Cancer Education & knowledge through people & …...Cancer, says: “We know that every country...

Education & knowledge through people & factsNumber 13, July-August 2006

➜ David Khayat: driving the French cancer plan ➜ Are you feeling lucky? Top tipson explaining risk and exploring options ➜ Moscow's smokebuster: fighting cancerin an era of political change ➜ Has the TNM system been overtaken by science?

David Khayat

CancerWorld 13

JULY-AU

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Contents

CANCER WORLD ■ JULY-AUGUST 2006 ■ 1

3 EditorialUICC – taking on mission impossible

4 Cover StoryDavid Khayat: driving the French cancer plan

14 Grand RoundAre you feeling lucky? Discussing risk and treatment options with patients

26 Drug WatchRNA-bound: the future of antisense drugs

32 ForumHas TNM been overtaken by science?

40 MasterpieceThe Moscow smokebuster

48 Impact FactorDoes regular use of aspirin reduce the risk of colorectal cancer?Factors predictive for response of follicular and mantle cell lymphoma to rituximabNewsround

60 Bookcase

EditorKathy [email protected]

Assistant EditorAnna Wagstaff

Editorial AssistantMariarita Cassese

Editorial BoardMariano Barbacid, Franco CavalliAlberto Costa (chair)Lev Demidov, Mario DicatoGordon McVie, Nicolas PavlidisHans-Jörg Senn, Antonella Surbone

Board of AdvisorsJan Betka, Jacques BernierVincent T. DeVita, Lex EggermontJan Foubert, Lynn Faulds WoodNeel Mittra, Santiago PavlovskyBob Pinedo, Mike RichardsMaurice Schneider, Tom VouteUmberto Veronesi (chair)

Contributing WritersMarc Beishon, Raphaël BrennerPatrick Lynch, Emma MasonKeith McCullagh, Peter McIntyreMichael Pfreundschuh, Anna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonChatrina Melcher

Project DesignerAndrea Mattone

Graphic and Layout DesignersPier Paolo Puxeddu+Francesca Vitale

Production ManagerGianfranco Bangone

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Cover photographHamilton / REA

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Direttore responsabileEmanuele Bevilacqua

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Copyright ©2006 European School of Oncology.All rights reserved

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

Editorial


For almost 75 years the International UnionAgainst Cancer (UICC)has been the only interna-tional non-governmentalorganisation dedicated

exclusively to the global control of cancer.But with many societies currently ‘goingglobal’, including ASCO and theAmerican Association for CancerResearch, questions could be raised aboutwhether the UICC is really needed any-more. I’m convinced it is.We need the UICC to ensure that cancerachieves and retains priority status on theagenda of the main political bodiesincluding the UN, G8, and the WorldBank.It was thanks in large part to sustainedpressure from the UICC that last yearthe general assembly of the World HealthOrganization finally declared the fightagainst cancer as a priority. But despitethis resolution, and despite cancer beinga bigger killer than tuberculosis, malariaand HIV together, experience shows thatgovernments won’t act unless forced toby pressure of public opinion. On a global scale, this level of pressurecan be organised and channelled onlythrough an established and representa-tive non-governmental organisation(NGO) like the UICC.

➜ Franco Cavalli* ■ GUEST EDITOR

People who are living in countries withmore limited resources need the UICCtoday more than ever.On top of the toll of poverty-related can-cers, demographic changes are now lead-ing to an upsurge in cancers related towestern lifestyles. As a result, while glob-ally cancer incidence is expected toincrease by 50% over the next 15 years,most of that rise will be in the developingworld, which by 2020 is expected toaccount for almost two-thirds of all newcases.And because most of these people willhave no access to screening, early diag-nosis and appropriate treatments, theystand less chance of surviving. By 2020,for every one cancer death in an affluentcountry, three people will die in thedeveloping world.Finding ways to avert a catastrophic can-cer epidemic may seem like an impossi-ble mission, but having worked with theUICC for many years, I know that greatthings can be achieved when the wholeoncology community pulls together. Asincoming president, I accepted the heavyresponsibility of leading this huge NGO,because I believe the UICC is the onlybody that can coordinate a successfulglobal fight for cancer control. I see noreason why ‘mission impossible’ shouldbe confined to the movie screen.

