiar to all car lovers and do-it-yourselfenthusiasts

Documents

C W 26 Education & knowledge through people & factsCoverStory 4 CANCERWORLD SEPTEMBER/OCTOBER2008 NadiaHarbeck: breakingwithconvention MarcBeishon Gynaecologistsdon’twintopawardsatASCO.Germanoncologistsdon’tmakeitonthe