cancer world 47

�John Crown:Move asidebureaucrats and let us take a lead�First treatment guidelinesfor advanced breast cancer are welcomed by patients andpractitioners� Join the battlefor biomedical research�Howarewedoing? Ifwe can’t answer that, howcanwe improve?

John Crown

Education & knowledge through people & facts

Number 47, March-April 2012

CancerWorld

47MARCH-APRIL

2012

CANCER WORLD � MARCH/APRIL 2012 � 3

Editorial

Thebattle ison toshape theagendafor European research up until2020.Theeighth research frame-

work programme– renamedHorizon2020–is currently being discussed at the EuropeanParliament andCouncil, and ithas somegoodthings going for it.Prompted by pressures to increase

public spending to boost growth and jobs,its budget of €80 billion for the period2014–2020 represents a significant increaseover the €55 billion allocated to the currentframework programme (FP7).And theCom-mission has clearly tried to respond to criti-cisms about howhard it is for researchers toget access to this funding. It has been at painsto highlight changes that have beenmade tosimplify rules and procedures – good newsfor any researcher who has had to strugglewith the red tape associatedwith applying foran EU research grant.Not suchgoodnews, however, is thedeci-

sion to cut the slice of the overall cake that isallocated to health research, from its currentlevel of 12% to only 10%. Critics point outthat, even in purely economic terms, this is amistake. Investing inhealth researchnot onlyhas the stimulatory effect associatedwith allpublic spending, but it can also help cuthealthcare costs and reduce the number ofpeople unable to work due to ill health.Both of these are major considerations.

An estimated $47 trillion will be lost glob-ally over the next two decades because ofdisease and ill health; for Europe the big

� Kathy Redmond � EDITOR

challenge will be coping with an increasingburden of chronic disease as our populationages. ‘Health is wealth’ is the new mantra,and giving greater priority to research intothe former will help boost the latter.A campaign has now started to secure a

greater slice of the Horizon 2020 fundingfor health research. Led by theAlliance forBiomedical Research (BiomedAlliance) inEurope, of which ECCO is a foundingmember, the campaign is also calling for theEuropean biomedical research communityto have more of a say in defining researchpriorities, and for a dedicated infrastructurein the form of a European Council forHealth Research.There is a lot at stake here. A compre-

hensive strategy involving the entire bio-medical community in Europe will be keyto addressing the fragmentation of the cur-rent research landscape, and to sustainingsuccessful research projects long term andfacilitating the translation of innovationinto clinical practice. It will also provideopportunities for young researchers whosetalents may otherwise be lost to Europe,particularly now thatAsian economies areinvesting so heavily in this area.Active support from across the cancer

community will be crucial. The final pack-age will be agreed at the end of 2013, so wenow have a small window of opportunity toinfluence the outcome. The cancer com-munity urgently needs to make its voiceheard at both EU and national levels.

Join the battle forbiomedical research

CoverStory

4 � CANCER WORLD � MARCH/APRIL 2012

John Crown:Move aside bureaucrats

and let us take a lead

� Marc Beishon

Good healthcaremanagers will always be needed, but decisions on howbest to deliver high-qual-

ity care shouldbe left to theclinicianswho run the services. JohnCrown,whohas longplayeda lead-

ing role in both the clinic and research, is by nomeans the only oncologist tomake this comment.

He is one of the few, however, to seek elected office in order to pursue the pointmore effectively.

Outspoken oncologists, willing totake on ‘the powers that be’, canoften play a very helpful role in gal-vanising administrators and policymakers and pushing the priorities of

clinicians higher up the agenda. There are notablesuch characters around Europe, but one oncolo-gist has taken a bigger step into the realm of poli-tics by becoming a senator in his parliament – fromwhere he is able to directly challenge politiciansand bureaucrats with the protection of parlia-mentary privilege.

John Crown’s day job is consultant medicaloncologist at St Vincent’sHospital group inDublin,a position he took up in 1993; he also holds pro-fessorships at twoDublin universities.A breast can-cer specialist, he was elected last year to Ireland’ssenate as one of a caucus of six academics in the

upper house. Hismove into politics follows a longhistory of confronting the Irish authorities aboutcancer care and resources, in particular about hisspecialism,medical oncology, andwith good reason.

“When I came back to Ireland after working inthe United States, I was just one of four medicaloncologists in the whole country, and we were allbased in Dublin. We also had no radiation oncol-ogy in some areas. Women were routinely gettingmastectomieswith little adjuvant treatment outsideof Dublin and those with metastatic disease wereoften referred to hospices, not to an oncologist. Itwas a catastrophic situation.”

Much has improved sinceCrowndecided to gopublic on these issues in themid-1990s. Not onlywas he taking on the politicians, but also the ‘oldschool’ health professionals who were part of theproblem. “It was only when a new minister of

CoverStory


health,MichaelNoonan, came into post and statedthat he wouldn’t send his relatives to certain hos-pitals if they had cancer that things really started tochange,” he says.

Now there are more medical oncologists, bet-ter care throughout the country, and Ireland hasbecome a substantial contributor to cancerresearch, thanks toCrown and colleagues startinguphigh-quality translational research collaborationsand entering a good percentage of patients in trials,especially in breast cancer.

As he points out, there is no reason why acountry the size of Ireland should not have a first-rate oncology effort. “We are more than four andhalf million people, and Dublin is a cosmopolitancity of well over one and half million in its metroarea [Greater Dublin]. There are only a few veryrare conditions where we should send a patient

abroad for treatment. But we tend to have adefeatist attitude that a country thatwas historicallypoorly developed shouldn’t aspire to have a health-care system as good as the best.

“And as with many other countries, the politi-cians put bureaucracy before visionary leadership.It’s a fundamental issue that needs to be addressednot only in Ireland but throughout Europe – theleadership role of health professionals is beingundermined by the emergence of a managerialclass.” Crown is passionate about this issue, whichhe believes is crucial to improving outcomes in can-cer and indeed across the health spectrum.Healthprofessionalsmust be allowed to assume leadershippositions as they have the vision to act as trueadvocates for patients, he says. Professional man-agers have their place in any institution – butwhere they set the agenda it is likely to be serving

EAMONNFARRELL/PHOTOCALLIRELAND

political edicts to balance budgets andmeet targets.“That oftenmeans thewelfare of patients comes

second, and also – and thismay be an old-fashionedview – I do not think that doctors act solely in theirown self-interests.We have higher ethical consid-erations than other professions.”

The link between overbearing bureaucracy andpoor cancer outcomes can be seen in Ireland andtheUnitedKingdom in particular, he says, pointingto slow access to treatment and drug availability (intheUK especially) as two key factors.Wearing hispolitical hat, hewould ‘fix’healthcare by reforminghealth insurance so that the “money follows thepatient” and patients are able to choose theirprovidersmore easily, and of course that healthcareleadership is passed to medics.

Healthcare cannot exist in isolation from thewider economy and societal trends, of course.Crown is also concerned about how countriessuch as Ireland that are under severe economicpressure can become more stable. He worries,too, that science and technology are not being pri-oritised as they should be.While he favoursmeas-ures such as lowering corporation tax and public

sector reform to make it more efficient, he is noadvocate of wholesale privatisation of healthcare.“I’m a social democrat at heart with the head of apragmatist – I believe that no one should be deniedcare because they can’t afford it, but the health sys-tem should not be a giant bureaucracy andweneedto empower patients with mixed public/privateinsurance such as in Germany.”

A good deal ofCrown’s formative years in oncol-ogywere spent at one of theworld’s top cancer cen-tres,Memorial Sloan-Kettering in theUS, and hisfirst-hand knowledge of how excellence can beachieved at a not-for-profit institution with greatclinical leadership has inspired his work in Ireland.It is a background he shares with most of hiscolleagues. Of the 33 medical oncologists nowin Ireland – itself a gauge of how far the countryhas come in 15 years or so – 23 were trained atAmerica’s top cancer centres such as Memorial,MDAnderson, theNCI, JohnsHopkins andDana-Farber. “When I was atMemorial I could be in anelevator with more Irish oncologists than therewere in Ireland,” saysCrown. “That’s a direct resultof our immigration culture.”

Crown himself was born in New York to Irishimmigrants and as a boy was influenced by theattention cancer was getting in the US, and byhealthcare in general, thanks to several nurses in hisfamily. “I knew Iwanted to go tomedical school andit was in the back of my mind that I wanted to bea cancer specialist.”With his family having returnedto Ireland, he did his main medical training inDublin and atGuy’s hospital, London, and took theinternal medicine path towards cancer, landingan oncology fellowship at Mount Sinai MedicalCenter in New York. In fact there was only onemedical oncologist in Ireland then – the inspira-tional JamesFennelly, who single-handedly broughtthe specialty to the country – although Crownalso encountered other top specialists in London.

“In New York at Mount Sinai I was under JimHolland – a great oncologist who was a founder ofone of the first large cooperative groups, Cancer

“It was easy to get caught up in the excitement

about high-dose chemotherapy for breast cancer”

CoverStory


ENDADORAN/EPA

one of the golf playing, rugby following physiciansfrom a fancy family – the health system was verypatriarchal, as it was too in the UK, where therewere thosewhowantedmedical oncology stoppedin its tracks, and it was terribly sad that patientswere being denied treatments that were dismissedby certain senior doctors.” He adds that UKmed-ical oncology was set back for years when the bril-liant Gordon Hamilton Fairley was murdered byIrish terrorists in London. “That is a source of per-petual embarrassment for me, especially at thetime of the ESMO award in his name.”

With more public awareness of the issues inIreland, pressure from advocacy groups and moresupport from government, additional posts werecreated for some of the outstandingmedical oncol-ogists in the Irish–American diaspora, andCrownsays there has long been a solid tranche of excellent,mainly British-trained, cancer surgeons in place.AtSt Vincent’s, as tends to be the case at other Irishhospitals, there is no head of cancer, and thevarious specialists have enjoyed a good deal ofautonomy to work on their own systems of multi-disciplinary care, with freedom to order the testsand scans they needed, and early access to drugssuch as Herceptin (trastuzumab). “To British col-leagueswehave seemedmore like anAmerican set-up,” he says. “But our bureaucrats are catching upwith us now.”

He is certainly no fan of Britain’s NICE(National Institute of Health and Clinical Excel-lence). “It tends to make a generation of cancerpatients suffer before it approves drugs – and theeconomic tools theyuse such as quality life years areblunt instruments. NICE has taken a narrow viewon several drugs and been proved wrong – such asthe four kidney cancer drugs we have now. Beforewehadnothing to offer these patients andwe knowthe drugs canmake huge improvements. You haveto factor in the rarity of certain tumours and theavailability of other treatments – I doubt thatNICEwould have approved the drugs used in theMOPP

and Leukemia Group B (CALGB). He was aninspiring and methodical clinical researcher. Iwanted to work at Memorial Sloan-Kettering aswell, and managed to get there later.”

He spent six years at Memorial in faculty andstaff positions, developing interests in bonemarrowtransplantation and high-dose chemotherapy, andwas recruited by Larry Norton as the first contrib-utor to a new breast group.

Crown says it was easy to get caught up in theexcitement about high-dose chemotherapy forbreast cancer because early use showedhigh remis-sion rates, although very high toxicity. Manywomen, especially in the US, were treated in thisway, and at great cost, and it wasmandated by someAmerican states. But of course when large ran-domised trialswere carried out, including byCrownafter he had moved to Ireland, with British oncol-ogist Bob Leonard, the results were disappointingwhen comparedwith conventional chemotherapy.

As he noted in a comment in The Lancet in2004, there is probably “no other treatment inmedical history that has had such ameteoric rise oras humiliating fall from grace as high-dosechemotherapy”.When one ‘positive’ trial was foundto be fraudulent, there was added notoriety for theapproach. “But it was very important to do thenegative trials of course,” he says.

Other work that Crown did in theUSwas ulti-mately more fruitful. “I also worked on paclitaxel(Taxol) and docetaxel (Taxotere) and found myfeet as a drug developer, and I spent a year workingin the lab with Janice Gabrilove, a great scientist,on approaches using G-CSF and interleukin.”

With a post at such an illustrious cancer centre,it was only a rare consultant’s position that temptedCrown back to Ireland and, as he now knows, hewas competingwith several others whowent on tobecome eminent in other places. “But it was areal riches to rags experience,” he says. “When Istarted to speak out against the poor cancer carewehad then there were attempts to gag me. I wasn’t

CoverStory


“When I started to speak out against the poor cancer

care we had then there were attempts to gag me”

regime for Hodgkin’s lymphoma at the time.”As he adds, the cost of funding drugs for a few

thousand kidney cancer patients in an economysuch the UK is not high, and spending on health-care is no bad thing, particularly in a recession,given that some economists take the Keynesianviewpoint of stimulating growth. “But obviouslywemust ensure we do not spend wastefully. TheAmericansmade a colossalmistake in cancerwhenthey allowed oncologists to sell the drugs theywere themselves prescribing.”

Some government decisions have been easy tomake in cancer services, such as cutting out hospi-tals performing too fewbreast cancer operations, butthere is a constant battle to counter bureaucraticdecisions, says Crown. A recent programme toestablish centres of excellence for cancer care hasmet the full force of his pen. On reallocating serv-ices, though strongly in favour of the principle, heis scathing aboutwhat he sees as arbitrary decisionsthat ignore evidence of local expertise.

Another part of his armoury is a business mas-ters degree (MBA) he completed in 2000, with athesis on strategy for Europeanmedical oncology,such as proper recognition of the specialism andtrue multidisciplinary care, much of which hasnow happened. “One of the first things they teachyou on an MBA is the difference between man-agement and leadership,” he says, pointing also tohugely critical comments he has made aboutbailouts of the Irish banks and what that moneycould have bought in the health service, from hos-pital funding, to hiring colorectal cancer specialists,extendingmammography to the over 65s, cervicalcancer vaccination andmore. “We could have vac-cinated the whole world against cervix cancer forwhat we spent on our bank bail out.” His messagewas: “don’t kill the health service to pay goons” –and nowhe is in parliament he has become an evenmore formidable advocate.

Other topics that have received the Crownbroadside include complementary therapies (“intel-

lectually dishonest”), local financial mismanage-ment, and – not least – attempts to gag physiciansfrom speaking out (he himself made headlineswhen he was dropped from appearing on a televi-sion programme alongside health officials).

Like other oncologists returning to ‘unfashion-able’ parts of Europe, it has been research that hashelped give Crown this platform. Not only did heset up a clinical trials unit at St Vincent’s, but in1997 he founded, with JohnArmstrong, the IrishClinicalOncology ResearchGroup (ICORG), fill-ing a major gap. Until then, Ireland had been theonly country in western Europewithout a nationaltrials group.

He carried out a great deal of work on con-ventional chemotherapy while in Ireland, includ-ing trials with various international cooperativegroups on paclitaxel and docetaxel. For the latterhe was one of the senior investigators who pre-sented evidence that it was superior to doxorubicin(Adriamycin) to theUS regulatory body, the FDA,leading to its approval. His experience with trialdesigns for these and other drugs such as cis-platin and carboplatin was especially valuablewhen he became involved in trastuzumab andthe dawn of clinical molecular medicine – but itwas, as he admits, a lucky break.

“I got a call fromDennis Slamon, whom I knewonly by repute, saying he’d like to bring a group ofIrishAmericans to Dublin, and we hosted a semi-nar onHER2.He also said he’d like to include Irishpatients in the original pivotal trial of the drugtrastuzumab.” Slamon of course is the legendaryoncology chief at theUniversity ofCalifornia inLosAngeles (UCLA) who spent years researchingHER2 biology and pushing for drug development.“We said we would love to be part of the trial butunfortunately we then spent months arguing withour ethics committee, which said we shouldn’t beexperimenting on cancer patients, and we onlymanaged to get one person on the trial and somissed out on authorship. But when the next trials

He supports reorganising services around centres of

excellence, but is scathing about the way it is being done

CoverStory


elegant, sophisticated molecular drugs as if theywere chemotherapy – itself a by-product of thechemical weapons industry.”

He adds that scepticism stemmedmostly fromdoubt that a consortium of investigators wouldfollow a complex, radical protocol for a large trial,and that a more open, permissive design was nec-essary to carry out such studies. “I didn’t doubt wecould do it and neither didmy colleagues.And forBCIRG-6 we got 3220 patients signed up – anextraordinarily high rate of trial compliance.”

ICORG, which also covers researchers inNorthern Ireland, has been a success, saysCrown.It now employs 20 people and includes some 100researchers, and has a full portfolio of patients intrials in most tumour types, and at one point 35%of all breast cancer patients were in studies. “Mostpharmaceutical companies have now opened clin-ical trials offices in Ireland, andwe’ve been able toprovidemanymillions of eurosworth of free drugs,”he says. In keeping withAmerican links, ICORGwas also the first group outside of NorthAmericainvited to join the National Surgical Adjuvant

came along we were jointly leading them.”The trastuzumab trials run by Slamon and col-

leagues were under the BCIRG (Breast CancerInternational ResearchGroup), now part of TRIO(Translational Research inOncology), andCrownsays they were well designed, according to ‘vision-ary’ questions that Slamon wanted to test, and bya close-knit group of researchers – in contrast tosomeother trials that he describes as often “dismal”.