UICC - taking onmission impossible

*Franco Cavalli is Director of the Oncology Institute of Southern Switzerland, and will take on the presidency of the UICC at theWorld Cancer Conference, Washington, 8–12 July

CoverStory

David Khayat:driving the French cancer plan

A committed medical oncologist, David Khayat reluctantly dragged himself away from his

patients in 2003 to oversee the implementation of the French cancer plan. This grand and

sweeping venture exercises huge control over cancer services, education and research. But its

real value, says Khayat, is that it treats cancer patients as normal human beings.

What does it take to kick-start anational cancer plan that willdeliver fast and sustainableimprovements in cancer care,prevention and research?

Such plans are badly needed – as John Seffrin,president of the International Union againstCancer, says: “We know that every countryneeds to develop a cancer plan. If you’re notplanning, you’re planning to fail.”

In the UK, the shame of long waiting timesand one of the worst treatment records inEurope led to the NHS Cancer Plan in 2000;Australia, Canada and New Zealand also haveplans in place. In the US, politicians attemptedbut failed to pass a national cancer act in 2003to re-energise the famous ‘war on cancer’launched by President Richard Nixon in 1971.Indeed, it is similar top-level backing that hasseen the successful launch of arguably the mostcomplete and rapid initiative yet seen – France’snational cancer plan, which is one of the lega-cies chosen by President Jacques Chirac for hissecond term in high office.

➜ Marc Beishon

4 ■ CANCER WORLD ■ JULY-AUGUST 2006

France’s plan was announced in 2003, threeyears after another landmark cancer occasion inthe country – the Paris Charter, to which coun-tries and agencies have been signing up, pledgingtheir commitment to the cancer effort. Both theplan and the charter have one thing in common– the pivotal figure of David Khayat, a medicaloncologist who has been rather reluctant tospend time away from clinical work, but whoundoubtedly possesses the charisma and con-tacts to lead sweeping changes in France’s can-cer care and research provision, and to engageinternational colleagues in wider collaborativeinitiatives.

As he points out, France actually has a verygood record in cancer treatment compared withmost other European countries. “But while wehad the best survival after diagnosis on average,there were major discrepancies in outcomesdepending on where you lived – by a factor ofsix. For a country that has made equality thebasis of its constitution, that’s unacceptable.”Other major issues were too many researchinstitutions, diluting the research effort, and a

CoverStory

CANCER WORLD ■ JULY–AUGUST 2006 ■ 5

drop-off in the French contribution to seminalfindings in recent years; a lack of diagnosticequipment such as CT scanners; not to mentionFrance’s major consumption of cheap tobacco.

“That is to name just a few issues – the can-cer plan has a total of 70 key areas, and whilevery ambitious they are all being precisely fund-ed and evaluated,” says Khayat. The engineroom of the plan is the organisation over whichKhayat currently presides – the National CancerInstitute (known as INCa) – without which it ishighly unlikely that much ‘joined-up’ progresswould have been made.

Khayat says the institute has been set up as alegal entity – “It would take another law to abol-ish it and it’s hard to imagine that any govern-ment would vote to stop fighting cancer.” Whilethe initial cancer plan runs for five years, from2003 to 2007, the idea is that INCa will contin-ue to coordinate improvements, and it has beeninvested with considerable power. “For example,we have the responsibility to authorise howcancer is treated across France – it is not openanymore to individual doctors either in public orprivate practice to treat patients without specificapproval for their hospital. We can also authorise

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It would take another law to abolish INCa, and it’s

hard to imagine that any government would do that

CoverStory


interim approval of drug treatments before theyhave been passed at European and national level,as we did last year with Herceptin for peoplewith early-stage HER-2 positive breast cancer.”

Such powers might seem authoritarian, butKhayat is quick to point out that decisions arereached collaboratively with other agencies, andwhile raising standards will always make waves,no doubt many of its primary functions – suchas uniting fragmented research efforts and lead-ing investment in diagnostic equipment – arebroadly welcomed. And in Khayat, the institutehas a leader who has been plucked somewhatagainst his will from the coalface of patient care,and so knows first hand the day-to-day issues ofpractitioners. He is also head of medical oncol-ogy at Pitié-Salpêtrière hospital in Paris, one ofthe largest public hospitals in Europe, and pro-fessor of medicine at the Pierre and Marie CurieUniversity. He insisted when he took on theinstitute’s presidency that he retained theseposts, and that he would return later this year,once his work in establishing INCa was done.

Khayat was born in Tunisia into a Jewishfamily, and came to France after Tunisian inde-

pendence when he was four. Living in Nice, hisfamily were fairly poor, and they were fortunateto benefit from good medical treatment whenKhayat became seriously ill with rheumatic feverat the age of eight. “I had to take steroids andpenicillin for five years, but I was struck by thisgeneral practitioner who came to our little apart-ment, wrote out the prescriptions and madeeveryone smile. I decided then I would becomea doctor, and I never change my mind – just as I said to my parents there was a certain girl I wasgoing to marry.”

It was the young wife of a best friend, how-ever, who was to profoundly influence Khayat inhis career. By now a medical student, he sawthis young woman diagnosed with metastaticcancer and enduring two years of surgery andchemotherapy of the 1970s – and surviving. “I thought it was amazing that she could becured – and I knew then that I wanted to be partof this revolution.”

Khayat became an ‘intern’ – a competitiveposition attained by the top 5% of medical stu-dents in France – and moved to Pitié-Salpêtrière, where he worked with some of the

En famille. With hiswife, Jocelyne,and daughters Julie (left),Cecile (centre) and Barbara (right)

CoverStory


best oncologists of the time. Among them wasClaude Jacquillat, a pioneer in treatingHodgkin’s, who taught him his clinical craft, andanother who advised him to carry out some basicresearch. While doing his military service as acivil placement in a research laboratory in Israel,he worked on a mouse serum discovery, andlearned to appreciate the controlled conditionsfor basic research, as compared with the vari-ability in clinical conditions.

“In France we have a good history of encour-aging doctors to do basic research – it’s notmandatory but you can’t move up the professori-al scale if you don’t do it for some years. But onlya few people can continue with such research, asthere is just too much clinical and teaching workto do. In any case, it has become more evidentthat having small labs attached to departmentsis not viable – you need large research establish-ments to have a critical mass of people andequipment. Today, I think it is a good thing thatdoctors collaborate with large research unitsrather than doing things themselves.”

He also went to the Mount Sinai hospital inNew York where he purified the soluble Fcreceptor in mouse serum, and back in Paris didthe same in human blood, demonstrated itspathology and duly got a PhD in tumourimmunology and went on to become full profes-sor at the early age of 34. “This should have beena unique period, when I was set up with a goodsalary and conditions for the rest of my life andnot that much responsibility – but unfortunate-ly Claude Jacquillat, my head of department,died and I was asked to take over.”

While such responsibility has no doubtmade Khayat the organiser he is now, the earlydays as head of medical oncology at Pitié-Salpêtrière were very tough. “I had to fight otherdepartment heads for resources, manage somedifficult older colleagues and I also found outmy boss had been raising a lot of money from

charities to fund the department. Almost halfthe doctors around me were paid for by charity– I had no idea about this, and I was soon askedhow I was going to continue to raise funds.”

Jacquillat, who died of cancer, had beenwell known and was a hard act to follow. Khayatworked round the clock to build the departmentand meet fundraisers. He’s especially proud of continuing to put the hospital on the map for innovative clinical work. “We introducedneoadjuvant chemotherapy for breast cancerwhich, while quite normal now, was a hugestruggle back then, as if you delayed surgery youwere considered a potential murderer. But weshowed that with a combination of chemo- andradiotherapy you could avoid surgery altogether,and it stimulated the work of famous oncologistssuch as Tom Frie and Bernie Fisher.”

INCa is promoting itself as a key player

and mover in all manner of European initiatives

Great minds think alike. Gabriel Hortobagyi(right) is a closeassociate and waspart of the gatheringthat dreamt up the idea of the Paris Charter Against Cancer

CoverStory


manner of European initiatives, including avirtual tumour bank and a fledgling Europeanalliance against cancer, which looks to begrowing out of a meeting of European healthministers, and which Khayat says could producebacking for large-scale clinical research such asa major lung cancer screening study. INCa isalso helping other countries as far afield as theUkraine and Tunisia with cancer plans.

Khayat has also helped to build a multi-disciplinary cancer centre at Pitié-Salpêtrière,and it is his strong interest in holistic issues thatbrought him to prominence in France as a can-cer commentator and set in train his involve-ment with the cancer plan. “What gives us thevalue of what we do is looking at someoneaffected by cancer as a normal human being –reflecting their identity back to you like a mir-ror,” he says. “I’ve been talking about this for 10years in the media now – I believe it was the factthat we had to start considering the patientbeyond the disease that convinced Chirac weneeded to do something.”