One international trastuzumab phase III trialled by Slamon, in which Crown was closelyinvolved with the design, was BCIRG-6, a com-plexmulti-arm trial that tested various concurrentchemotherapies, and which he says was also rad-ical in that some patients would not be receivingdoxorubicin. “I crossed theAtlantic 13 times dur-ing the design phase, and there was much scep-ticism about it, including from the corporatehosts, who almost undermined it,” he says. “Therewere several other trastuzumab trials taking placethat just picked what was thought to be the bestchemotherapy and added Herceptin. Ourapproach was that you couldn’t be developing

CoverStory


ENDADORAN/EPA

possibility that we may be able to cure metastaticbreast cancer – I knowwedid cure somewith high-dose chemotherapy but the numbers were notworth the toxicity involved.With trastuzumab,mycolleague Giuseppe Gullo at St Vincent’s pre-sented a great abstract at ESMO showing we nowhavemany long-term disease-free survivors.” Oneof themost exceptional cases he’s seen in Ireland,he adds, was awomanwhose liver had deterioratedbadly and was given trastuzumab outside of a trialbecause she couldn’t take the chemotherapy aswell. “We got permission to give Herceptin to herand within a year her liver had returned to normaland she’s never relapsed. We stopped the drugthree years ago. I believe we are curing 5–10% ofadvanced breast cancerswe treat with trastuzumaband chemotherapy, and that’s unprecedented.”

He also mentions a potentially extraordinaryfinding from aNorthAmerican trastuzumab adju-vant trial, where about 160 patients who wereHER2-negative got on the trial – “But Herceptinseemed to work for them as well. It could be afluke, or there may be a biological explanationconcerning stem cells, or immunology, which isbeing researched.”

Given the increasing complexity of medicaloncology, it’s no surprise to find that Crown is astrong critic of other specialists, such as surgeonsand radiation oncologists, becoming involved withdrugs. “Those gynaecologists who deliver babiesand treat breast cancer with chemotherapy mustbemuch smarter thanme,” he says. “Seriously, thediscipline of drug therapy in internal medicine iscritically important and we are likely to see sub-divisions within medical oncology according tomolecular subtypes.”

Given that there has been no recent breastcancer drug successes on the scale of trastuzumab,Crown says it’s possible that the HER2 target is“low-hanging fruit”. He notes promising datathough on everolimus (Afinitor) for oestrogen-positive disease, but overall “the next generation of

“The HER2 target may be ‘low-hanging fruit’. The next

generation of drugs may be far harder to develop”

CoverStory


Breast and Bowel Project (NSABP), the majorUS-based trials group.

Another concern about trials, says Crown, isthe lack of effort going into looking for biomarkersin subgroups. “For example, I was involved in astudy on sunitinib in breast cancer. It does produceresponse in some patients but all the randomisedcontrolled trials were negative. The tragedy wasthere was no tissue collection to look for bio-markers. We are defining eligibility on old tech-niques and not matching the extraordinaryprecision of our new therapies with the right diag-nostics and prognostics. It cost the drug com-panymanymillions of dollars andwemay have lostan agent that could benefit some patients.We aredetermined that most of the trials we join fromICORG should have mandatory tissue collectionand a translational component.”

Too many companies think that finding bio-markers will restrict market size, he adds – butunless the benefit is clearly evident, there can be nomarket, such as with bevacizumab (Avastin) inbreast cancer, which Crown says he is no longerusing except in some existing patients.

“Weneed to stop thinking about existing phasesin drug development and start collecting tissueon day one with every patient, and try and designeach stage with meaningful molecular predeter-mination of eligibility, or if not we should at leastcollect larger tissue banks at phase II to see if apatient group benefits.We’ve become conditionedby small benefits. If we’d taken this approachwithHerceptin we would have seen excellent benefitsat phase I and II, and by the phase III adjuvantstage, instead of requiring four trials of 3000patients each, I bet we would have had a positiveresult with one trial of say 400 patients, because thebenefit was so big – aswe had the rightmarker andthe right molecule.”

The story of HER2 biology just keeps expand-ing, he adds, with a growing family of newmolec-ular treatments. “It’s fascinating and there is the

Off duty. Withhis childrenKatie (left),Mia and Jack

impact, speaking out in the senate for a ban onsmoking in any enclosed space where childrenmay be, such as in cars. He described their expo-sure to smoke as “a form of child abuse”, addingmedical details of the different respiratory rate ofchildren. “I used to be a smoker myself and I’veheard all the so-called arguments about civil liber-ties – they are just addiction thinking. I’d like to seetheEuropean parliament giving say 10 years’noticethat it will be illegal to manufacture and importtobacco products.”

Europe presents a possible future avenue forCrown.On the cancer front, he is keen to promotesmall, fast-moving research groups, as exempli-fied by BCIRG/TRIO, that can harness diversitybut will avoid the ‘committeeism’ that he feelssome cooperative groups have succumbed to. Hewas among the founders of the campaign to stopthe European clinical trials directive, and perhapshe couldmake a bigger contribution at policy – andpolitical – levels by stepping away from the clinicand further into Irish and European affairs.

“I’m in the Irish senate for five years and I willcontinue to developMTCI – and the big questionis whether I put more time into politics. I couldalso aim to combine my medical research expe-rience with my interest in public adminis-tration – and we Irish certainly makegood bureaucrats.”

The trouble he faces is that, as withcancer research, there are just somanypolitical targets to aim at.

drugs may be much harder to develop”. In anycase, he reckons Ireland will be in the frontline ofmolecular selection in drug development in early-stage trials, and reports that there are now “brilliant”researchers in place. “I think youwill see a lot fromIreland in translational research in the next fewyears,” he says, mentioning a key enabler, Molec-ular Therapeutics for Cancer Ireland (MTCI), a‘strategic research cluster’ funded by ScienceFoun-dation Ireland and set up in 2009.

Crown is the principal investigator for MTCI,which is researchingmainly breast cancer targets,such as novel therapies for triple negative disease.MTCI and ICORG are uniting the country’s can-cer research effort, he says. Ireland has sixmedicalschools – a high proportion for its population,despite having a relatively low number of doctors –and there is now much more cooperation thancompetition among them and with researchers atother locations.

While Crown’s primary interests lie in treat-ment, he recognises that major advances lie inprevention and early detection. “You can’t overlookthe benefits of ending hormone replacement ther-apy and factors such as obesity in breast cancer,while the advances in imaging for detectionwill bebreathtaking.” Both his daughters received thecervical cancer vaccine, he revealed publicly – asensitive topic in Ireland.

Tobacco is an area of preventionwhere Crown has made a political

CoverStory


e-GrandRound


Endotherapy for Barrett’soesophagus with early neoplasia

Unnecessary oesophagectomies continue to be performed in many centres because of a lack of

knowledge about the efficacy and safety of more conservative options. Massimo Conio looks at

the evidence for two alternatives – endoscopicmucosal resection and radiofrequency ablation –

and discusseswhich patients should be eligible andwhere the treatments should be carried out.

We can safely and effectivelyuse an endotherapy approachin patientswhohaveBarrett’s

oesophagus lesions infiltrating to themuscularismucosae,whichmeans aT1acancer. The limit of endotherapy treat-ment is shown clearly in the figure over-leaf. Surgery is required forT1bcancers,which involve submucosal invasion ofthe oesophagus. The most well-knownapproach for endotherapy is endoscopicmucosal resection (EMR),whichenablesremoval of any malignancy in themucosa. It also provides an adequateassessment of the histology and enablesaccurate staging. This approach there-fore enables us to decide what to offerpatients as radical treatment.

A recent study showed how endo-scopic mucosal resection can improvestaging,with downstaging of the lesion in28% of cases and upstaging in 20%(Am J Gastroenterol 2010; 105:1276–83). This demonstrates how useful thistechnique can be.

Retrospective studies comparingendoscopic treatment and surgical treat-ment of muscosal T1a lesions in Bar-rett’s patients show comparable overall

The European School of Oncology pres-ents weekly e-grandrounds which offerparticipants the opportunity to discussa range of cutting-edge issues, fromcontroversial areas and the latest sci-entific developments to challenging clin-ical cases, with leading Europeanexperts in the field. One of these isselected for publication in each issue ofCancer World.In this issue, Massimo Conio, of theDepartment of Gastroenterology, San-remo Hospital, Sanremo, Italy, providesan update on the latest developments inthe use of endoscopic treatment inpatients with Barrett’s oesophagus com-plicated by superficial cancer.Peter Siersema, of the University Med-ical Centre Utrecht, in the Netherlands,

poses questions arising during thee-grandround live presentation.The presentation is summarised bySusan Mayor.

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

survival (Gastroenterology2009, 137:815–823). Thismeans that it is no moreeffective to send a patientwith such a lesion to thesurgeon to have theiroesophagus removed thanto treat with endoscopicresection. The major ad-verse effect on quality oflife means it is always bet-ter to avoid surgery whereappropriate.

In the past, resectionwas used to treat only visi-ble, focal lesions.However,the riskwith leaving behindawide surface of neoplasiais that metachronous lesions might bepresent. At the beginning, endoscopicmucosal resection was consideredmainly for patients of advanced age andthose with comorbidities. Until a fewyears ago the gold standard treatmentwas still, unfortunately, oesophagectomy,which had the advantage of providingnot only the entire specimen, but alsoof removing all lymph nodes. Thingsare changing today. In patients withsegments shorter than 4 cm, it is nowpossible to consider removalwithmuco-sectomy or similar techniques.

HOW IS RESECTIONPERFORMED?Resection is usually per-formed by using a plasticcap placed on the tip ofan endoscope or using amultiband ligator (MBM).Avery simple study showedthat the only significant dif-ference between the twoapproaches was proceduretime, which was shorter inthe MBM group (Gastro-intest Endosc 2011, 74:35–43). This technique is alsoconsiderably easier than

oesophagectomy and can therefore beperformed in centres with a lowerannual number of patients, althoughthey should nonetheless be sent to refer-ral centres. Unfortunately, the studyshowed that perforations occurred inthree patients undergoing EMR-capresection and in four patients undergo-ing MBM, but this rate is unusual, ascan be seen in the table on page 18.

Question:What is yourpreferencebetweenthe two techniques for removing tissue fromthe oesophagus: cap resection orMBM?


e-GrandRound

Answer: I started with capresection so am used to thismethod andwill continue touse it with most of mypatients because of the expe-rience gained, but I thinkthe risk of perforation shouldbe lower withMBM.

A historic paper analysingthe result of mucosec-tomy in patients with low-risk early adenocarcinomalesions (I, IIa, IIb andIIc), in which histologi-cal assessment showed nolymphatic or vein inva-sion, demonstrated that

complete resection was achieved in96% of cases (Gut 2008, 57:1200–06). Endoscopic resection failureoccurred in 4% of patients, resultingin their having surgery, and metachro-nous lesions were seen in 21%. How-ever, the five-year survival rate wasvery good, at 84%. If you are ableto select patients carefully, I thinkthat the five-year survival could bealmost 100%.

What about cases where there isminimal infiltration of the submucosa?A very limited study suggests that in

themost favourable cases –invasion of only the super-ficial layer of the submu-cosa, no infiltration of thelymphatic vessels or veins,a good histological differ-entiation grade G1 or G2,and macroscopic typeI or II – then maybeoesophagectomy shouldbe avoided (Am J Gastro-enterol 2008, 103:2589–97). However, when thereis oesophageal invasion andthe patient is fit for surgery,they should be referred toa surgeon.

THE LIMIT FOR ENDOTHERAPY TREATMENT

T1a cancers can be managed by endotherapy; for more advanced cancerssurgery is required

A SMALL EROSION AT THE TOP OF THE OESOPHAGUS

This patientcould betreated with acircumferentialmucosectomyto completelyremove Barrett’soesophagusSource: Image

courtesy of

Massimo Conio

plete eradication ofBarrett’s oesophaguswith stepwise endoscopic mucosalresection or with the new methods ofradiofrequency ablation.

A retrospective studyof stepwise rad-ical endoscopic resection in169patientsfrom four referral centres,with aBarrett’soesophagus length <5 cm and endo-scopic mucosal resection performedevery four to eightweeks until completeeradication of Barrett’s oesophagus,showed eradication of neoplasia wasobtained in 98% of patients, but eradi-cation of intestinal metaplasia occurredin only 85% (Gut 2010, 59:1169–77).Four perforations occurred acutely dur-ing the procedure, and two perforationsoccurred late during dilation of stenoses.The main drawback of this technique isthe onset of stenosis, which can be areal problem. In the study it affected50% of patients.

Question: Does endoscopic mucosalresection becomemore difficult when youdo this in a second procedure or in a thirdprocedure? Is it more difficult to com-

Question:This canbe quite a dif-ficult diagnosis for a pathologist tomake. What kind of pathologistshould look at this type of tissue?And can you comment onhow tis-sue should be delivered to thepathologist and how it should beprocessed in the laboratory?Answer:This is a very interestingquestion. First of all, after eachresection with EMR-cap you canimmediately retrieve the specimen,which should be fixed by pinningit on a tablet. If you put it in a bot-tle itwill shrink,making it difficultfor the pathologist tomake an ade-quate assessment, particularly ofthe depth of the lesion.Youneed tofix it as soon as you can. There areartefacts due to the resection andcauterisation, but in most caseswe can achieve quite a deep resec-tion. The pathologist should be trained inthis area. There are a lot of problems in dif-ferentiating low-grade dysplasia frominflammatory reactions, and so on. It isalways good tohave a couple of pathologistsjudging a specimen.

The figure on page 14 (bottom) shows apatientwith a small erosion at the top ofthe oesophagus. We decided to com-pletely remove Barrett’s oesophagus,performing a circumferential mucosec-tomy. The figure above shows a patientwith metachronous lesions, whom wedecided to send to the surgeon. The badnewswas that the patient underwent anoesophagectomy, but the goodnewswasthat therewas no remaining cancer andthe lymph nodes were negative.

METACHRONOUS LESIONSAFTER EMRThere is a 30% risk of developingmetachronous lesions after endoscopicmucosal resection. It has therefore beensuggested that we should ensure com-

plete the whole resection if youcome back a second or third time,because fibrosis could make itmore difficult to lift and removethe lesion?Answer: This is a problem, so inselective cases I prefer to carry outcomplete resection in one sessiononly, and not stepwise, because ofthe risk that fibrosis due to scarringmay prevent an adequate resectionof the residualmetaplastic tissue inthe following endoscopic sessions.

The figure overleaf shows a sig-nificant stenosis occurring twoweeks after a procedure (topleft). In refractory cases we usea removable stent (top right),left in place for four to sixweeks, which is easy to remove.We do not usually use stents

larger than 16mm. For the future,stents are being developed that willreduce the risk of migration, which canoccur in these patients.

The BARRX system can be used toachieve destruction of the oesophagealwall, using radiofrequency ablationwith probes of 360o or 90o, until themuscularis submucosa. The stenosisrate with this system seems to belower. A study by Shaheen publishedin 2009 (NEJM 360:2277–88) ran-domised 127 patients (64 with low-grade dysplasia, 63 with high-gradedysplasia) to radiofrequency ablationor a sham procedure. Complete erad-ication of intestinal metaplasiaoccurred in about 75% of patients withradiofrequency ablation at 12 months(see figure overleaf, bottom); eradica-tion of low-grade dysplasia wasachieved in about 90% of patients andhigh-grade dysplasia in 80%. Therewas a striking difference compared topatients who did not receive this treat-ment. However, follow-up was rela-tively short, at only 12 months, and

e-GrandRound


METACHRONOUS LESIONS IN THE OESOPHAGUS

This patient could not safely be treated with endoscopic mucosalresection and was referred to surgery for a full oesophagectomySource: Image courtesy of Massimo Conio

there was a problem with subsqua-mous intestinal metaplasia. The num-ber of strictures was very small,however, at 6%.

Question: In terms of the complete erad-ication rate, 75%may represent a good suc-cess, but on the other hand it means that25% of patients have Barrett’s oesophagusleft behind. This is not good because of therisk of developingmalignancy.Answer: I think that many thingsmust be analysed inpatients under-going radiofrequency ablation andwe should, of course, achievehigherrates of eradication of intestinalmetaplasia. There is always the riskof subsquamous mucosa andpatients need to be maintained ona surveillance protocol.

The same group analysed thedurability of response to radiofre-quency ablation in a group of 106patients with Barrett’s oesopha-guswith dysplasia. They aimed toevaluate the eradication of neo-plasia; the eradication ofBarrett’soesophagus; the durability of

response; disease progression andadverse events. The results for eradica-tion of neoplasia and Barrett’s oesopha-gus at two years (n=106)were very good–95%and93%, respectively – andmoreor less the same at three years (n=56)–98% and 91%, respectively (Gastroen-terology 2011, 141:460–468).

At three yearswithoutmaintenance,complete eradication of neoplasiaoccurred in more than 85% of patients

and complete eradication ofintestinal metaplasia in morethan 75%. There is always therisk of persistence ofmetaplasia.Adverse events were reported in3.4% of cases; oesophageal stric-tures accounted for 7.6% ofadverse events.

In terms of disease progres-sion, three patients with low-grade dysplasia progressed tohigh-grade dysplasia, one pro-gressed fromhigh-gradedysplasiato cancer, and one from low-grade dysplasia to adenocarci-noma. This ratemeans that 4.2%of patients must undergo endo-scopic follow-up (one per 73patient-years). The cost of sur-veillance of these patients will

be maintained, but it still represents agreat advance.

In an editorial accompanying thepaper by Shaheen and colleagues,Inadomi pointed out that you need fourradiofrequencyablationsessions toobtaincomplete eradication, and then 50% ofthese patients require further radiofre-quency ablation sessions in the secondand third year (Gastroenterology 2011,141:417–419).This indicateswe should


e-GrandRound

COMPLETE ERADICATION USING RADIOFREQUENCY ABLATION

At 12 months follow-up a strikingdifference was seen between thepatients in the control arm, who weretreated with a sham procedure andthose treated with radiofrequencyablation, in the rates of completeeradication of low-grade and high-grade dysplasia (LGD/HGD) as wellas intestinal metaplasia (IM)Source:NJ Shaheen, P Sharma,

BF Overholt. NEJM 2009; 360:2277–

88; © Massachusetts Medical Society,

reprinted with permission

MANAGING STENOSIS

Stenosis – severe narrowing of the oesophagus – is a complication that may occur in up to 80% of patientstreated with a circumferential endoscopic mucosal resection (left). In refractory cases it can be treated witha temporary stent (right)

performed at a centre where there is anexpert and use of stents is routine, andweneed to explain this to patients.Com-plete eradication of neoplasia andmeta-plasia was achieved in 96% of patients.