A journalist included Khayat as one of 10profiles in a book on the work of doctors, and itwas his story of fighting cancer with his boss atPitié-Salpêtrière, who was fighting cancer him-self, that attracted media interest and led to himbeing perceived as “the doctor who talks aboutcancer on TV”.

At the same time, he made several major con-tributions to the profession. He says he wasinstrumental in founding the French federationof medical oncologists, a union of Parisian oncol-ogists, a Paris oncologists’ club and a master’sdiploma in oncology. These initiatives were fairlystraightforward in the latter half of the 1990s, asmedical oncology had been recognised in Franceas a speciality in 1989 – that though had been abattle against vested interests, comments Khayat.

Naturally, Khayat would like to see moreconsistency around Europe in the recognition ofmedical oncology, and he is concerned thatoncologists are not always taking the lead inteaching their subject, with organ specialists fill-ing the gap. “The knowledge you have to acquireand maintain in oncology means you have to doonly that,” he comments. A battle he’s still fight-ing today at the hospital, however, is the funding

Other achievements include the introduction ofwhat is now called biochemotherapy for thetreatment of melanoma, and generally theestablishment of the hospital as one of the mostimportant centres for phase I and II trials inFrance.

That said, Khayat says French clinical trialshave only been running at about the Europeanaverage for some time. “It’s been very unsatis-factory – apart from a few large phase III ran-domised studies, the average patient populationinvolved in trials has been less than 2%. This ispartly because a majority are treated in the pri-vate sector, which has no incentive to run trials.Further, most of the protocols are funded bypharmaceutical firms, so there has also been alack of independence.”

Several aspects of the cancer plan deal withthis. “We ran hearings from experts around theworld about what they’ve done to improve thequality and quantity of clinical research, and wechose to model our approach on England’sNational Cancer Research Network, but adapt-ed a bit.” Both the English and French approachhave area-based research networks, but Khayatexplains that the French system is fundingresearch units not on a population basis, as inEngland, but on the number of patients enteredin trials. “This year we will have set up 28 expertgroups, covering topics such as lung, breast, psy-cho-oncology, surgery and so on – and we willproduce a set of clinical research protocols. Wehave divided France up into 35 territories, eachreceiving a budget to recruit clinical researchassistants and data managers. Each doctor thatenters patients into the protocols will receivepayment.” The goal is to recruit 10% of newpatients into trials.

The relationship between France andEngland/UK is becoming quite intimate on thecancer front – if less so on other issues –following the centennial of the Entente Cordialein 2004. As Khayat notes, the countries haveagreed to cooperate on developing their cancerplans, with specific reference to joint work onall type of research, including epidemiology, andtraining. But as he adds, France is also keen tocollaborate with other countries and INCa ispromoting itself as a key player and mover in all

CoverStory


of extra resources and staff such as psycho-oncologists. If anything, charitable donationshave been harder to attract since France’s majorcancer charity, ARC, was victim to a majorfinancial scandal in the 1990s, for which itsdirector was jailed. Khayat eventually had tochange the name of a charity he inherited fromhis department head – CRAC has becomeAVEC to avoid association in the public mind.

The Paris Charter Against Cancer cameabout in 1999 when Khayat and close oncologistfriends and colleagues were discussing how bestto raise awareness of cancer for the new millen-nium. Khayat has an enviable network of inter-national colleagues, and has a particularly close

association with Gabriel Hortobagyi, head ofbreast oncology at the MD Anderson in the US,with whom he has organised an educationalconference that now takes place each year inParis (the International Congress on Anti-Cancer Treatment). It was with Hortobagyi andother senior oncologists such as Peter Harperand Martine Piccart, in the famous Guy Savoyrestaurant in Paris, that the charter idea cameup for the year 2000.

“We wanted to declare war on cancer likeNixon did in 1971, and for support I wrote toUNESCO, the then French minister of healthand President Chirac [who was on the oppositepolitical wing to the minister]. UNESCO said

“The value of what we do is looking at someone

affected by cancer as a normal human being”

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‘yes’, the minister said ‘no’, and Chirac asked meto explain further. He said that if we called it acharter, not a war, we had his support – andwhen the president supports something inFrance, it opens a lot of doors.”

The Paris Charter was duly signed on TV byChirac and others on 4 February 2000 at anevent called the World Cancer Summit, and thatdate is now World Cancer Day each year. So farmore than 15 nations are on the signatory list.“The idea is to remind governments about thebasic rights of cancer patients through its 10articles,” says Khayat. “We were amazed thatthe idea of a group of friends should turn into aglobal story.”

Khayat had the ear of Chirac now, and in2002 when Chirac was re-elected as President,along with a government of his own complexionthis time, there was an opportunity to put weightbehind a cancer plan. There had been a plan onthe stocks since the late 1990s, but Khayat saysthere “wasn’t a single euro behind it”. WithChirac making the cancer plan, the rights of thedisabled and a cut in traffic accidents his triplelegacy for his second term – in preference tobuilding another arts project, which many presi-dents favour – Khayat and colleagues set up anexpert committee that suggested several routesfor the plan, with Chirac selecting the 70 stepsnow in play, plus of course the founding ofINCa.

“We calculated how much the 70 measureswould cost, and asked for 1.7 billion euros – andwe got it,” says Khayat. There is a lot of sub-stance to the plan, which has the great merit ofhaving very visible measures – in the two reportsissued so far, there is clear indication of progresson each and well-written discussions on ration-ale, with case studies to illustrate.

About half the plan had been completed byearly 2006, says Khayat, and he expects every-thing to be in place by the end of 2007.

There are 11 departments at INCa focusing onvarious aspects of the plan – Khayat says it wasdecided not to focus on a few priority areas butto do all elements of the plan together.Commenting on a few items, he says the waitingtimes for CT/MRI/PET scans have been cutgreatly by investment in new machinery (thenumber of PET scanners has gone up to 72 fromjust five in 2002). Over 100 psycho-oncologypositions have been created – “There was a hugelack here – there was a time in France when wereally didn’t listen to the patient.”

Other notable parts of the plan include aninformation disclosure procedure for allpatients, coordinated care programmes, the set-ting up of seven regional cancer research hubs,and a ramp-up of screening programmes forbreast and colorectal cancers.

He’s particularly pleased with INCa’s role inthe interim funding of Herceptin in the early-stage setting – “This cost 80 million euros andcould save 2,000 lives over 9 months,” he reck-ons, adding that if the drug had not beenapproved eventually by the regulatory agencies,only then would INCa have withdrawn the drug.

There has been some criticism that notenough emphasis has been placed on prevention– for which about 13% of the budget has beenallocated – but Khayat says that given France’sprevious record, notable progress has been made.“The government has increased the price of ciga-rettes by 45% in the first two years – and we have1.8 million fewer smokers as a result,” he says. “It was courageous – we had a revolt of tobaccosellers and had to buy them off.” Recently, theFrench government seems to have backed downon plans for a smoking ban in public places, butKhayat is confident it will come to pass before theend of this year.

“We also did a big campaign on TV aboutthe dangers of sun exposure – it has been new inFrance to do so much on prevention,” he says.

“We calculated how much the 70 measures would cost,

and asked for 1.7 billion euros – and we got it”

CoverStory


Work on alcohol, diet and occupational exposureis also included in the plan, although not asmuch as some critics would like.

As president of INCa, Khayat’s role hasbeen very much hands on – he says it’s more ofa CEO’s role (despite there also being a CEO) –but he’s still been putting two half days a weekin at the hospital. He can be justifiably proud ofgetting INCa off the ground from nothing to astaff of 185 in just six months, and he reckonsits research programme and budget can passmuster with other agencies, notably the USNational Cancer Institute (NCI). “If you com-pare the NCI’s extra-mural activities – take awaythe researchers and labs – with us, we are fairlysimilar in budget, and our funding goes directlyon research not on salaries, as most Frenchresearchers are existing public servants, and wealready have enough labs and beds.”

While the cancer plan is going well, Khayatrecognises that progress also throws up otherproblems. “As soon as you share informationwith patients you share power. And when youshare power you share decisions and need torespect the patient’s right to choose.” A health-care system that builds large centres of excel-lence will inevitably take people further awayfrom home – and with the growing backdrop ofchronic degenerative illness, the existing ‘oper-ate or die’ model of acute care may well need tobe radically rethought. Balancing such ethicaland economic arguments has been a preoccupa-tion for Khayat in various talks and writing.