Of the 47 patients treated withcircumferential endoscopic mucosalresection, only two underwent surgery:one took a personal decision to undergooesophagectomy and the other under-went superficial adenocarcinoma.

During follow-up of theremaining 45, seven (16%)had residual areas of Bar-rett’s oesophagus, whichwere very small (<5 mm)and were successfullytreated with endoscopicablation using argon plasmacoagulation (APC).

Overall, studies of one-step circumferential EMR-cap resection in Barrett’soesophagus with early neo-plasia show good outcomes(see table overleaf). Themaincomplication is stenosis,which affects between 2%and 88% of patients in thedifferent studies.

Massimo Conio (MC):What do you think about risk

of stenosis?Peter Siersema (PS): Stenosis is one ofthe concerns with this technique. On theother hand, as shown clearly in your data,patients undergo a median of only onedilation session, so the majority of thesestrictures can be managed very easily inone or two dilation sessions. Inmy experi-ence, stent placement is generally notrequired for dilation of these restrictions.So risk of stenosis is a cause for concern,but it is a manageable concern that doesnot affect your patients’ quality of life.Bleeding can be a concern, however, if youare not experienced. It seems quite severeand quite dramatic, but inmy experience

use the term ‘remission’andnot ‘completehealing’or ‘complete regression’, becausethere is always the risk of subsquamouspersistence, even if it is minimal, whichmeanswe need to follow up.

Amulticentre randomised trial com-pared stepwise endoscopic mucosalresection (SEMR) against radiofre-quency ablation (RFA) with or withoutendoscopic mucosal resection to lookat the recurrence of stricture. It inclu-ded patients with Barrett’soesophagus length <5 cmwho underwent at least foursessions of SEMR or RFAfollowing resection of focallyresectable visible lesions(Gut 2011, 60:765–773).The study was relativelysmall, including only 47patients (25 undergoingSEMR; 22 RFA±EMR). Atthe end of the follow-up,complete response of neo-plasia occurred in 100% ofpatients in both arms, andcomplete response for intes-tinal metaplasia occurred in20 out of 25 patients under-going SEMRand in 18 out of20 treated with RFA±EMR.But we are waiting for moreresults, because the numberof patients is small and follow-up wasonly three years in the studymentionedpreviously, so we have to see what willhappen in another two or three yearsbefore making decisions on treatingevery Barrett’s oesophagus patient withradiofrequency ablation.

What aboutcomplications?Themostimportantcomplicationswerestenoses: inthe SEMR group, stenoses accountedfor fiveof thesix severecomplicationsandfor 17 of themoderate complications; intheRFAgroup, threestenosesoccurred inpatients with moderate complications.Overall, the rate of stenosis was 88% inthe groupundergoingmucosal resection

versus14%in the radiofrequencyablationgroup (see table below).

Based on current evidence, radiofre-quency ablation should be offered topatients with low-grade and high-gradedysplasia and a long extension of Bar-rett’s oesophagus, because there is alow rate of stenosis and it is very easy toperform. Unfortunately, there is a lackof histological examination andwe needto follow up.

PERSONAL EXPERIENCE OFONE-STEP CIRCUMFERENTIALEMR-CAP RESECTIONI have just submitted for publicationmygroup’s experience of one-step circum-ferential EMR-cap resection of Barrett’soesophagus with early neoplasia. Thestudy includes 47 patientswithBarrett’soesophageal length of about 3.0±1.4 cm,all with either high-grade dysplasia orintramucosal carcinoma (Conio et al,submitted 2012). Results showed astenosis rate of 30% using one-stepEMR in this group of patients. This is asignificant rate of stenosis, butwe shouldnot worry about this if the procedure is

e-GrandRound


COMPLICATIONS: STEPWISE EMR VS RFA

Stenosis accounted for the majority of severe and moderate complications inthis multicentre randomised trial. All six serious complications and the greatmajority of moderate complications were in the mucosal resection groupSource: FG Van Vilsteren, RE Pow, S Seewald et al. Gut 2011; 60:765–773

most of these bleedings can be managedendoscopically very easily with all thedevices we have nowadays.MC: I agree.When you perform this tech-nique you must be able to cope with anycomplications. The most feared compli-cation is perforation, which almost neveroccurs, and bleeding. We can stop thebleeding quite easily andwellwithnewhotbiopsy forceps and it is not usually neces-sary to use clips. I had an experience threemonths ago in a patientwith a long sectionof Barrett’s oesophagus who had torrentialbleeding, and I was unable to pass anydevice through the channel. Because ofhigh outflow of the blood I decided totamponade by placing a Blakemore–Sengstaken tube, and I left it there for

24 hours. This was a first time forme, butthe bleeding stopped after 24 hours.

I think that this type of treatmentshould be performed only in referral cen-tres where endoscopy experts are avail-able. You must have every kind of device,and youmust have the experience to copewith severe complications.

MANAGING PERFORATIONSThe figure opposite (top) shows a newmethodwhich allows the sealing of gas-trointestinal perforation with an over-the-scope clip device (OVESCO).(Details can be found in GastrointestEndosc2010, 72:881–886,with videos.)

The figure opposite (bottom) showsan oesophageal perforation that

occurred during radiofrequency abla-tion (Endoscopy 2011, 43:67–69). Thiscorroborates my point that this proce-dure should only be performed in a cen-tre that has all available instruments.This case was treated with removableplastic stents, but nowadays I think wecan afford to use other stents.

In a patient with Barrett’s oesoph-agus, high-grade dysplasia andintramucosal cancer, we performendoscopic ultrasonography, mainlyfor the evaluation of the lymph nodes.But if is quite short (C ≤ 4 cm, usingthe Prague classification) we can prob-ably treat the patient with endoscopicmucosal resection. If it is longer, Iwould suggest it is better to perform


e-GrandRound

RESULTS OF ONE-STEP CIRCUMFERENTIAL CAP-ASSISTED EMR OF BARRETT’S OESOPHAGUS WITH EARLY NEOPLASIA

The nine studies reportedto date on the use ofone-step circumferentialEMR (EMR-C) in patientswith Barrett’s oesophaguswith early neoplasiashowed good outcomes,and varying rates ofcomplications, whichincluded stenosis,bleeding and perforationHGD– high-grade

dysplasia; BE – Barrett’s

oesophagus; MBM –

multiband ligator; APC –

argon plasma coagulation;

CEN – complete

eradication of neoplasia;

CEM – complete

eradication of metaplasia

EMR focally plus HALO radiofre-quency ablation. The histology willdetermine the patient’s further treat-ment. If there are no dysplasia oreverything is confined above themuscularis mucosa, we can offersurveillance. But surveillance shouldprobably stop after a couple of years ifwe have removed everything. Thisapproach has not yet been proved forpatients with submucosal cancer, andwe have to send them to surgery.

Question:What is the next step of follow-up after EMR in your study?Answer: I have not provided all the datafrommy studies, but we did not find can-cer or dysplastic lesions after two years offollow-up. So we suggest that in patientswho had complete resection, follow-upshould be carried out every five years ratherthan two years. There are other issues,such as what happened at the level ofthe new squamous/columnar juncture,because it has been shown that a lower-

grade dysplasia might be found. But Iwould say that complete resection mayallowus to observe these patients every fiveyears after the first year of intense control.

A study on the risk of progression inpatients with non-dysplastic Barrett’soesophagus showed that 96%of patientsfollowed for five years did not developcancer; after 10 years, 97% of thisgroup had still not developed cancer(Clin Gastroenterol Hepatol 2011,

e-GrandRound


SEALING A GASTROINTESTINAL PERFORATION WITH AN OVER-THE-SCOPE CLIP DEVICE (OVESCO)

Figure a shows the perforation in a patient with a sleeve gastrectomy. In figure b, the tissue is grasped and put inside the cap, with a clip outside.Figure c shows the clip as it is being released. Figure d shows the contrast medium and closure of the fistulaSource: X-ray images with gastrographin, courtesy of Massimo Conio

PERFORATION ARISING FROM RADIOFREQUENCY ABLATION

Patients should only be treated incentres that are equipped to dealwith any complications that mayarise. This perforation was treatedwith a plastic stent, but improvedversions that can reduce the risk ofmigration will soon be available

Source: B Vahabzadeh, A Rastogi,

A Bansal et al. (2011) Endoscopy

43:67–69; © Thieme Medical

Publishers, reprinted with permission

a b c d

9:220–227). The risk of pro-gression was very small, andwas only in patients withlonger extension (0.65% peryear in patients with a Bar-rett’s oesophagus measuring≥6cm). In my opinion, thismeans that radiofrequencyablation should be the pre-ferred option in all patientswho have a long extension,even if they have no form ofdysplasia, because it is verydifficult to sample everything.

MC: A Danish study pub-lished recently in the NewEngland Journal of Medicine(2011, 365:1375–1383) ofmore than 11,000 Barrett’spatients showed the risk of dis-ease progression was very low.So it is a nonsense to recom-mend radiofrequency ablationin every patient with Barrett’soesophagus that is not com-plicated even by low-gradedysplasia. What do you think?PS: I do think that theremight be a ques-tion for patientswith low-gradedysplasia inthe long term, especially now we knowsome more long-term results on this. Butthere is now a tendency in theUS for peo-ple to start treating patients without anydysplasia. We know that the risk in thatgroup is very low and there is no justifica-tion for treatment with radiofrequencyablation. I think for low-grade dysplasia itis still too early, and in recognised andcharacterised low-grade dysplasia theremight be a case for ablation therapy.Question: Looking at your treatmentalgorithm for high-grade dysplasia andintramucosal cancer (see above), youperformed EMR or EMR+HALO RFA.When histology showed no dysplasia youperformed surveillance, and for invasivecancer you performed surgery. I agree,but I do not fully understand what you

mean for patients with high-grade dys-plasia and early cancer who then undergosurveillance. Is that not something thatyou need to treat?Answer: If histology detected intra-epithelial neoplasia, then the patientshould undergo endoscopic follow-upfor at least a couple of years. I am talkingabout patients with radical removal ofintestinal metaplasia in Barrett’s oesoph-agus. In the future, we should avoidperforming focal mucosal resectionbecause it does not make sense. The riskof metachronous lesions is very high.

SUMMING UPRadiofrequency ablation is a very prom-ising technique,butweare stillwaiting forlong-term results after three years.Thereis plenty of room for further randomisedstudies. I would suggest these shouldideallybepan-Europeanstudies, because

this is quite a raredisease andnot many centres are able torecruit a largenumberof thesepatients.Ahigh level of endo-scopic expertise is requiredandpatients shouldbe sent toreferral centres that have awide range of multimodalitytreatments.

PS: While chairing a sessionon Barrett’s oesophagus foryoung gastroenterologists at therecentUEGW(UnitedEuro-peanGastroenterologyWeek),I found that it is sometimesdifficult for gastroenterologiststo convince their surgeons thatpatients with early cancers orhigh-grade dysplasia shouldundergo endoscopic treatmentand not surgical treatment.How would you advise thesegastroenterologists to convincetheir surgeons that it’s reallyworthwhile to consider endo-scopic treatment in these

patients instead of performing an openresection,which is still being done in quitea few centres all over Europe?MC: Themost important evidence is theliterature. The data have shown that theresults are comparable. In the best centresin the world, the mortality rate foroesophagectomy is 3% and the morbidityrate is about 40%. Surgeons should under-standwe are not competitors –we have towork together. If there is a patient inwhommucosectomy shows an invasive cancerinfiltrating themuscularismucosa – eventhe upper layer – surgery should be carriedout. But the quality of life with endo-scopic treatment versus surgery is very dif-ferent. Even the first day after endoscopictreatment, the patient feels very well, withno pain, and can go home in 48 hours. Incontrast, there are a range of complicationswith surgery, including anastomosis leak-age and impaired ability to eat normally.


e-GrandRound

Management algorithm for patients with high-grade dysplasia orintramucosal cancerHGD – high-grade dysplasia; IMC – intramucosal cancer; EUS – endoscopic

ultrasonography; pN – positive lymph nodes; C, M – Prague criteria for grading

extent of Barrett’s oesophagus; AC – adenocarcinoma; IM – intramucosal

MANAGEMENT ALGORITHM

At about 1pm on 5 November2011 – just after the scheduledend of the ABC1 (Advanced

Breast Cancer) conference in Lisbon,organised by the European School ofOncology (ESO) – history was madewhen a large multidisciplinary panelcomposed of experts from 15 countriescompleted its voting on the first globalrecommendations for the treatment andcare ofwomen andmenwithmetastaticbreast cancer.

For the first time, oncologists caringfor patientswith advanceddiseasehaveaset of evidence-based international con-sensus recommendations that can guidetheir decision-making.Patientswhowantto understand their treatment optionsand make informed choices have a doc-ument they can refer to that representsthe optimalmanagement of this disease,

andareapplicablealmost anywhere in theworld. And the prospects for improvingresults for patientswithmetastaticbreastcancerhave takena leap forwardnowthatthere is an agreed standard of care pro-viding a benchmark against which alter-native management strategies can becompared, introducing some structureto a field of clinical research that hasbeen chaotic for so long.

The panel voted on more than 50guideline statements thatwill be edited,confirmed and presented early this yearin a special paper inThe Breast, coveringall aspects of advanced breast cancer,frompsychosocial care to chemotherapyand targeted agents, to treatment of spe-cific sites of metastases.

Some statements about chemother-apy couldnot be agreed at the time–andotherswere far fromunanimous–which

was expected given the uncer-tainty and lack of evidence in anumber of areas. Indeed, theneed formuchmore researchis a themeunderpinning thenew consensus and wasmuchdiscussed at the conference.But given that this was the first interna-tional meeting of its type, a major goalwas achieved with agreement on a widerange of recommendations thatwill nowset abenchmark for apatient communitythat has long been suffering from incon-sistent treatment and lack of support.

SIX YEARS IN THE MAKINGThese recommendations, which aresummarised on pages 28 and 29, werenot thework of a few experts, cookedupover a period of weeks or months. Theymark a stage in an inclusive process that


CuttingEdge

Groundbreaking international consensus recommendations onmanagingmetastatic breast can-

cer have been welcomed by patient advocates and professionals alike. When backed by

strong political advocacy, they believe the guidelines will raise standards of care, give much-

needed structure to clinical research and improve awareness about a group of patients whose

needs have been neglected for too long.

International guidelines offerhope of speeding up progress

in advanced breast cancer� Marc Beishon


CuttingEdge

startedmany years ago. FatimaCardoso,one of the four senior breast oncologistscoordinating ABC1, who heads thebreast unit at the Champalimaud Can-cer Centre in Lisbon, opened the con-ference with a look back at thepreparatorywork that ledup to the event,which started with the formation of theinternational metastatic breast cancertaskforcebyESO in2005.This taskforceput forward initial recommendations

More than six years since the start of thislong process, Cardoso had a very clearmessage for the assembleddelegates: “It’stime to change. It’s time for treatment ofmetastatic breast cancer to follow guide-lines–anapproach thathasdonesomuchto improve results inearlydisease–and it’stime to tackle the lack of psychosocialsupport for women andmen.

“The same high-quality principlesused in the early-stage setting should

and proposals, whichwere published inThe Breast and the Journal of the NationalCancer Institute, andwere put up for dis-cussion inwell-attended sessions duringthe last three European Breast CancerConferences. Theprocess culminated inthis ABC1 conference, where an inter-national consensus groupmet to vote ona full, updated set of statements, in asimilar way to the StGallenmeeting forearly-stage breast cancer.

apparent than inOctoberwhenwe in theUS are awash with pink ribbons andupbeat messages about early detectionandsurvivorship,” she said. “Patientswithmetastaticdiseaseoften feelunwelcome,representing as theydoa fearedoutcomefor thosewith primary breast cancer.”

Now there are support groups forthosewith advanced cancer, she added,noting that several had posters at theconference. As more people are livinglonger, thanks to new treatments, theirday-to-day concerns take on newurgency, saidMayer. How do you man-age the effects of treatment and cancerprogression, or the impact of treatmentfailure, and the loss of function andplace in the community? “These take aheavy toll,” she said, adding that it is dif-ficult to plan and fund services for thisgroup of patients because there are noreliable statistics on how many haveadvanced cancer and where they are.“We lack an accurate count of this pop-ulation in theUS as distant recurrencesare not captured by cancer registries.”

It’s time for patients with advanceddisease to be counted and made a pub-lic health priority, said Mayer, who alsocalled for better funding for researchon metastases, and a rethink of clinicaltrials, particularly regarding the choice ofendpoints for efficacy, and full integra-tion of quality-of-lifemeasures, for exam-ple using patient-reported outcomes.

“If the confusion patients face in

by jointUS-European coordinators, andthe consensus panel included represen-tatives from nursing, psycho-oncologyand patient advocacy alongside toponcologists from several disciplines andawide variety of countries covering fourcontinents.

Leading it all, alongside Cardoso,were two top American breast medicaloncologists, Larry Norton fromMemo-rial Sloan-Kettering andEricWiner fromthe Dana-Farber Cancer Institute,together with Alberto Costa, a seniorbreast surgeon and director of ESO,whohelped ensure thepresenceofmanyof theworld’s leading specialists to pres-ent the state of the art for research andtreatment. And there was no holdingback on the highly complex scienceunderlying thehuge challenge of improv-ing outcomes.

GUIDELINES HELPINFORMED CHOICESBut this conferencekept a clear focus onpatients, so itwasMusaMayer, a patientadvocate who runs AdvancedBC.org, apatient support site,whogave thekeynotetalk.Mayer spoke of her experience as asurvivor of early breast cancer, of howshe met many fellow patients who laterdied from advanced disease, and of howlittle information and support there hadbeen. “Women and men living withmetastaticdiseasehavebeen largely invis-ible andunheard–atno time is thismore


CuttingEdge

apply,” she said,with allwomenandmenwith advanced disease seen by a multi-disciplinary team in a specialised breastunit, with each subtype of metastaticbreast cancer treated differently andaccording to evidence, with many morepatients inhigh-quality trials.At present,she added, in the majority of oncologydepartments even in the developedworld, patients with advanced cancerare often cared for by individual physi-cians, outside amultidisciplinary team.

Cardoso’s message on the need forurgent changewas strongly supportedbythe results of a survey carried out amongthe breast cancer community in the runup toABC1.More than 80% of respon-dents agreed that advancedbreast cancerdoesnothave thehighprofile of earlydis-ease, and they listed the lackof clear andapplicable management guidelines andthe lack of high-level evidence for treat-ment options as themain reasons why.

These guidelines are key, saysCardoso, because they not only repre-sent an international consensusbasedonavailable evidence, but they also help toprovide the setting to raise standardseverywhere, with greater consistency intraining and care, and to identify areas ofresearch priorities that needmore fund-ing and resources to optimise the man-agement of this disease.

ABC1 can claim to offer a strongbase for building such an internationalconsensus, she said, because it was led

“Patients with metastatic disease often feel unwelcome,

representing as they do a feared outcome”

“ABC1 is a crucial first step and patients and advocates

are watching and grateful that our time has finally come”

making treatment decisions can bereduced, andmeaningful guidelines canbe crafted that account for individual dif-ferences and respect patient preferences,it will help women and men withmetastatic breast cancer manage theanxiety and loss of confidence they feelwhen a treatment fails,” she said, adding,“ABC1 is a crucial first step andpatientsand advocates arewatching and gratefulthat our time has finally come.”

MANAGEMENT OFADVANCED DISEASEClinical aspects of advanced breast can-cer occupied themajority of the confer-ence, from imaging developments, wellsummarised byNehmatHoussami fromSydney, Australia, and pathology chal-lenges, discussed by Giuseppe Viale,from the European Institute of Oncol-ogy,Milan, to state-of-the-art treatmentof HER2-positive, triple negative andER-positive subtypes, and treatmentapproaches for specific sites (bone andbrain) and specific populations (olderand very young patients). These presen-tations set out the current evidence fromwhich the majority of the consensusstatements have been developed.

HER2+ subtypeOn the HER2+ subtype, for example,Cardoso set out the evidence for itsmanagement – that it is awell-identifieddisease and selection of patients is cru-cial; the targeted drugs trastuzumab andlapatinibworkwell; there is a good safetyprofile of the agents; and trastuzumabcan be combined with several differentchemotherapies. But brain metastasesare an important problem, and resistanceto therapies inevitably occurs – a topiccovered in somedetail byGeorge Sledgefrom Indiana University, and the thenASCO president. Ian Krop fromDana-Farber looked at someof the drugs in thepipeline thatmight help address someofthese issues.

brain metastases, with contributionsfrom Robert Coleman, of Sheffield,UK, and Nancy Lin of Dana-Farber.In bone, a new antibody drug, deno-sumab, is showing benefit.

Younger patients, older patientsParticular issues in the managementof patients who are very young (below35 years old) were also discussed.Data on optimal therapy for womenaged below 35 are sparse becausefew develop metastatic disease. KarenGelmon from the British ColumbiaCancer Agency, Canada, said it is notknown whether therapies for olderwomen are equally applicable in thoseunder 35 or 40, and she charted pos-sible options, noting that there is ahigher proportion of triple negativeand HER2+ disease in some youngerpopulations. There are also manysocial and lifestyle factors to considerwith these groups, she said.

Prudence Francis, from the Mac-Callum Cancer Centre in Mel-bourne, Australia was among thosewho travelled furthest to ABC1. Shenoted the under-representation ofolder people in clinical trials despitethe rising incidence of metastatic dis-ease in an ageing population. Shealso described how comprehensivegeriatric assessment can help meetgood quality of life and function, andoutlined the treatment strategies –some of which are underused – thatare more suitable to older patients.

CuttingEdge


Triple negative diseaseIn contrast, there are no targeted ther-apies approved yet for triple negativedisease, which causes a disproportion-ate number of deaths, reported EricWiner. The conference heard fromAndrew Tutt, based at Guy’s Hospitalbreast unit in London, about the latestdevelopments in PARP inhibitors,which have been the subject of muchattention but also disappointment inthe cancer world, and from Angelo DiLeo, Prato, Italy, on other possible tar-geted approaches. Despite early hopes,the anti-angiogenesis drug bevacizumabnow appears to have no survival value(and indeed the FDA has withdrawnapproval in the US for use in advancedbreast cancer).

ER+ subtypeThe much more common endocrine-responsive (ER+) category – whichaccounts for 75–80% of cases – was alsogiven a thorough review. A group of toponcologists, including Bella Kaufman(Israel),OliviaPagani (Switzerland),NadiaHarbeck (Germany)andCliffHudis, fromMemorial Sloan-Kettering and ASCOpresident-elect, covered the topics of hor-mone therapy, the complexity of applyingchemotherapy in this group, and theappli-cability of targeted therapies.

Managing bone and brainmetastasesThe conference heard too about com-plex management issues for bone and

TREATING PATIENTS IN POORER COUNTRIES

Nagi Saghir, from the Breast Center of Excellence in Beirut, described the growing burdenof breast cancer in low- and middle-income countries, where in many it is common for womento be diagnosed with locally advanced or metastatic cancer. Much work is needed on rais-ing awareness, improving access to drugs and to high quality palliative care, and counter-ing the ‘brain drain’ of health workers through better local training opportunities, he said.


CuttingEdge

General recommendations� As management of ABC is complex it is

crucial that it is carried out by a multi-

disciplinary team

� From diagnosis, patients should be

offered routine psychosocial and symp-

tom-related care

� The virtually incurable nature of the disease

must be explained and discussed, as

well as realistic treatment goals

� Patients and their families/caregivers

(where appropriate) should be invited

to take part in decision making

� As there are few proven stan-

dards of care, inclusion in clin-

ical trials must be a priority

whenever available

� Balanced decisions about

costly treatment should

be made, but patient

preference, wellbeing and

length of life should be the

main decision factors

� Validated patient-reported

outcomes provide useful infor-

mation and should be integrated

with clinical assessments

GUIDELINES FACILITATE RESEARCHEricWiner stressedhowcommon it is forgeneral oncologists, and not just breastspecialists, to take care of patients withadvanced disease, adding to the impor-tance of getting international guidelinesagreed, disseminated and used. Yet healso argued that guidelines are not ananswer in themselves. “I think sometimespeople forget thepurposes that guidelinesserve.Theydo lead tobetter carebyelim-

inating some variability, and especiallyunnecessary care.Butwhatmaybemoreimportant from my perspective is thatguidelines facilitate research.”

He described three inputs intoresearch – first, if patients are treatedaccording to guidelines it ismuch easierto look back and assess how they havedone, which will contribute to compar-ative effectivenesswork. Second, a greatdeal is learnedwhenprofessionals strug-

gle to come up with a guideline for agiven problem, as there is a lot of debateand uncertainty, and that automaticallymeans there is a need for prospectiveclinical research.And finally, practisingaccording to guidelines helps craft anoverall clinical trials agenda. He calledfor better partnership with basic scien-tists, improved access to biopsy tissueand an end to the ‘intolerable’ delayscaused by regulations.

Assessment� Minimal staging work-up recommendations; tumour markers can be an aid;

a framework for response to therapy; safe biopsies of metastatic lesions

at first diagnosis; reassessment of ER and HER2 status at least once

� The panel did not recommend routine brain imaging for HER2+ and triple

negative patients

If you are responsiblefor treating patients

with advanced breastcancer, or are a patient

trying to decide on thebest treatment options,

these guidelines are for you!

use the guidelines !

This text is a brief summary.The Guidelines will be publishedin full in the Breast and online

at www. abc-lisbon.org

Guidelines formanaging patients with advanced breast cancer

CuttingEdge


Treatment� Targeted therapies should be consid-

ered after a receptor-positive test in

either the primary or metastatic

tumour, as it is unknown which

should be taken into account

� Treatment choice should take into

account a wide range of factors

(these were detailed)

� Age should not be a reason to with-

hold therapy

� The small subset of patients who can achieve

complete remission should be treated in a specific way

� A range of treatment options and approaches were agreed for

disease in these categories: HR+; ER+/HER2-; HER2+ and

ER+/HER2+

� Sequential chemotherapy is the preferred choice; combination

chemotherapy should be reserved for cases of rapid progression

� Bevacizumab can be considered in highly selected cases but

there are currently no predictive factors

� A bone-modifying agent (bisphosphonate, denosumab)

should be routinely used for bone metastases; radiological

investigation and treatment may be

needed for bone pain; spinal cord com-

pression should be investigated accord-

ing to symptoms

� Two statements were made on brain

metastases and appropriate surgery,

radiosurgery and whole brain radiation

� The true value of the removal of the

primary tumour in stage IV breast cancer

patients is currently unknown, but it can be

considered in selected patients if techni-

cally possible and only if performed opti-

mally. There is ongoing research on this

� Treatment of men with metastatic breast cancer:

� Endocrine therapy is the preferred option as ER+ comprises

the majority of cases, with tamoxifen the endocrine agent

of choice

� An aromatase inhibitor is an option for men progressing or

relapsing on tamoxifen, but should be given concomitantly

with an LHRH agonist

The conference discussed many topicsof research that may hold the key toprogress in treating advanced disease.

The mechanics of metastasesThe science of metastases was coveredby several speakers. Primary tumoursseem predisposed to invade differentorgans at the metastatic stage, and sci-entists are homing in on mechanismsand targets for the selection of say bone

or lung for cancer spread, exemplified bythework of RogerGomis from the Insti-tute for Research in Biomedicine,Barcelona. The loss of ametastatic sup-pressor in certain breast cancers, forexample, is one area to target; another isthe Src gene that allows cancer cells todevelop in the bone in a so-called ‘seedpre-selection’mechanism.

Much of this work is made possibleby analysing the gene expression signa-

tures and single gene alterations oftumours, andLaura van ‘t Veer, a pioneerof gene signatures, described how clini-cians will be able to make use of newtools to developpersonalised approachesfor metastatic patients.

The ‘seed–soil’mechanismThe way tumour cells are prepared forcirculation and seeding was also upfor discussion. David Lyden, at Weill

Palliative/supportive care� Supportive care should always be part of the treatment plan

� Expert palliative care including pain control should be a priority and patients

should have access to effective control of pain including morphine

� End-of-life care discussions should start earlier in the course of

metastatic disease

ILLUSTRATION:FREDVANDEELEN,W

WW.ORGANISART.CO.UK


CuttingEdge

hypothesised ‘seed–soil’mechanism.LarryNorton told the audience about

‘self-seeding’, where primary cancers areboth the source and a recipient oftumour cells – which is very differentfrom the widely held model of one-wayspread to distant sites, andhas nowbeenconfirmed in many experiments.

GUIDELINES ANDTHE QUALITY OF LIFEThe focus then returned to the experi-ence of patients, with discussion ofissues in palliative care and balancingbenefits andharms.Radiation oncologistAlanRodger discussed the role of radio-therapy inmetastatic breast cancer, not-ing its proven role in palliating bone andbrain metastases. Patricia Ganz, fromthe Jonsson Comprehensive CancerCenter in Los Angeles, looked at end-points for treatment, arguing that patientpreferences must be included, particu-larly where therapies that have a benefitonly on progression-free survival alsolead to increased toxicity.

This theme was taken up by LesleyFallowfield, an outspo-ken pyscho-oncologistfrom theUK. “Wehaveto be very clear aboutthe benefits andharms of the treat-ment we are recom-mending,” she said.“Patients have tomake somevery dif-ficult decisions.”

Fa l l owf i e ldquestioned someof the researchsuggesting that

CornellMedicalCollege, presentedworkon exosomes – tiny particles secretednormally by bone marrow, but also bytumours,whichcontain information thatcan ‘educate’ and prepare the environ-ment (in particular the blood vessels) forremote metastasis. Early intervention inthis process could be valuable in what isa detailed development of the long-

MANAGING COSTS

The issue of cost was tackled head on byDavid Cameron – not the British Prime Min-ister but an oncologist based in Edinburgh.More money is lost to economies through can-cer than other diseases, he said, so there isa case for spending more on cancer to helpthe financial situation. Drugs are often put for-ward as the major expense but are onlyabout a fifth of cancer spend at present incountries such as France, he noted, so it isalso important to look at optimising the other80% of spend. In the US, the fastest risingcosts are in imaging.“Could we also save money in how we organ-ise healthcare?” he asked, suggesting thatmore people could be treated as outpatients,which may be more convenient to them, if notto health professionals. Drug costs are risingtoo of course, although much spend is on con-ventional chemotherapy as the cancer pop-ulation rises and more older people receivetreatment as 'ageism' disappears.Cameron weighed up the debate on usingcost-effectiveness bodies such as England’sNICE to determine often tough decisions aboutwhat will be paid for. “We have to understandhealth economics so we can drive the agendaon behalf of our patients,” he said.

patients will accept all sorts of toxicitiesforminimal benefit, arguing thatmuchofit is flawed, and that the veracity ofmuchof the safety and side-effect data fromtrials is doubtful and often does not tallywith patient-reported outcomes.Qualityof life experience is often “under-reported, under-recognised and under-treated”, she said, and she called for theuse of better systems for capturingpatient-reported outcomes, which arenow available.

Patient advocacy groups will have acrucial role to play in improving thewaypatient experiences are reported andevaluated, thereby improving the qualityof information onwhich future patientscan base their decisions. But, as StellaKyriakides andBettinaBorisch, past andcurrent presidents of the EuropeanBreastCancerCoalition,EuropaDonna,both pointed out, strong patient advo-cacy will also be essential if the newguidelines are to have the desiredimpact on improving research, treat-ment and support. A strong politicalvoice for advocates is needed to raiseawareness about the needs of patients

with advancedbreast cancer,generate support forthe resources tomeet those needs,and ensure patientsget to know about thenew guidelines – andtheir doctors start touse them.

The ABC conference takes placeevery two years, alternating with theBreast Cancer in Young Womenconference. ABC2 is scheduled for7–9 November 2013, in Lisbon

“We have to be very clear about the benefits

and harms of the treatment we are recommending”

Living with the timebombof a childhood cancerAward for article on a mother confronting her worst nightmare

One shouldn’t walk through lifewith one’s eyes closed and,when you hear about terrible

things, think that they cannot happen toyou. Even the most terrible things hap-pen somewhere.You simply have to learnto livewith them.” So says themother ofa girl who has been diagnosed twicewith a brain tumour.Karin, themotherof theeight-year-old

Karmen (thenameshavebeenchanged),admits that, somewhere in her subcon-scious, the awareness of a brain tumourticks away like a timebomb. When thetime approaches to call the doctor for anappointment, she gets very nervous.Herfamily certainly don’t miss the nerve-wracking days they went through duringthe treatment of their little girl’s twice-diagnosed brain tumour.Karmen was an ordinary, lively little

girl from Tallinn who could walk andtalk by the time she was around a yearold. Shewasnotprone to illnessuntil onemorning, when she had a seizure. “Wewent straight to the hospital, where she

was given treatment and examined. Ahead scan showed that she had a braintumour. According to the initial assess-ment, it was the size of a baseball.” Thisis how Karin describes the news, whichcame as a major shock to the girl’s par-ents. “I cried for days,” she admits.The doctors’ hopes that the tumour

was benign was some consolation –malignant tumours usually announce

themselves beforehand through someailment or general poor health.Having gone to the hospital due to a

seizure, Karmen was not allowed to gohome.Aweek later, sheunderwent brainsurgery, and afterwards the doctor toldthe girl’s mother that the tumour wassuspicious. “I was terribly shocked –how can anyone say something like thisto a mother until they are absolutelycertain? But I suppose doctors haveexperience,” sighs Karin. It did give hertime to get used to the bad news – thetumour was larger than the doctors hadat first thought, and it turned out to bemalignant as well.WhenKarmen’s doctor, KarinOrgu-

las, informed her, Karin decided it wastime to fight and move on. “I under-stood that it was not the worst type ofbrain tumour, but it could growextremely fast,” she says.The child received chemotherapy

and, fortunately, coped well.


BestReporter

Don’t bury your head in the sand – being alert to early signs of cancer gives the best chance of

survival. This is the message the mother of one very young cancer patient wanted to pass on.

Silja Paavle, reporter on the Estonian dailyÖhtuleht, helped her do so in this article, which

won her a Best Cancer Reporter merit award.