Although he’s cut out much internationaltravel while at INCa, Khayat admits he’s oftenlate home to see his wife, Jocelyne, a pharmacistturned art historian, and his three daughters,none of whom are turned on by medicine. Histwo great hobbies are food (and it has to beworth asking for an oncologist’s discount at GuySavoy) and writing. He is a prolific author ofmedical fiction and non-fiction, and also

screenplays; two of his medical dramas havebeen recorded for French television, one onlylast April.

At just 50, Khayat has a huge collection ofawards and positions, both real and honorary, tohis name – he’s even a Commander of theBritish Empire, an honour rather lost on him.The one he values above all else, however, is anadjunct breast cancer professorship at the MDAnderson, an institution he considers “a dream– it’s by far the best in oncology.”

He is stepping down from INCa this year,once a successor is found, to return full time toPitié-Salpêtrière to focus on his patients. Healso intends to go back to the lecture circuit andperhaps to industry consultancy, which he wasobliged to set aside owing to conflict of interestwith INCa. It is hard to imagine that Khayatwill sink out of either the public or professionalspotlight, however. As he says: “My secretary isalways afraid when I come in on Monday morn-ing with yet another idea such as a charter or afederation.” The next idea will no doubt not belong in coming – and will be well worth theshort wait.

“The government hiked the price of cigarettes

by 45% – and we have 1.8 million fewer smokers”

Friends in highplaces. PresidentJacques Chiracchose cancer as a defining issueof his presidency,and his personalbacking was key to getting the French cancer planapproved. In theforeground areBernadette Chirac(right) and JocelyneKhayat (left)

GrandRound


Cancer is beset by uncer-tainty. Despite dramaticincreases in the amountof information fromclinical trials and trans-

lational research, doctors are stillunable to accurately predict who willsuffer recurrence or relapse or whowill respond to a particular therapy.Patients often have to decide whetherto opt for adjuvant chemotherapy,radiation therapy or hormone therapyto protect themselves from somethingthat may never happen. Treatmentscan expose the patient to seriousrisks, and may make them feel worsethan the disease. People at high famil-ial risk may decide to take radical pre-ventive measures such as havingovaries or breasts removed, withoutany certainty that they would everdevelop cancer. Patients withmetastatic disease have to understandthe trade-off between treatment and

side-effects, and decide whether tosacrifice quality of life for the chanceof extra months of life.

Not only must patients makechoices that could save their lives ormean damaging treatment for no ben-efit, but no-one can ever be surebefore or after the decision whether itis, or was, the best decision for them.So it is very important that these deci-sions on treatment options should bemade jointly by the doctor and patientin partnership.

This is easy to say, but not so easyto do, because doctors reach deci-sions on treatment options through aprocess which is alien to the waymost patients approach the samedecisions. Most patients are ill-equipped to grapple with statisticsand science; while many doctors havetrouble seeing beyond the disease andits epidemiology. It is easy to overlookwhat the diagnosis and treatment

options might mean for the patient’swork life, family life, social life andsex life.

Doctors base their knowledge onevidence-based medicine, which isoften derived from trials involvingthousands of individual patients, whohave been stripped of personal char-acteristics and reduced to a selectionof potential prognostic and predictivefactors, from which appropriateguidelines and protocols are derived.

Deciding on the best treatment foran individual patient involves match-ing them up with the relevant prog-nostic and predictive factors, andthrowing in data on comorbidity.These calculations become increas-ingly complex as research uncoversnew biological and molecular mark-ers. Nowadays, doctors often makeuse of nomograms to make risk-bene-fit calculations, to support their ownclinical judgement.

➜ Anna Wagstaff

Are you feeling lucky?Discussing risk and treatment options with patients

Doctors use trial-based evidence and years of experience to assess risks of treatment

and relapse. But patients make choices based on their own experiences and priori-

ties. How can doctors best explore treatment options with patients? CancerWorld

asked the experts and offers Ten Tips for Effective Communication About Risk.


GrandRound

Evidence-based medicine is notunder question. However, nomo-grams do not provide data about anyindividual patient, all they do is offervalues for the apocryphal ‘average’patient with a defined set of prognos-tic and predictive factors. Drawing upguidelines involves value judgementsabout relative costs and benefits,which can lead in different directions.There is, for example, a greater use ofadjuvant chemotherapy for earlybreast cancer patients in the US thanin Europe, while UK paediatricianshave tended to opt for less intensiveuse of radiotherapy in young rhabdo-myosarcoma patients compared withtheir US counterparts.