Silja Paavle

“

apy, shehad to lie completely still and flatonher stomachunder amachine –with-out a full anaesthetic. This is difficult forsmall children,” says her mother.The chemotherapy lasted a year. The

family spent their days going to theChil-dren’s Hospital, then to the OncologyClinic in Hiiu, and then back to theChildren’s Hospital.There were times when the whole

familywas at the hospital –Karmen’s lit-tle brother suffered from laryngitis, anditwas not rare for themother to be in the

BestReporter


This was a difficult time for the wholefamily: Karin had just started a job, butnow she had to take her daughter to thedoctor every 10 days. During the day,when Karin was at work, Karmen’sgrandmother stayed in hospital withher. In the evenings and at nights, Karintook over.Karmen would only eat food pre-

pared by her grandmother, which shecooked after returning home from thehospital. “If mymother had not helpedus, it would have been extremely diffi-cult,” says Karin gratefully.The first period of treatment lasted

a year, after which Karmen, as with allcancer patients, remained under obser-vation; she had to be examined everythreemonths.When the family returnedfor her head scan, several unfortunateincidents occurred – one time themachine was out of order, another timethe doctor was on holiday.When the procedurewas finally car-

ried out, it became evident that themalignant tumour had returned to thethree-year-old’s brain.“I was horrified to think whatmight

have happened if we had succeeded ingetting the scan at the first attempt.Since the tumour grew very fast, itmight have gone unnoticed the firsttime, and early discovery is essential forsuccess,” says Karin.This time the doctors considered

surgery too dangerous, so radiation andchemotherapyhad to beused to fight thetumour. First, Karmen received 30 ses-sions of radiotherapy.“In fiveweeks, shewas under anaes-

thesia 30 times in all. During radiother-

“During radiotherapy, she had to lie completely still and

flat on her stomach. This is difficult for small children”

When it comes to childhood cancers,coverage in the popular press tends to

score higher on quantity than quality.This particular story gave readers

important information as well as anunsentimental insight into the stresses,hopes and fears associated with having

your child diagnosed with cancer

“Once Karmen shouted at a grown-up:What are

you staring at? Never seen anyone like me before?”

BestReporter


oncologywardwith their daughter,whilethe fatherwas in the infectious diseasesward a few floors below with their son.Karmen experienced no serious side-

effects from chemo- and radiotherapy,though Karin spits three times over hershoulder for luck when she says so. “Shecopedwith the treatment very well.”Between each period of treatment,

Karmen had to be taken to hospital forblood tests. During breaks between thechemotherapy sessions, the familyhad tovisit the hospital a couple of times –Karmen suffered terribly fromvomiting.Due to the hormone treatment

accompanying radiotherapy, Karmen’sappetite and weight increased. “This

was awful – in the end, she evenhaddif-ficulty walking.A child that young can-not understandwhy she is not allowed toeat. She only feels hungry and criesabout it,” sighsKarin, adding that theynolonger have problems with excessweight.Karmen is now eight years old and

there is nothing to show that shehas suf-fered a serious illness. She takes herdisease with childlike levity and knowsthat, however bad it is, doctors can help.Karmennowhas to have a brain scan

at regular intervals; she also has to beinjected with growth hormones, as theradiotherapy interferedwith her growth.“At first, we feared that growth hor-

mones would make the cancer growagain, but the endocrinologist reassuredus, telling us that the body usually pro-duces its own growth hormones andtherefore theywill not cause the tumourto grow back,” says the mother.Karmen must also avoid being hit on

the head; having lost her hair duringchemotherapy, she isused towearingahat.Karin remembers thatwhen the four-

year-old Karmen lost all her hair andwas unusually chubby due to hormonetherapy, peoplewould often stare at her.“Once Karmen shouted at a grown-up:what are you staring at?Never seen any-one like me before?” she laughs.Karin says that, although Karmen’s

difficult disease, which took up somuch of their energy, did put a strain onrelationships within the family, theycoped relatively well. Throughout thecourse of treatment Karmenwas utterlypositive and respondedwell. “However,there were several childrenwith cancerat the hospital who never recovered.Each of these stories was very sad,”sighs Karin.Whenever she heard sad news, she

toldherself that every tumour is differentand each child’s disease is different.Karin is very grateful toherGPaswell

as to the doctors and nurses at the Chil-dren’sHospital,whoarehighly committedto their work and answer all the parents’questions, in spite of the difficulties.When things get tough, they are

always there for their patients – evenat night.

This article was first published in Öhtuleht, on 31 August2010, under the title ‘The mother of a girl suffering from abrain tumour: awareness of cancer ticks away like a time-bomb’. It is reprinted here with permission.©SLÖhtulehtAS

ALL BRAIN TUMOURS ARE DANGEROUS

“In essence, all brain tumours are malignant, but their speed of growth and level ofmalignancy differ,” says Karin Orgulas, a doctor in the oncology ward of the Tallinn Children’sHospital. She was also Karmen’s doctor.Like the principal character in the recently published book ‘Regina: Mu imekaunis võitlejanna’(‘Regina: My beautiful fighter’), Karmen was diagnosed with a primitive tumour in the upperpart of the brain, which always develops very rapidly. Orgulas adds that brain tumours canoccur in all parts of the brain.In Estonia, around 8–10 children undergo brain tumour surgery every year, and brain tumoursmake up one-third of all childhood malignant tumours. While all other malignant tumours alsorequire medical treatment, i.e. chemotherapy, only a quarter of the most malignant braintumours receive this treatment. “With brain tumours, the important question is whether thetumour can be entirely removed or if this is impossible because of its location and extent,”says Orgulas. On average, three children a year need chemotherapy.Early diagnosis is of the utmost importance in brain tumours. Orgulas advises that parentsshould consult a doctor at once if their child is experiencing headaches, vomiting andproblems with balance.A brain tumour diagnosis is extremely serious and, in the early stages of the disease, it isvery difficult to say whether the child will recover or not, because so many different factorsare involved. In some cases, children may have to remain under observation for the rest oftheir lives and live with the knowledge that the disease could return at any time.

� Anna Wagstaff

A chemical explosion in Toulouse 10 days after the twin-towers attacks in theUSA traumatised

the French city. But from this disaster arises an innovative hospital with unique links to

research and industry. Jean-Pierre Armand has seen his dream cancer centre at the Toulouse

‘oncopole’ through to completion. Now a new chief executive must bring the dream to life.


Spotlighton...

A world-class centre arisesfrom the French ground-zero

ANDERGILLENEA,C.PICCI

Ifonlywecould start fromscratch.”This thoughthasnodoubt crossedthe minds of many senior figuresin cancer as they try to reshapeslow-changing systems and

processes to keepupwithdevelopments.Whether integrating biobanking into

surgical pathology, convincing smallerhospitals not to treat patientswhere theylack the necessary experience andexpertise, or facilitating cooperationbetweenhospital-based researchers andbasic scientists, the option of startingfrom scratch seems very enticing.Following a decade-old tragedy, just

such anopportunitywill soonbebearingfruit in the south of France, with thecompletion of the Toulouse ‘oncopole’, apublic–privatepartnershipwhich “aims tobecome theEuropean leader in the fieldover the next ten years” andwill be “ded-icated towinning the fightagainstcancer”.The brand new campus, covering

more than two square kilometres,will behome to a newUniversity Cancer Hos-pital, attached to a large public–private

research facility, geared to collaboratingwith thehospital in translational researchprojects.A group of small biotechs usinguniversity lab facilities on the oncopolesitewill linkwith basic researchers at thecity’s highly-ratedUniversity of Scienceand Medicine, and will look for oppor-tunities to develop and market innova-tions, specialising in selected fields suchas the application of nanotechnology incancer therapies.Completing the onco-pole line upwill be Pierre Fabre labora-tories, which brought the cytotoxic drugvinorelbine to market, and has a partic-ular interest in cancer immunotherapy,andSanofi, one of France’s biggest phar-maceutical companies.It all beganwith a catastrophic event.

On 21 September 2001 – 10 days afterthe9/11attacks in theUSA–anexplosionripped through an area in the southernpart of Toulouse, generating a shockequivalent to an earthquake measuring3.3 on the Richter scale, or 100 tons ofTNT. Itwasnot a terrorist attack, asmanyinitially assumed, but an industrial acci-dentat a largechemical complex. It left30people dead and 2500 severely injured,with many school children numberedamong the casualties; 40,000 peoplefound themselves temporarily homeless.It was in response to this disaster

that the proposal for theToulouse onco-pole arose.Thecityneeded investment torepair the physical damage and replacejobs. But it also needed something posi-tive on a human level to help heal thewounds andpull the community througha period of shock,mourning and recrim-ination. Using the devastated industrialwasteland to create a top-class centrefocusedon the fight against cancer fittedthe bill perfectly, and played to the city’s

strengths and history. Toulouse is hometo one of the earliest centres of radiumtherapy – the Claudius Regaud Insti-tute, named in 1923 afterMarieCurie’sclosest clinical collaborator. The city isalso very strong inboth science and inno-vation, being home to someof the coun-try’s top-ranking universities, as well asFrance’s prestigious aerospace industry.The Toulouse oncopole truly is an

opportunity to ‘start from scratch’, saysJean-Pierre Armand, who, to his greatdelight, was drafted in from the presti-gious Gustave Roussy Institute in Paristo oversee the development of the newUniversityCancerHospital. In doing sohe has helped to create a ‘promised land’for his successors, althoughhehimself isreturning to Paris.But he has high aims for those who

will follow. “The aim is not to improve orupdate. It is to use the expertise andexperiencewe have in high-quality can-cer care to invent new jobs and developmore effective research, discovery ofnew types of drugs and a better connec-tion between this central hospital andthe network of clinics serving threemil-lionpeople in theMidi-Pyrénées region.”

CENTRED ON THE HOSPITALArmandhas been an outspoken critic ofwhat he sees as a damaging dislocationbetweenuniversity-basedacademicmed-icine and the oncology clinicians whocarry out themajority of treatments. Hebelieves the new set up inToulouse pro-vides an opportunity to get this relation-ship right, which accounts for his greathopes and infectious enthusiasm.Key toits success, heargues, is having a real can-cer hospital at its heart. “This is not thetype of place where you just do experi-ments and get experience. This hospitalwill be treating cancer patients from theregion, just like anyother cancerhospital,with real doctors tackling the same treat-ment dilemmas and attending to thesamecareneeds as in anyotherhospital.”

Spotlighton...


Like a phoenix from the ashes. The Toulouseoncopole is built on land left devastated by acatastrophic explosion at a chemical works in2001. The University Cancer Hospital – the curvedbuilding in the centre – will open in early 2013

“

Armand expects two major benefits toflow from this. The 30 or so researchteams attached to the hospital will bemore likely to focus on resolving prob-lems that are a priority forpatients and doctors, andmore likely to focus on solu-tions that will be of valueand practical to implementin the real world. They willalso have access to a veryrich source of informationemanating from cancertreatment centres through-out the Midi-Pyrénéesregion. These clinics willroutinely feed informationback to thenewhospital viaa custom-built IT systemsupporting whatArmand describes as a‘living biobank’, designed to capturepatients’clinical and biological informa-tion over the course of their disease.This patient-driven approach should

feed through to thework of the biotechs,which will be looking to pick up poten-tially marketable results. To ensure therelationship between patients andresearch works to the benefit of bothsides, safety mechanisms have beenbuilt into the system. One seat on theboard of the hospital is reserved forsomeone with responsibility for thewhole of the Midi-Pyrénées, whosefunction will include ensuring accessto clinical trials even for patients locatedat the furthest periphery of this verylarge region. An ethics committee willoversee thework of thebiotechs andpro-tect the interests of the patients.Both Sanofi and Pierre Fabre labo-

ratories have long had a presence inToulouse, but theirmove to the oncopoleis expected to herald a much greaterdegree of interaction between thesepharmaceutical giants and the rest of theresearch and clinical community inToulouse.ASanofi spokesperson talks ofthe oncopole as “an ecosystem” that

“allows liaisons between the researchteams, clinicians and patients”. TheSanofi team in Toulouse specialises inearly innovation, including in the field oftumourmicroenvironment, andwill, forinstance,welcome to its site teams fromINSERM – the National Institute forHealth andMedical Research.

BURSTING WITH INNOVATIONThis collaborative, synergistic approachextendswell beyond the confines of can-cer science. The aeroplane manufac-turerAirbus has been invited to put tworepresentatives onto the board to boostthe culture of innovation.And a sharedinterest has been identified with theaerospace industry in terms of access toamassive and expensive piece of equip-ment. It turns out that the sort of parti-cle accelerator that is used to fireprotons, carbon ions and other large par-ticles for use in a particular variant ofradiation therapy (hadron therapy) isthe same as that required to test theability of space materials to withstandexposure to neutrinos. Collaborating todevelop such a facility at the oncopolesite will give patients from the regionaccess to hadron therapy, while allowing

the aerospace industry to test theirmate-rials locally rather than sending them tonorthern Europe.This is not only about thebenefits for

Toulouse.Armand andhis teamarewellaware of how rare itwas, evenbefore thefinancial crisis, to get government invest-ment of €300 mn for a project like this,and it comes with a responsibility to therest of the country and beyond. The ‘liv-ing’ biobank is one precious resourcethat will be made available to the widerresearch community. Therewill also be acomprehensive education programmefor all the oncology specialisms, includ-ing post-doctoral education covering allthe jobs to do with oncology, research,industry, medicine.There is also a unique solution bor-

rowed from the aero industry aboutwhatto dowith the existingClaudiusRegaudHospital in the centre of Toulouse.Instead of closing it down, itwill becomea training environment where medicalstudentswill learn in a setting as close asyou can get to aworking cancer hospital.The Claudius Regaud, complete withoperating theatres, radiation bunkers,labs, wards, bathrooms and toilets, willbecome a simulator hospital where stu-dents can learn about the different path-ways and approaches to all aspects ofcaring for cancer patients – radiotherapy,chemotherapy, surgery, nursing, psycho-oncology and pathology. Armand isenthusiastic: “We will adopt the tech-nique used byAirbus.When they builda newplane they don’t train pilots first onthe real plane, but in a simulator.”Innovatory approaches to communi-

cations is another areaArmand is thrilledabout. The new IT system now linkingthe cancer hospital with all the cancerclinics throughout the Midi-Pyrénéesdoes far more than facilitate the ‘livingbiobank’. It is a crucial component thatallows them to deliver on a commitmentto care for patients as close to theirhomes as is safely possible, andwill also


Spotlighton...

Bridging the gap between bench and bedside.Jean-Pierre Armand stands in the concourse thatconnects the University Cancer Hospital to theassociated research centre

comeand train their staff or accept themon courses down here.”Armand feels that this sort of patient-

centred approach,when combinedwiththe critical mass of scientific, technicaland industry know-how on site, givesthe Toulouse oncopole the potential tomake an important contribution to theglobal fight against cancer.Nowhehas set up the dream factory,

it is for others to make those dreamscome true. Armand has overseen everystage of the planning of the new hospi-tal, but it is time for him to pack his bagsand head home to Paris. The actualmove from the currentClaudiusRegaudhospital to the new sitewill take place in2013 under a new director. In the tenyears that have passed since the explo-

make it possible for local clinics to par-ticipate in clinical trials.An equally innovative and perhaps

recognisably French approach is beingtaken to ensure fruitful interactionbetween the clinical staff and the aca-demic researchers who share the sameplace of work: good food. Some of thecommunications budget has been usedto upgrade catering facilities to the levelof aMichelin one-star restaurant, wherestaff will want to spend time. “That willbe a place where the real doctors withtheir own real problemswill discusswithreal scientists. Sometimes they have dif-ferent interests, but they will listen toeach other and theywill exchange. Thisis one of the advantages you can havewhen you work on one site.”But it is a new thoroughly low-tech

approach to communication withpatients that Armand is probably mostproud of. This innovation has alreadyattracted attention from cancer centresthroughout France and beyond. “In myhospital we have discovered that today apatient spends 15minuteswith the doc-tor in the day, but two hours with thepeople cleaning the ward. And so wehave developed a very thorough com-munications training for the peoplecleaning the room.”Cleaning and other ancillary staff

are in a good position to communicatewith patients, says Armand, preciselybecause they are not highly educated.Patients feel relaxed talking to themabout how lousy they feel, their hopesand fears for the future, or perhaps justthe fortunes of le Téfécé, Toulouse’spremier league football club. “It worksfantastically, and now people are con-tacting us from elsewhere, asking us to

sion that started it all, cancer survival hascontinued its maddeningly slowprogress, while the financial crisis nowthreatens public spending onbothhealthand research. But asArmandpoints out,the crisis has alsomobilisedmany youngpeople who are impatient for change –les indignés, los indignatos – and this isthe spirit he feels in needed to get themost out of the wonderful facilities inToulouse. “We’ve built the hospital, wehave very strong support from patientsand families, but we also need deter-mined men and women,” he says. “Wehave a lot of doctors nowwho just acceptthebad resultswehave in cancer and arenot really fighting to improve them.Wenow need many of these youngerindignés to enter the game.”

The old hospital – its operating theatres, wards, labs and

radiation bunkers – will be used as a simulator hospital

COULD YOU BE THE FIRST CEO?

The University Cancer Institute of Toulouse Midi-Pyrénées, Oncopole (http://www.oncopole-toulouse.com), is looking for a committed, innovative chief executive officer. Could that be you?The CEO will run the University Cancer Institute, including the hospital and the research centre;direct orientations for research and care; work with stakeholders; and implement the project.Main responsibilities include:� Drawing up medical and scientific programmes, budgets and reports;� Establishing new clinical and research labs at the UCI;� Promoting the UCI on an international level as one of the world’s top cancer centres;� Advancing UCI findings; and� Developing strategic partnerships with industry groups and innovative enterprises to stim-

ulate technology transfer.The CEO must be a MD and PhD and have a successful record managing a hospital, a trans-lational research lab or a national health or research organisation. International health andscience management, fundraising and diplomatic skills are highly valued.The CEO will start no later than January 1, 2013.Candidates should email their CV + letter of application + list of publications + letters of rec-ommendation to: The President of the University of Toulouse 3, Pr. Gilles FOURTANIER([email protected])For more information, contact the Toulouse UCI search firm, Your Voice: [email protected]

Spotlighton...