Prostate cancer most clearly illus-trates the catastrophic results thatcan occur when treatment optionsare not informed by the priorities andvalues of the patient. The introduc-tion of PSA screening led to a gener-ation of men having their lives blightedby incontinence and impotencebecause a generation of urologists

failed to understand or communicatethe true risk associated with moreslow-growing or indolent prostatecancers, or to explore with patientsthe effect of treatment on quality oflife. As a result, it is estimated that atleast one-third of patients with goodprognostic signs treated with radicalprostatectomy in the previous two tothree decades never would haveneeded it. Today, a doctor is muchmore likely to recommend intensivemonitoring, than plunging in with theknife.

Patients often have huge faith intheir doctors, and sometimes want topass on the responsibility of takingthe decision. “What would you do inmy shoes, doctor?” is a question thatis often asked, but no doctor is in aposition definitively to answer it.

Presenting information to patientsin a way they can understand and acton is a high-level skill. Yet manyoncologists finish their training inade-quately equipped to communicateeffectively with their patients.

He or she has to understand how thepatient perceives their diagnosis,their hopes and fears, their back-ground and responsibilities, theirpreferences and their level of know-ledge. To help the patient to make adecision, a doctor requires listeningskills, time with the patient, opportu-nities for repetition, endless patienceand the ability to call on other meansof support.

But circumstances are stackedagainst this. The medical setting inwhich the consultation takes placetends to undermine the patient’ssense of identity, individuality andautonomy, and time is at a premium.As Louis Denis, Director of theAntwerp Oncology Centre, says:“The doctor is in a hurry, the patientis panicking.”

CancerWorld has talked topatients, oncologists, cancer nursesand a genetic counsellor and distilledtheir knowledge into Ten Tips forEffective Communication AboutRisk.

A partnership. The doctor knows more about the disease and treatment options, the patient knows more about how these may affect his life

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Tip 1

It takes two

Effective communication requiresequal status for what the doctor

and patient bring to the consultingroom. Too often authority wears awhite coat, while the patient feels likea number or a bundle of case notes.

Both sides can do something tochange this. The patient can bring afamily member or trusted friend tothe consultation as a way of retainingtheir personal identity, and forpractical back-up (see Tip 6). Thedoctor can involve other healthprofessionals, such as specialistcancer nurses or psycho-oncologists(Tip 7), who are able to spend moretime getting to know the patient inadvance and talking things throughlater on.

Having a row of medical studentsobserving the consultation can feelvery intrusive. Medical students haveto learn, but the patient should begiven the option to refuse theirpresence before inviting them intothe room, numbers should be limitedto one or two, they should beproperly introduced.

Terms of address should reinforcea sense of equality. Patient and doctor


should either both use first names orboth adopt a more formal ‘Mr’ and‘Dr’. If possible, avoid carrying out aphysical examination at theconsultation session, particularly ifthis involves undressing or wearing ahospital gown. It is hard to feel equalwithout clothes.

Make it clear that there is no rush toreach a decision, and that the patientwill have time to absorb theinformation and, if need be, comeback and discuss it further. Be awarethat patients often pick up a sense thatthe doctor’s time is short while they aresitting in the waiting room. Patientswho feel under time pressure will beinhibited from asking questions orexpressing their concerns.

Many patients are torn betweenwanting to know, and fear of hearingsomething they cannot cope with. If adoctor launches into a routine expla-nation, the patient is unlikely to entera dialogue. Doctors can ask thepatient what they understand is thepurpose of the consultation, givingthem an early opportunity to talkabout what they hope, fear and feelabout what they are going through.

“It is a dialogue. Not, ‘here are the facts, now make a decision,’ butbeing able to establish a rapport. Let them talk a bit about how theyfeel, and where they are at, and that will help you tailor the infor-mation to them.” Clara Gaff genetic counselor

“It’s so important to encourage the initiative of the patient, so theyare not automatically led into something they have not had thechance to absorb, never mind consent to… Listen, listen and listenagain to the patient. What is the patient saying between the lines?”Rita Pilbrow Carlsson breast cancer patient

Tip 2

Keep language simple

Make an effort to use languagethat is easy for non-medical peo-

ple to understand, and explain wordsthat carry a different meaning ineveryday language. For instance,“response” means that a tumourshrinks or grows less quickly – butpatients may assume it means “cure”.“Aggressive” means the cancer is fast-growing or will spread quickly, but itcarries other connotations in daily lan-guage. Avoid euphemisms like “lump”or “tumour” or “neoplasia”, at leastuntil the patient understands thatthese words relate to cancer. Patientsare not stupid and most will suspectthey might have cancer. Until they areclear about whether or not they do, itwill not be possible to move on tofocus on examining options.