I M P A C T F A C T O R

ImpactFactor

The importance of localcontrol in pancreatic cancer

� Edgar Ben-Josef and Theodore S. Lawrence

The ECOG E4201 study adds another piece of information to a growingbody of evidence pointing strongly to the importance of local control andthe role of radiotherapy in unresectable pancreatic cancer. Based on thisevidence, we believe radiotherapy should be used routinely in this setting.

The role of radiotherapy in unre-sectable adenocarcinoma of thepancreas has been in question

for the past three decades. Radiotherapycan palliate common symptoms such aspain, duodenal ulceration and bleed-ing but its impact on survival has notbeen clear. Whereas older trials wereinconclusive, the recent phase III trialreported by Loehrer et al.1 has shownthat radiotherapy improves overall sur-vival when added to gemcitabine.Patients with non-metastatic unre-sectable adenocarcinoma of the pan-

creaswere randomly assigned to receivegemcitabine alone (1000 mg/m2 perweek for 6 weeks, followed by 1 weekrest, then five more cycles of1000 mg/m2 for 3 out of 4 weeks) orgemcitabine (600mg/m2 perweek) con-currently with three-dimensional con-formal radiotherapy (50.4 Gy in 28fractions) followed by additional gem-citabine (five cycles of 1000 mg/m2 for3 out of 4weeks). The studywas closedearly owing to poor accrual but, in the 74patients enrolled, median survivalimproved from 9.2 months to 11.1

months (P=0.017). This came at a costof increased frequency of grade 4 toxiceffects (although combined grade 3 or 4toxic effects were the same in eacharm). These results lend support to thenotion that radiation therapy improvesthe survival of patients with unre-sectable pancreatic cancer throughintensification of local therapy, giventhat uncontrolled local growth is thecause of death in 30% of patients withthis malignancy.2

The trial conducted by Loehrer etal.1 is one of two trials conducted inthis decade addressing the question ofwhether radiotherapy can be of benefitin unresectable adenocarcinoma of thepancreas. The other study, the Fédéra-tion Francophone de CancérologieDigestive and Société Française deRadiothérapie Oncologique (FFCD–SFRO) trial3 showed a worse survival(8.6 months vs 13 months; P=0.03)when chemoradiotherapywas added togemcitabine. However, the chemora-diotherapy regimen tested in that trial(60 Gy in 30 fractions in 6 weeks con-comitant with a 5-fluorouracil infusion[300 mg/m2 per day] days 1–5 for


This article was first published in Nature Reviews Clinical Oncology vol. 9 no.1, and is published with permission.© 2012 Nature Publishing Group. doi:10.1038/nrclinonc.2011.182

CLINICALONCOLOGY

ImpactFactor

6 weeks and cisplatin [20 mg/m2 perday] days 1–5 on weeks 1 and 5) washighly toxic (65.5% grade 3 or 4 toxiceffects) and, no doubt, contributed tothe worse outcome.

Unfortunately, radiotherapyhas beenused suboptimally in this disease. Thesensitivity of the organs to radiotherapyin the upper abdomen has limited theradiation dose to ineffective levels, andattempts to increase the radiation dosehave been unsuccessful, resulting inhigh morbidity and mortality.4

An alternative strategy is to useradiosensitising drugs that enhance theeffect of radiation preferentially withinthe tumour. The two drugs that are usedmost commonly with radiation in thetreatment of pancreatic cancer, gem-citabine and 5-FU, both appear todecrease the ability of cancer cells torepair radiation-induced DNA dam-age.5 At the University of Michigan wehave carried out a series of trialsusing full therapeutic doses of gem-citabine – a potentradiosensitiser6 – andconcurrent three-dimensional confor-mal radiotherapy tomaximise systemicand local control.However, toxicity hasprevented the esca-lation of the radiationdose beyond 36 Gyin 2.4 Gy fractionseven when only the tumour was tar-geted and clinically negative lymphnodes were excluded.7

An option that might allow deliver-ing an increased radiation dose to thepancreas without exposing the dose-limiting organs to toxic levels of radiationis intensity-modulated radiotherapy(IMRT).8 For example,we recently com-pleted a trial inwhichwe used IMRT tosimultaneously reduce the dose to thestomach and intestines and increase

the dose in the tumour in patients withunresectable pancreatic cancer. Wehave established that high-dose radio-therapy (55 Gy in 25 fractions) can bedelivered safely with concurrent full-dose gemcitabine,with the use of IMRTdelivered during breath hold. The rate ofsevere toxicity (24%) observed whenusing this chemoradiotherapy dose9

compares favourably with toxic effectsreported with other contemporaneousregimens. In addition, there are encour-aging signals of efficacy; the medianoverall survival and two-year overall sur-vival in this trial9 (14.8months and 30%,respectively) are significantly better(hazard ratio = 0.63, log-rankP=0.028)than historical controls (11.2 monthsand 13%, respectively).10 These resultsalso compare favourablywith other con-temporary phase II and phase III trialsin this patient population, with either5-FU-based or gemcitabine-basedchemotherapy.High-dose radiotherapyalso improved the two-year local control

from 38% (historicalcontrols)10 to 59%.9

Most importantly, 12of 50 patients (24%)receiving high-doseradiotherapy wereable to undergoresection with goodoutcomes; 10patients (83%) hadR0 resection and fivepatients (42%) had a

major pathological response. Themedian survival in these patients whohad undergone resection was 32months.9

Thus, the results from the EasternCooperativeOncologyGroup (ECOG)trial1 coupled with the finding that asignificant proportion of patients withpancreatic cancer die of complicationsof uncontrolled growth,2 and resultsshowing improved local control and sur-vival in patients receiving high-dose

radiotherapy, suggest a new paradigm.The question now is not whether radio-therapy is of benefit in this disease butrather how tomake itmore effective andhow to combine it optimally with sys-temic therapies.

A number of strategies can beexplored to further intensify local ther-apy. Firstly, improvements in radiother-apy planning and delivery: we need toimprove targeting of the tumour whileavoiding the critical normal tissues andto incorporate individual susceptibilitiesto radiation toxicity into treatment plan-ning. Secondly, we have to explore theuse of novel tumour-specific radiosen-sitisers: with somany targeted agents inthe pipeline, this strategy ismore prom-ising than ever. Potential candidatesinclude CHK1 inhibitors, nab-pacli-taxel, PARP inhibitors,MEK inhibitors,and many others. Thirdly, we have tocarefully study the potential role of sur-gery in selected patients.

Finally, potential progress can bemade by individualising therapy. Onesuch effort underway is an attempt touse the status of SMAD4 (also knownasDPC4) to select patients for intensivelocal therapy versus intensive systemictherapy. Loss of DPC4 is associatedwith a widely metastatic phenotype,while patients with intact DPC4 aremore likely to die of local complica-tions.2 Thus, in a currently plannednational trial,DPC4 statuswill be deter-mined upfront by cytology. Patientswith


Practice pointRadiation therapy with gemcitabineimproves the survival of patients withnon-metastatic unresectable pancre-atic cancer comparedwithgemcitabinealone. Therefore, gemcitabine com-binedwith radiation canbeconsidereda standard of care for these patients.

“The question nowis not whether radio-therapy is of benefitin this disease butrather how to makeit more effective”

ImpactFactor

intactDPC4will be randomly assignedto receive an intensive or a standardchemoradiotherapy regimen (following12 weeks of gemcitabine) whereaspatients with DPC4 loss will be ran-domlyassigned to receiveFOLFIRINOX(5-fluorouracil, leucovorin, irinotecanand oxaliplatin) versus gemcitabine (fol-lowed by standard chemoradiotherapy)for two weeks.

In summary, the current ECOG trialadds onemore piece of information to agrowing body of evidence pointingstrongly to an important role of radio-therapy in local control for unresectablepancreatic cancer. Future advancescould come from better selection ofpatients for intensive local therapy usingmolecular biomarkers.

References

1. PJ Loehrer Sr et al. (2011) Gemcitabine alone versusgemcitabine plus radiotherapy in patients with locallyadvanced pancreatic cancer: an Eastern CooperativeOncology Group trial. JCO 29:4105–122. CA Iacobuzio-Donahue et al. (2009) DPC4 genestatus of the primary carcinoma correlates with patternsof failure in patients with pancreatic cancer. JCO27:1806–133. B Chauffert et al. (2008) Phase III trial comparingintensive induction chemoradiotherapy (60 Gy, infusional5-FU and intermittent cisplatin) followed bymaintenance gemcitabine with gemcitabine alone forlocally advanced unresectable pancreatic cancer.Definitive results of the 2000–01 FFCD/SFRO study.Ann Oncol 19:1592–994. HM Ceha et al. (2000) Feasibility and efficacy of highdose conformal radiotherapy for patients with locallyadvanced pancreatic carcinoma. Cancer 89:2222–295. DS Shewach and TS Lawrence. (2007) Antimetaboliteradiosensitizers. JCO 25:4043–506. TS Lawrence, EY Chang and TM Hahn. (1996)Radiosensitization of pancreatic cancer cells by2′, 2′-difluoro-2′-deoxycytidine. Int J Radiat OncolBiol Phys 34:867–872

7. CJ McGinn et al. (2001) Phase I trial of radiationdose escalation with concurrent weekly full-dosegemcitabine in patients with advanced pancreaticcancer. JCO 19:4202–088. M Bockbrader and E Kim. (2009) Role ofintensity-modulated radiation therapy ingastrointestinal cancer. Expert Rev AnticancerTher 9:637–6479. E Ben et al. (2011) Phase I/II radiation dose-escalation trial of intensity-modulated radiotherapy(IMRT) with concurrent fixed dose-rate gemcitabine(FDR-G.) for unresectable pancreatic cancer. Int JRadiat Oncol Biol Phys 81 (Suppl. 2):127–12810. JD Murphy et al. (2007) Full-dose gemcitabineand concurrent radiotherapy for unresectablepancreatic cancer. Int J Radiat Oncol Biol Phys68:801–808

Author affiliations

Edgar Ben-Josef and Theodore S. Lawrence:Department of Radiation Oncology, University ofMichigan, Ann Arbor, Michigan, USA


Time for another rethinkon prostate cancer screening

� Andrew J. Vickers and Hans Lilja

Screening for prostate cancer usingPSA is a careful balance of benefits andharms. But current US practice involves testing older men who have littleto gain and aggressively treating low-risk cancers. Debates about whetherto test need to be replaced by debates on how to test better.

The US Preventive Services TaskForce (USPSTF) recently issueda recommendation against the

use of prostate-specific antigen (PSA)testing for prostate cancer screening.1

They concluded that “there ismoderateor high certainty that [prostate cancerscreening] has no net benefit or that theharms outweigh the benefits.” In thisarticle, we review the USPSTF reportandmake three simple points. First, theUSPSTF report is riddledwith errors, so

much so that we would be sympatheticto accusations that the task force wasbiased. Second, if the USPSTF wereindeed biased against PSA screening,this would be entirely understandable:urologists, radiation oncologists and oth-ers have made such a mess out of PSAscreening that it is easy to see why agroup of family practitioners, obstetri-cians and paediatricians would like towrite the whole thing off. Third, PSAscreening can be done in differentways,

and the ratio of benefit to harm willdepend on choices regarding how PSAtests are used.As mid-life levels of PSAare strongly predictive of long-term riskof prostate cancermorbidity,2, 3 wewouldargue for risk-stratified approaches, tominimise harms formenunlikely to ben-efit from screening and ensure carefulfollow up of those at the highest risk ofunfavourable outcome.

Regarding our first point, the USP-STF report is riddledwith errors of fact,interpretation and statistics. Some ofthese errorsmight be considered under-standable. Take, for example, the claimthat in the interim report from theEuropean randomised screening trial(ERSPC) after a median follow up of9 years,4 “48 men received treatmentfor every prostate cancer-specific deathprevented.” The number of 48 patientswas obtained by dividing the between-groupdifference in prostate cancer diag-noseswith thebetween-groupdifferencein cancer deaths. As not all men diag-nosedwith prostate cancer in this studywere treated — some were placed on

This article was first published in Nature Reviews Clinical Oncology vol. 9 no.1, and is published with permission.© 2012 Nature Publishing Group. doi:10.1038/nrclinonc.2011.181

active surveillance — the USPSTFstatement is incorrect. It is also highlymisleading, as the ratio of diagnoses todeaths that are avoided is time depend-ent; consider that this ratio is infinity atearly follow up because screening doesnot prevent death in a man diagnosedwith advanced-stage cancer at his firstPSA test. The empirical estimate fromtheGöteborg armofERSPC,which haslonger follow up (14 years) is that 12menneed tobediagnosed to prevent onedeath from prostate cancer.5 Still, theERSPC report4 used the phrase“number-needed-to-treat” and cited thenumber 48, so perhaps the USPSTFerror is understandable.

The principal flaw of the USPSTFmight also be seen as an understandablemistake. Specifically, theUSPSTFdrawsdefinitive conclusions of “moderate orhigh certainty of no benefit” on the basisof interim data: the largest randomisedtrial of prostate cancer screening – theEuropean ERSPC trial – has not yetreported on themain endpoint of cancer-related mortality at its prespecified pri-mary timepoint, datawere only reportedbecause the difference between groupscrossed a prespecified significanceboundary at interim analysis. It seemsbizarre to be certain of “no benefit”whena major trial is yet to report in full.

What is less understandable is thatthe USPSTF make unsupportableclaims that seemdesigned to emphasisethat screening is harmful and that thereshould be less of it. For example, theUSPSTF cites a perioperativemortalityrate from radical prostatectomy of 0.5%,far higher thanmost contemporary esti-mates, such as 0.1%.6 This is becausetheyused a study ofMedicare patients todraw their conclusions, that is, the old-est patients at highest risk for perioper-ative death. In addition, it is hard tounderstand the biological mechanismbehind the claim that because “the [neg-ativeUS] trial evaluated a shorter screen-

ing interval [than the positive Europeantrial] ...more conservative screening andtreatment strategies might be moreeffective than more aggressive ones.”1

Less regular screeningmaywell decreasethe harms of screening, but there is sim-ply no mechanism by which it could bemore effective.

Our second point is that contempo-rary PSA screening and treatment is afarrago and so if the members of theUSPSTFwere indeedprejudiced againstPSA screening, it is not hard to seewhy.There is a lot to dislike about howprostate cancer is detected andmanagedin the US. For example, PSA screeningis routinely used inmenwhohave noth-ing to gain from it,with testing applied toone-third of men aged over 70 yearswho have a greater than 50% risk ofdeathwithin five years.7 In addition, dig-ital rectal examination is widely usedeven though it is not informative in ascreening setting.8 Urologists are thenextremely quick to biopsy, with currentguidelines recommending biopsy foralmost any indication: a raised PSA, alowered ratio of free-to-total PSA, a highPSA velocity or a positive digital rectalexamination.Worst of all, radiotherapy or

surgical treatment is almost universallyrecommended: empirical studies showthat fewer than 10% of men with low-risk disease are offered active surveil-lance.9 Couple this with apparentconflicts of interest, such as groups ofurologists purchasing radiation equip-ment and then self-referring patients,and it is not hard to see why those out-side of the prostate cancer field seePSAtesting as nothing more than a scam.Prostate cancer screening is not a single

intervention, such as a certain dose of aspecific drug; it can be implemented innumerous different ways. Starting PSAscreening at, say, 70 years, using a verylow PSA threshold for biopsy and thenaggressively treating all cancerswill leadto enormous amounts of overdiagnosisand overtreatment and will have littleeffect onmortality.Conversely, focusingon younger men, only biopsying thosemeeting stringent criteria, andmanaginglow-risk cancers by active surveillancewill lead to a better balance of harms andbenefits. Indeed, given the diversity ofapproaches to PSA screening and sub-sequent management of PSA-detectedtumours, it is hard to knowwhether it iseven coherent tomake statements suchas “PSA screening is associated with a

42% rate of overdiagnosis” or“48 men need to be diagnosedafter aPSA test to save one life”.1

We would argue that theinterim analysis of ERSPC andprespecified analysis from theGöteborg randomised trial in

Europe demonstrates that PSA-basedscreening can reduce cancer-specificmortality and, as such, our questionshould really be how to make it workbetter.A keymethodwill clearly be riskstratification: focusing PSA screeningon the men at highest risk of prostatecancer morbidity and mortality willimprove the ratio of benefit to harms.Asit turns out, themost powerful risk fac-tor is PSA itself.2, 3 Indeed, re-analyses ofthe EuropeanERSPC trial suggest that

ImpactFactor


Practice pointsThe outcomes of PSA screening couldbe dramatically improved by:� Avoiding screening in older men

(age ≥70 years)� Useofactive surveillance tomanage

low-risk disease

“...current PSA testing as itis commonly practised in theUS is indefensible”

ImpactFactor

if men with a low baseline PSA levelwere exempted from further screening,there would be a dramatic reduction inthe number ofmen screened, biopsied,diagnosed and treated per prostate can-cer death avoided.10

In summary, the question isshould we abandon PSA testing? Oneanswer might be that yes, we should:current PSA testing as it is commonlypractised in the US is indefensible.However, we should avoid throwingout the baby with the bathwater andinstead grasp the opportunity toimplement a more-rational, risk-strat-ified approach to PSA screening,which avoids testing of men with lit-tle to benefit and uses active surveil-lance to manage low-risk prostatecancer. Such a strategy has the bestchance to reduce prostate cancermortality while minimising overdiag-nosis and overtreatment.

References1. R Chou et al. (2011) Screening for prostatecancer: a review of the evidence for the U.S.Preventive Services Task Force. Ann Intern Med155:762–7712. H Lilja et al. (2011) Prediction of significantprostate cancer diagnosed 20 to 30 years later with asingle measure of prostate-specific antigen at orbefore age 50. Cancer 117:1210–193. AJ Vickers et al. (2010) Prostate specific antigenconcentration at age 60 and death or metastasis fromprostate cancer: case-control study. BMJ 341:c45214. FH Schröder et al. (2009) Screening and prostate-cancer mortality in a randomized European study.NEJM 360:1320–285. J Hugosson et al. (2010) Mortality results from theGöteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 11:725–7326. S Carlsson et al. (2009) Nationwide population-based study on 30-day mortality after radicalprostatectomy in Sweden. Scand J Urol Nephrol43:350–3567. MW Drazer, D Huo, MA Schonberg et al. (2011)Population-based patterns and predictors of prostate-specific antigen screening among older men in theUnited States. JCO 29:1736–438. FH Schroder, M Roobol-Bouts, AN Vis et al.(2001) Prostate-specific antigen-based early detectionof prostate cancer – validation of screening withoutrectal examination. Urology 57:83–90

9. MR Cooperberg, JM Broering and PR Carroll. (2010)Time trends and local variation in primary treatment oflocalized prostate cancer. JCO 28:1117–2310. PJ van Leeuwen et al. (2010) Balancing theharms and benefits of early detection of prostatecancer. Cancer 116:4857–65

AcknowledgementsSupported in part by funds from the GoldsteinFoundation, a P50-CA92629 SPORE grant and a R33CA127768-03 grant from the National CancerInstitute, Swedish Cancer Society (08-0345),Swedish Research Council (Medicine no. 20095),David H. Koch provided through the Prostate CancerFoundation and by the Sidney Kimmel Center forProstate and Urologic Cancers

Author affiliationsAndrew J Vickers: Department of Epidemiology andBiostatistics, Hans Lilja: Departments of LaboratoryMedicine and Surgery (Urology) and Department ofMedicine (GU-Oncology), both at the MemorialSloan-Kettering Cancer Center, New York,New York, USA

Competing interests statementHans Lilja is an inventor and owner of patents WO0227323, US 2002123616, WO 0193861, WO 9201936,WO 9626442, EP 0635575, and DE 9117047. Andrew JVickers declares no competing interests


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

the research agenda?� Are you getting the career

breaks you need?� Which is better? Medical

oncologist or organ specialist,robot or surgeon?

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

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

www.cancerworld.org

NewsRound


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

Everolimus plus octreotideimproves progression-freesurvival in advanced NET� The Lancet

The addition of everolimus to octreotideimproved progression-free survival in

patientswithadvancedneuroendocrine tumours(NETs) associatedwith carcinoid syndrome, thephase III RADIANT-2 study has concluded.

Advanced NET remains a clinical challengedue to the lack of effective treatment options.Generally, chemotherapeuticdrugsarenotactivein advanced non-pancreatic NET patients, andthey have furthermore been associated withsubstantial toxic effects. Currently there are notreatments forNET tumoursoutside thepancreasthat are approved by the US regulator the FDA.

Everolimus, an oral inhibitor of the mam-malian target of rapamycin (mTOR), has recentlyshown antitumour activity in patients withadvancedpancreaticNETs. The roleof everolimusinNETs of other primary sites or in combinationwith other drugs, however, has not beenexplored. In the current study, James Yao, fromMDAndersonCancerCenter,Houston, Texas, andcolleagues, set out to assess the combinationofeverolimus plus octreotide long-acting repeat-

patients. Therefore, our findings that show theefficacy of themTOR inhibitor everolimus plusoctreotide LAR in advanced neuroendocrinetumours are important,” write the authors.“These data support the efficacy of everolimusfor the treatment of patients with a broadspectrum of advanced neuroendocrinetumours,” they conclude.

In an accompanying editorial, Guido Rindi,from the Università Cattolica-Policlinico A.Gemelli (Rome, Italy), andMartyn Caplin, fromtheRoyal FreeHospital (London, UK), write thatwhile everolimus is undoubtedly an importantadvance in the management of carcinoidtumours, the toxic effects are “not insignificant”and the survival benefit is unknown. Questionsremain, they add, around whether everolimusshould be used alone or in combination, beforeor after other drugs, and for how long. Addi-tional issues include whether the agent hasany role in the adjuvant setting andwhat effectit has on overall survival and quality of life.� M Pavel, J D Hainsworth, E Baudin et al.

Everolimus plus octreotide long-acting repeatable for

the treatment of advanced neuroendocrine tumours

associated with carcinoid syndrome (RADIANT-2):

a randomised, placebo-controlled, phase 3 study.

Lancet 10 December 2011, 378:2005–12

� GRindi andMCaplin. mTOR inhibitor therapy

for patients with carcinoid. ibid pp1978–80

able (LAR) in patients with low-grade or inter-mediate-grade NETs. The long-acting formula-tion of octreotide, a somatostatin analogueknown to improvehormone-related symptomsassociatedwithNETs, hasbeen showntoprolongtime to disease progression in patients withcertain types of NETs.

Between January 2007 and April 2010, 429patients with unresectable locally advanced ordistantmetastaticNETs were randomised ina1:1ratio to receive either everolimusplusoctreotide(n=216) or placebo plus octreotide (n=213).Patientswere recruited fromAustralia, Belgium,Canada, Czech Republic, Finland, France, Ger-many,Greece, Israel, Italy,Netherlands, Slovakia,Spain, Sweden, Turkey and theUSA.

Results show that themedian progression-free survivalwas 16.4months in the everolimusplus octreotide LARgroup (basedon103events)versus 11.3 months in the placebo plusoctreotidegroup (basedon120events) (HR0.77,95%CI 0.59–1.00; P=0.026).

Adverse effects were higher but manage-able in the combination arm, including stom-atitis (62%vs 14%), fatigue (31%vs 23%), anddiarrhoea (27% vs 16%).

“No approved antitumour drugs are avail-able for treating progressive disease in patientswith gastrointestinal or lung neuroendocrinetumours, consequently affecting the survival of

NewsRound


Study supports dualblockade of HER2growth factor� New England Journal of Medicine

The addition of pertuzumab to standardchemotherapy (trastuzumabplus docetaxel)

results in an additional six months of progres-sion-free survival in patientswithHER2-positivemetastatic breast cancer, the CLEOPATRA studyhas found. The studywas presented at the 2011San Antonio Breast Cancer Conference andsimultaneously published online.

Pertuzumab is designed towork in combi-nationwith trastuzumab as a dual blockade ofthe HER2 growth factor, which fuels aroundone-third of all breast tumours. Both drugs aremonoclonal antibodies that bind to the HER2receptor protein in different locations. Per-tuzumab plays an additional role as a ‘dimeri-sation inhibitor’ that prevents theHER2 receptorfrom linking to HER3 and thereby forming adimer that further signals tumour growth.

In the Clinical Evaluation of Pertuzumaband Trastuzumab (CLEOPATRA) study, JoséBaselga and colleagues, from the HarvardMedical School and theMassachusetts GeneralHospital Cancer Center (Boston, Massachu-setts), randomised 808 women with HER2-positive metastatic breast cancer in a 1:1 ratioto receive a placebo plus the standard therapyof trastuzumab plus docetaxel (n=406), orpertuzumabplus the standard therapy (n=402).

Results showed median progression-freesurvival was 12.4 months in the control groupversus 18.5 months in the pertuzumab group(HR for progression or death = 0.62,95%CI 0.51–0.75; P<0.001).

The interimanalysis of overall survival, per-formed after 165 events (43% of the prespeci-fied total number for the final analysis) showeda strong trend in favour of the combination ofpertuzumabplus trastuzumabplusdocetaxel.Noincreased rates of symptomatic or asympto-matic cardiac dysfunctionwere observed in thepertuzumab group compared with the controlgroup. Diarrhoea, rash, mucosal inflammation,

febrile neutropenia, anddry skin, however,werereported more frequently in the pertuzumabgroup, although most of these effects weregrade 1 or 2 and occurred during the period ofconcomitant docetaxel administration.

“Our findings suggest that targetingHER2-positive tumors with two anti-HER2 mono-clonal antibodies that have complementarymechanisms of action results in a more com-prehensive blockadeofHER2,”write the authors.

Enrolment is already underway in a newdouble-blind, randomisedclinical trial (APHINITY),they add, testing use of pertuzumab andtrastuzumabasadjuvant therapy inpatientswithnewly diagnosedHER2-positive breast cancer.

In an accompanying commentary,WilliamGradishar, from the Robert H. Lurie Compre-hensiveCancer Center, NorthwesternUniversity,Chicago, writes, “For patients with metastaticbreast cancer who have progressive disease,theremaybenumerous anti-HER2agents avail-able that could be used in combination or insequence. In patients with early-stage breastcancer, more effective anti-HER2 agents asadjuvant therapiesmay translate intometasta-tic disease developing in fewer patients.”� J Baselga, J Cortés, S Kim et al. Pertuzumab plus

trastuzumab plus docetaxel for metastatic breast

cancer. NEJM 12 January 2012, 366:109–119

� WJ Gradishar. HER2 therapy – an abundance

of riches. ibid pp 176–178

Androgen deprivationalone inadequate forhigh-risk prostate cancer� The Lancet

Combining radiation therapy (RT)withandro-gen deprivation therapy (ADT) reduced

overallmortality and disease-specificmortalityin men with locally advanced prostate cancercompared toADT treatment alone, a jointUK,USandCanadian studyhas found. The study,whichwas funded by theAmericanNCI, the CanadianCancer Society Research Institute, and the UKMedical Research Council, reported an interim

analysis, planned for publication when two-thirds of final analysis events had taken place.

Until now the question of whether theaddition of radiation therapy improved overallsurvival inmenwith locally advanced prostatecancer managed with ADT has been unclear.

Between March 1995 and August 2005,investigators from the Princess Margaret Hos-pital in Toronto, Ontario, Canada, theMRCClin-ical Trials Unit in London, UK, and CardiffUniversity School of Medicine in Wales, ran-domly assigned 1205 prostate cancer patientsto receive either a combination of ADT andradiotherapy (n=603) , or ADT alone (n=602). Ofall patients in the study, 1057 had locallyadvanced T3 or T4 prostate cancer, while 119had a T2 tumour with PSA concentrations>40 ng/ml and 25 had T2 with Gleason scoresof 8 or higher.

After a follow-upperiod of six years, 320 ofthe patients had died. Of these, 175were in theADT-only group and 145were in the combinedADT and radiotherapy group. Altogether atseven years, 74% of patients in the combinedADT and radiotherapy group were alive com-paredwith only 66% in theADTgroup (HR0.77,95%CI 0.61–0.98; P=0.033).

The addition of radiation therapy slightlyincreased toxicity and reduced health-relatedquality of life, the investigators found, but fewpatients suffered serious side-effects as a resultof either treatment strategy.

“Our findings suggest that the benefits ofthe combination of ADT and RT should be dis-cussed with all patients considering a curativetreatment approach,” write the authors.

The65–69Gydoseof radiation therapyusedin the trial, they add,while lowbymodern stan-dards, represented the standardof carewhen thetrialwas initiated in the1990s. “The improvementinsurvivalwith theadditionofRT toADTrecordedin this trial could be increased again withmod-ern RT dose fractionation,” theywrite.

In anaccompanying commentary,MatthewCooperberg, from theUniversity of California inSan Francisco, writes, “This study has providedthe strongest evidence to date that androgendeprivation therapy alone for men with high-risk prostate cancer is not adequate. These

NewsRound


patients require an aggressive, multimodalapproach incorporating prostate-directed localtherapy. However, the crucial question –whether the optimum initial strategy shouldinclude radiation combinedwith androgendep-rivation therapy, or surgery followedby selectiveradiation on the basis of pathological findingsand early biochemical outcomes – is still open.”The definitive answer, he adds, will comethrough trials randomisingmenwith high-riskdisease to receive surgery or radiation as aninitial treatment.� P Warde, M Mason, K Ding et al. Combined

androgen deprivation therapy and radiation therapy

for locally advanced prostate cancer: a randomised

phase 3 trial. Lancet 17 December 2011,

378:2104–11

� MR Cooperberg. High-risk prostate cancer:

treat the prostate [commentary]. ibid pp 2056–57

Uncertainty overdenosumab’s effectson bone metastasisin prostate cancer� The Lancet

Targeting the bonemicroenvironment withdenosumab delays bone metastasis by

4.2 months in men with non-metastaticcastration-resistant prostate cancer, theauthors of a phase III study have concluded.The author of the accompanying editorial,however, took issue over this interpretation.

Bone metastases are a major cause ofmorbidity andmortality in menwith prostatecancer. Preclinical studies have suggestedthat osteoclast inhibitionmight prevent bonemetastases, and that one approach might bevia a molecular pathway involving the sig-nallingmolecule RANKL. Denosumab is a fullyhumanmonoclonal antibody that specificallytargets, binds and inactivates RANKL.

In the current study, Matthew Smith, fromthe Massachusetts General Hospital CancerCenter, Boston, and colleagues, set out toevaluate the effects of denosumab on bone-

While the study supports the use of deno-sumab as an alternative to zoledronic acid,argues Logothetis, it fails to support its broaduse as a preventive agent for bonemetastases.� MR Smith, F Saad, R Coleman et al.

Denosumab and bone-metastasis-free survival in

men with castration-resistant prostate cancer:

results of a phase 3, randomised, placebo-

controlled trial. Lancet 7 January 2012, 379:39–46

� CJ Logothetis. Treatment of prostate cancer

metastases: more than semantics. ibid pp 4–6

Hodgkin’s lymphoma:chemotherapy alonedelivers greater long-term survival� New England Journal of Medicine

Standard chemotherapy alone is moreeffective than radiation in keeping

patients with limited-stage nonbulkyHodgkin’s lymphoma alive long-term, the lat-est results of the Hodgkin’s Disease 6 (HD6)trial has found.

In 1994, RalphMeyer and colleagues fromthe NCIC Clinical Trials Group and EasternCooperative Oncology Group initiated the HD6trial to investigate whether ABVD chemo-therapy alone (doxorubicin [Adriamycin],bleomycin [Blenoxane], vinblastine [Velbe],and dacarbazine) in patients with nonbulkystage IA or IIA Hodgkin’s lymphoma resulted insimilar disease control to that achieved withradiation-based therapy, butwith fewer deathsfrom late treatment effects.

Altogether in the study 405 patients wererandomly assigned to receive ABVDchemotherapy alone or subtotal nodal radia-tion at a dose of 35 Gy in 20 daily fractions.Patients in the radiation group withfavourable risk profiles received radiationalone, while those with unfavourable risksreceived two cycles of ABVD followed by radi-ation therapy.

In an earlier publication, after a medianfollow-up of 4.2 years the investigators

metastasis-free survival in men with castra-tion-resistant prostate cancer with no evi-dence of bone metastases at baseline, but ahigh risk of progression based on raised PSA orshort PSA doubling times.

Between February 2006 and July 2008,1432men, enrolled at 319 centres in 30 coun-tries, were randomly assigned in a 1:1 ratio toreceive subcutaneous denosumab 120 mg(n=716) or subcutaneous placebo (n=716)every four weeks until a study event, definedas bonemetastasis or death, occurred. Partici-pants underwent bone scans every fourmonths to detect bone metastases.

Results showed that the time to develop-ment of bonemetastases was 29.5months formen receiving denosumab versus 25.2monthsfor men receiving placebo (HR 0.85; P=0.028).However, overall survival was not found to dif-fer between the two groups (HR 1.01; P=0.91).

Rates of adverse events and seriousadverse events were similar in both groups,except for osteonecrosis of the jaw, whichdeveloped in 5% of patients taking deno-sumab versus none taking placebo.

“Our finding that denosumab increasesbone-metastasis-free survival provides clini-cal evidence for the important role of thebonemicroenvironment and RANKL signallingin development of bone metastases in menwith prostate cancer,” conclude the authors.

In an accompanying commentary, Christo-pher Logothetis from the MD Anderson Can-cer Center, in Houston, Texas, pointed out thatthe delay in the time to metastases foundwith denosumab in the study of 4.2 months,was similar to the delay in time to skeletal-related events reported in earlier studies com-paring denosumab and zoledronic acid inmenwith metastatic castration-resistant prostatecancer. It is possible, he adds, that Smith andcolleaguesmight have included patients withundetected metastases in their study.

“If clinically undetected metastases werepresent at study entry, the investigators didnot study the so-calledmetastasis preventionproperties of denosumab, but rather exploredthe drug’s effect on the biological contin-uum of metastases,” he writes.

NewsRound


reported that the rate of freedom from diseaseprogression was higher among patientsassigned to radiation therapy than ABVD ther-apy alone, and that no differences in survivalwere detected.

In the current publication, investigatorsreport that the latest results show that, at12 years, 94% of patients who had receivedABVD chemotherapy were alive, comparedwith 87% of patients who were given subto-tal nodal radiation with or withoutchemotherapy (HR for death = 0.50; P=0.04).

The difference, say the authors, was due tothe number of deaths from causes other thanHodgkin’s lymphoma, including second can-cers and cardiovascular events. Among thepatients randomly assigned to ABVD, six diedfrom Hodgkin’s lymphoma or an early treat-ment complication, while 12 died from othercauses; whereas among patients who under-went radiation therapy, four died fromHodgkin’s lymphoma or early treatment com-plications, while 20 died from other causes.Event-free survival was similar – 80% withradiation therapy and 85% with ABVD(HR 0.88; P=0.60).

“Our results show that improving long-term survival is less dependent than previouslyassumed on further reducing deaths due toprogressive Hodgkin’s lymphoma and insteademphasize a need for treatments that willnot lead to deaths from late treatmenteffects,” write the authors. Trial endpoints,the add, should be redefined so that theimportance of deaths from causes other thanHodgkin’s lymphoma is captured.

In an accompanying commentary DavidStraus, from Memorial Sloan-KetteringCancer Center, New York, writes, “Althoughradiation therapy remains a useful tool for thetreatment of some patients with Hodgkin’slymphoma, the challenge is to define the sub-group of patients for whom the benefits out-weigh the increased risk of late complications.”

Limiting the use of radiation therapy tothe fraction of patients who require it, headds, would make an important contribu-tion to the ultimate goal of maximising thelong-term cure rate while minimising late

morbidity and mortality.� RM Meyer, MK Gospodarowicz, JM Connors

et al. ABVD alone versus radiation-based therapy

in limited-stage Hodgkin’s lymphoma. NEJM

published online 11 December 2011,

doi:10.1056/NEJMoa1111961.

� DJ Straus. Chemotherapy alone for early-stage

Hodgkin’s lymphoma. ibid published online 11

December 2011, doi:10.1056/NEJMe1113291

Serial FDG-PET/CTpredicts chemotherapyoutcomes in mCRC� Annals of Oncology

Metabolic response measured by FDG–PET/CT can be used to identify patients

with metastatic colorectal cancer (mCRC)who will not benefit from chemotherapyafter a single course of treatment, a studyhas shown.

The fact that tumour shrinkage is knownto be the final step in a complex cascade ofchemotherapy-induced alterations, suggeststhat earlier changes in cellular metabolismmight be used to predict treatment response.Alain Hendlisz and colleagues, from the Insti-tut Jules Bordet (Brussels, Belgium), rea-soned that FDG-PET/CT might be used as asurrogate marker of tumour glycolytic activ-ity, allowing the assessment of tumourresponse to treatment after just one or twocycles. “The aim of identifying patients withnon-responding metastatic disease early is toquickly stop ineffective treatments. This canavoid unnecessary toxic effects and possiblyallow alternative more effective therapies,”write the authors.

Between November 2005 and October2009, FDG–PET/CT scans were undertaken on41 patients with unresectablemetastatic colo-rectal cancer undergoing treatment with abiweekly regimen of chemotherapy (29patients received chemotherapy as first-linetherapy and 11 as second line) both at baselineand on day 14. For the study, metabolic non-

response was defined by <15% decrease inFDG uptake in the patient’s lesions, or if alesion was found to be metabolically pro-gressive. The PET-based response was thencorrelated with the primary endpoint of radi-ological Response Evaluation Criteria in SolidTumours (RECIST) and the secondary end-points of progression-free survival and over-all survival.

Results show that the RECIST responserate in metabolically responding patients was43% (10 of 23) compared with 0% (0 of 17) innon-responding patients (P=0.002). Comparingmetabolically responding versus non-respond-ing patients, theHR for overall survivalwas 0.28(95%CI 0.10–0.76) and for progression-freesurvival it was 0.57 (95%CI 0.27–1.21).

The authors add that 68% of participantsdisplayed a mixed metabolic response, i.e.both responsive and non-responsive PETlesions coexisted within the same patient,and sometimes even within the same organ.

Patients with exclusively metabolic non-responding lesions or at least one metabol-ically progressive lesion showed the worstoutcomes, with the overall survival of these10 patients being significantly worse thanthe remaining 30 patients (HR 4.78;P=0.001), as was progression-free survival(HR 2.30; P=0.043).

The target sample size of 45 patients wasnot achieved, write the authors, due to slowstudy accrual and replacement of the FDG-PET/CT scanner used for the study.

“Early FDG-PET/CT metabolic reassess-ment after one chemotherapy cycle inpatients with nonresectable mCRC is able todiscriminate, with a high NPV [negative pre-dictive value], tumors unlikely to respond totreatment,” write the authors. If independentlyvalidated, they add, the results could have asignificant impact on future treatment strate-gies and design of clinical trials.� A Hendlisz, V.Golfinopoulos,C. Garcia, et al.

Serial FDG–PET/CT for early outcome

prediction in patients with metastatic colorectal

cancer undergoing chemotherapy. Published

online 23 November 2011, Ann Oncol

doi:10.1093/annonc/mdr554

How are we doing?The question that could help drive up standards across Europe’s cancer services

� Janet Fricker

Information onhow the performance of individual clinicians, teams andhospitals compareswith

the best is key to driving up standards in cancer care. In the absence of any lead from national

or regional health authorities, ECCO is designing and implementing an audit framework named

EURECCA. But could patients’ interests suffer to protect professional reputations?

Improving the quality of cancercare through performance feed-back to hospitals and healthcareprofessionals is a topic of growinginterest for policy makers and

cancer professionals alike. Well-performing health systems make thebest possible use of finite health budgets.Monitoring performance across hospi-tals, health regions and countries alsohelps identify and spread best practiceand can potentially save patients frombeing treated in places and by profes-sionals who are not up to scratch.

But how can such monitoring beorganised in something as complex ascancer care, andwho should be respon-sible? These were two of the questionsthat were addressed at the ‘oncopolicy’session on Inequalities in Cancer Care,organised at the ECCO conference

in Stockholm last September.Chairing the session, ESMO presi-

dent David Kerr emphasised the needfor effective audit systems. “In the bid toimprove clinical standards it’s reallyimportant to develop systemswhich cap-ture clinical outcomes and make themreadily available to citizens,” he said.

The urgent need to harmonise can-cer care throughoutEurope, he added, isunderlined by the results of successiveEUROCARE epidemiological studies,which reveal persistent differences incancer mortality between countries.Despite improvements in survival ineastern European countries due to bet-ter cancer care and screening, the east–west gap in Europe still continues. TheEUROCARE-4 study, which was pub-lished in theEuropean Journal of Cancerin 2009, covering 42 types of cancer in

23 European countries, showed thatfive-year relative survival for all cancersranged from 58% in Sweden to 39% inPoland.Marked survival differences alsoexist amongwestern countries, with sur-vival in theUKandDenmark for severalcancers being relatively low. Otherpublications on social inequalities andcancer have revealed large differenceswithinwestern countries in both cancerincidence and mortality. In a study oneducational inequalities in cancer inci-dence done in Turin, Italy, and pub-lished in theEuropean Journal of CancerPrevention in 2009, a low level of edu-cationwas associatedwithhigher risks ofupper aero-digestive tract (UADT),stomach, lung, liver, rectal, bladder, cen-tral nervous system and ill-defined can-cers in men, and with stomach, liverand cervical cancers in women.


Systems&Services

“The way cancer services are organised has the

power to determine whether people live or die”


ment systems all play a role. “The waycancer services are organised has ahuge influence on patient outcomesand has the power to determinewhether people live or die,” she said.

Redmond referred to the OECD’sdraft report ‘What Explains Differencesin Cancer Survival Rates?’ which waspublished in 2011. Based on exten-sive data gathering and analysis,together with questionnaires and inter-views coveringmany cancers and coun-tries, theOECD report concluded thataround 50% of differences in survivalrates can be explained by financialresources (such as access to drugs,

number of oncologists, number of com-prehensive cancer centres), 33% byprocess quality (i.e. whether popula-tions have access to services such ascancer prevention, early detection andevidence-based cancer care) and 17%by governance – ensuring the wholesystem functions as well as possible.Drawing up national cancer controlplans, introducing cancer-specific tar-gets with timeframes, developing net-works for service delivery, setting inplace quality assurance mechanismsand monitoring progress, said Red-mond, are all essential aspects of goodgovernance.

Systems&Services

THE ROOTS OF INEQUITYIn the key note presentation, KathyRedmond, editor ofCancer World, tooka closer look at some of the factorsthat contribute to such variations inincidence and outcomes. Differencesin the level of public investment inhealth care (total health expenditure asa share of the country’s GDP), thetechnology available (such as numberofMRImachines), access to specialistdoctors and nurses, the number of hos-pital beds available and reimburse-


WW.ORGANISART.CO.UK

USE OF INTENSITY-MODULATED RADIOTHERAPY

Patients in Ontario view performance data telling them how safe, effective, accessible, responsive,efficient, equitable and integrated their cancer services are (www.csqi.on.ca/ click on ‘QualityDimensions’). Many of these are available on a hospital by hospital basis. The example here showswhat percentage of head and neck cancer patients treated with a radical course of radiotherapy haveaccess to the gold standard intensity-modulated radiotherapy (IMRT) at each cancer centre

THE ONTARIO EXAMPLEThe Cancer System Quality Index(CSQI) developed and used inOntario,Canada, offers a prime example of howgood governance initiatives can improveservice delivery by setting standards forcare and measuring their implementa-tion, said Redmond. Launched in 2005by the Cancer Quality Council ofOntario (CQCO) – a quasi-indepen-dent body with a mandate to monitorand report publicly on cancer system

performance – in partnershipwithCan-cer Care Ontario (CCO) – a public(provincial) agency responsible for con-tinually improving cancer services –CSQI now undertakes an annual auditreviewing the province’s progressagainst cancer.

The audit reports on 36 evidence-based quality measures covering everyaspect of cancer care fromprevention toend-of-life issues. Measurementsinclude the percentage of liver and pan-

creatic cancer patients whose surgery isdone at designated referral centres, thepercentage of patients who have theircare discussed atmultidisciplinary caseconferences, and the percentage ofpatients undergoing a radical course ofradiotherapy who receive the gold stan-dard intensitymodulated radiation ther-apy. Other aspects covered by the auditinclude waiting times between cancersurgery and adjuvant chemotherapy,the percentage of patients treatedaccording to guidelines, and patientsatisfaction with care, including theirsatisfaction with the emotional sup-port offered by healthcare professionals,continuity of care and respect for theirpreferences.

Health professionals, cancer organi-sations, planners and policymakers canuse theweb-basedCSQI audit results toidentify cancer trends andplan improve-ments to the service.A significant rise inthe proportion of lung cancer patientsbeing screened for symptoms using theEdmonton Symptom Assessment Sys-tem (a screening tool rating the severityof nine symptoms commonly experi-encedby cancer patients) is one exampleof an improvement that has beendirectlyattributed to the CSQI. In 2008, whenCSQI first began reporting on theuse ofESAS, 43%of lung cancer patientswerescreened using the tool, but two yearslater this had climbed to almost 60%,with some cancer centres reporting thatover 85%of patients hadbeen screened.“TheCSQIprocess helpedhighlight thevalue that patients place on the ESASscreening tool as a crucial component oftheir care,” explained a representative ofCSQI later toCancer World.


Systems&Services

“Health professionals and policy makers can use the

audit results to identify trends and plan improvements”

The variability of cancer incidence andmortality within and across Europeancountries shows there is an urgent needfor governments on this side of theAtlantic to follow theOntario example,and establish clearly defined standardsof care for cancer patients and thenmonitor and improve their delivery,Redmond argued.

EURECCA – A NEW QUALITYFRAMEWORKIn the absence of the sort of public ini-tiatives representedby theCSQIaudit inOntario, issues of audit and qualityimprovement inEuropehave so far beenlargely left up to professional organisa-tions.Bodies likeEUSOMAandEMBThave introduced quality improvementinitiatives in their respective fields ofbreast cancer care andbloodandmarrowtransplantation,while theOrganisationofEuropean Cancer Institutes has imple-mentedanaccreditation scheme for can-cer centres, with a commitment tocontinuous improvement among theassessment criteria.NowECCOitself isintroducing a new quality framework,EURECCA (European Registration ofCancerCare),which is kickingoffwithsome core countries, focusing oncareof colorectal cancerpatients.

Speaking in the paneldiscussion, Cornelius vande Velde, president ofECCO, and a cancersurgeon at Leiden Uni-versity Medical Centre,in the Netherlands, described howEURECCA will work, and outlinedECCO’s plans to develop it into aninfrastructure where every cancer treat-ment centre across Europe can upload

information about tumour character-istics, treatments, and patient out-comes onto a single site.

“The aim is to first identify bestpractice, and then use this informationto shape guidelines that can spreadthe word throughout Europe. Theapproach can also provide perform-ance feedback to individual centres,”explained van de Velde, speaking laterto Cancer World.

By inputting data on the treatmentand outcomes ofmultiple patients from

age, gender or comorbidities ofpatients,” said van de Velde.

Nine independently founded, upand running, national colorectal auditregisters have already committed toparticipating in EURECCA (see table).

A TRACK RECORD OFIMPROVEMENTSThese established systems offer aninsight into the enormous gains that canbe achieved through audit. Take theexample of Denmark – after the intro-duction of a national colorectal cancerdatabase in 1994, the five-year overall

survival for rectal cancer rose from37%of patients in 1994 to 51% in2006. A similar story emergeswith theNorwegian colorec-tal cancer registry, wherefive-year survival for col-orectal cancer patientsincreased after its launchin 1993, from55% to 71%.

If EURECCA is tosucceed in its aim to rollout the audit framework to

address other solid tumourtypes, additional registries will

need to be developed for instance inbreast, oesophageal and gastric cancers.

The framework will be multidis-ciplinary, including information notjust on surgery but also on medicaland radiation oncology. In additionto showing overall survival statistics,the system could also flag up specificcomplications of surgery or side-effects associated with drug treat-ments. “Cancer is like a war situation– not only do many people die fromthe disease, but survivors experienceenormous suffering. All these data

Systems&Services


“Established systems offer an insight into the

enormous gains that can be achieved through audit”


WW.ORGANISART.CO.UK

centres across Europe,EURECCA should make it pos-

sible to tease out the approachesassociated with the best overall sur-vival statistics and least side-effects.Data from large numbers of patientswould allow comparisons of ‘like withlike’. “It’s only then that you can estab-lish that the differences observed aredue to treatments or techniques ratherthan confounding factors such as the


Systems&Services

could be represented in the analysis,creating the possibility for identifyingstrategies that prevent problems,”says van de Velde.

Patient’s views on treatments andthe approach of health staff may alsoeventually be incorporated into themix. “The system could identify rea-sons why patients perceive one centreto be better than other, and indicatechanges that could be implementedto make services more user friendly.”

EURECCA offers the potential totransform the development of cancerguidelines and allow them to repre-sent ‘real world’ patient situations.“Traditionally guidelines have beenbased on the beliefs of charismaticleaders backed up by clinical trials,”explains van de Velde. “Incorporatingthe EURECCA data would allowguidelines to become much more evi-dence based and include data onpatients who are normally excludedfrom clinical trials, either becausethey’re too old or have comorbidities.”

Ultimately, he adds, the hope is thatEURECCAwill offer an online systemgiving individual cancer centres accessto their own confidential data, whichwould also allow them to compare theirperformance with other anonymisedcentres across Europe. “The approachis like giving health professionals amir-ror. It allows them to take a good look atthemselves and identify how thingsmight be improved.”

Where centres are found to beunderperforming, mechanisms willneed to be introduced to helpimprove practice, and also identifyhealth professionals who need

retraining. But key to the success ofthe initiative, van de Velde insists, isthat there should be no public nam-ing, blaming and shaming of individ-uals or institutions.

A PATIENT’S RIGHT TO KNOWThe EURECCA initiative was given avery enthusiastic reception at themeeting, but many felt that cliniciansand hospitals do need to be heldaccountable for performances.

“With people’s lives at stake, pro-fessional sensitivities need to be putto one side,” said Redmond. Ifpatients are to actively participate inthe decision-making process, addedRegine Hagmann, from the GermanCancer Information Service, there isa need for full transparency. How canthey make informed decisions aboutwhere to go and who to trust if out-come information is all anonymised?Survival statistics are the onespatients need most of all, commentedStella Kyriakides, chair of the ECCOPatient Advisory Committee, andthese should be publicly available.

Redmond offered an examplefrom Italy to show that making qual-ity-related information publicly avail-able does help pull up standards. Aleading Italian daily paper, the Cor-riere della Sera now publishes data forevery hospital in the country, showingthe number of cancer patients thatthey treat annually, broken down bycancer type. The figures are collectedby the health authorities, but it is thenewspaper that presents them ontheir own website (www.corriere.it/salute/sportello_cancro/), in a way

that is easy to search – you just clickthe relevant body part to identify thecancer of interest, and then click aregion on a map of Italy for details onevery hospital in the region. The ini-tiative led to patients identifying thecentres that performed only a fewprocedures annually and ‘voting withtheir feet’ to avoid them.

The natural competitive instinctsof countries, healthcare regions andindividual clinicians can all be leveragedto the patient’s advantage, said Kerr.When the EUROCARE survey identi-fied the UK as a country with poornational cancer survival figures, itshamed the former Prime Minister,Tony Blair, into launching theNationalCancer Plan.

In the UK the process could soonbe taken one step further. The WhitePaper ‘Equity and Excellence: Liber-ating the NHS,’ published in October2010 by the Department of Health, islooking to create a system that willallow clinical teams to see meaning-ful, risk-adjusted assessments of theirperformance against their peers. ThePaper plans for the information to beplaced in the public domain, allowingpatients to check on the care resultsof individual doctors before choos-ing their provider.

Recording the five-year survivalrates of individual clinicians, saidKerr, is likely to result in the creationof league tables in the UK. “The pro-fessional pride of clinicians findingthemselves at the bottom of suchtables would doubtless be responsiblefor improving care, which would driveup standards,” he said.

“If patients are to participate in the decision-making

process, there is a need for full transparency”

cancer world 47

Documents

research intothe

fundingfor health research

foran eu research grant

current research landscape

ill health

increasepublic spending

red tape associatedwith

john crowneducation