“My consultant [specialist], I thinkwas frightened of my responseand said something like: ‘On ascale of cars, you have a 2CV asopposed to a Ferrari,’ and didn’tmention the word cancer. My GP(family doctor) drew me a dia-gram, explained it to me and gaveit a name.” Eve Setch haemangioendotheliomapatient

“Generally speaking the patient asksthe nurse for more explanation orclarification, because the nurseusually speaks in simpler terms.” Kath MacLachlan and Lynn Dowdespecialist breast nurses

Kath MacLachlan and Lynn Dowde work for BreastCancer Care, UK: www.breastcancercare.org.uk


It is important to consider how eachpotential side-effect might impact

on each individual patient.The doctor needs to understand

the patient’s lifestyle, priorities andpreferences and be willing to have ameaningful dialogue exploring whateach option could mean. Care shouldbe taken to avoid making assumptionsabout, for example, who will be mostconcerned about possible impotence.The side-effects of treatment maydamage someone’s self-image, self-

Deciding on the best treatmentoften involves complex trade-offs

between alternative risks or combina-tions of risks. For instance, adjuvanttherapy becomes more attractive thehigher the risk of recurrence, the moreserious that recurrence would be, thegreater the effect of therapy in reducinga risk, and the less serious the risk ofside-effects and their consequences.

Although not all patients want toexplore statistics, doctors need to beable to help them navigate their waythrough choices by explaining num-bers in the simplest possible way. Agreat deal of research has been doneon how to do this most effectively.

Risk factors and probabilities can bepresented in a variety of ways: 20% is1 in 5, or 20 in 100, or a ratio of 1:4.Try to stick to one system.

Patients find it easier to interprettrade-offs when risks are presented inthe form of ‘N in base’ comparisons (20in 1000 compared with 70 in 1000).

However, they understand percent-ages best when interpreting asequence of risks (for instance a 70%risk of relapse and a 20% risk that anyrelapse will be fatal). Any percentagesmaller than 1 is poorly understood.

Studies also show that some peopleunderstand 1 in 10 as a higher

THE PERCENTAGE GAME

Asurvey asked respondents how many people out of 100 would develop adisease if the chance of getting it was 10%. One person in five could not work

it out. People are most proficient at comparing two risks and indicating which oneis larger. They are less proficient at adding risks, interpreting a trade-off in risks(e.g. a drug cuts one risk in half but doubles another) or understanding asequence of risks (the probability of a side-effect occurring, and the probabilitythat if it occurs it will be serious).

Tip 3

Side-effects: keep it personal

Tip 4

Statistics: explaining the figures

esteem and self-confidence, justwhen they need those things most.

A doctor understands infertility,early menopause, incontinence,impotence, neutropoenia, fatigue andneuropathy, but not what each ofthese means to the patient.

Mastectomy, hair loss, hot flushes,incontinence or impotence can eachhave a devastating effect on onepatient, while others may find themeasier to cope with. Fatigue may beless important to a patient who can

take time out to look after themselves,than to a patient who feels obliged tokeep working, or to continue ‘normal’family life. Some people will be des-perate to avoid the risk of becominginfertile, while for others this couldbe a minor issue. Neuropathy maymean trouble with buttons for somepeople but loss of a job for others.

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“Some oncologists do tend to assume that a patient with a disability, perhaps in a wheelchair,won't want to attend daily radiotherapy. But some people want treatment to minimise the risk,no matter how old they are. And we know from experience that any woman, regardless of herage, can be devastated at the thought of losing a breast.” Kath MacLachlan and Lynn Dowde specialist breast nurses

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women with your type of diagnosis,the chances are that 20 will have arecurrence within 5 years, and 80will not. We don’t know whether youwill be one of the 20 or one of the 80.If all the women took adjuvant hor-monal therapy, it is likely that only 10will have a recurrence and 90 will not.”

Using comparisons such as “aslikely as being struck by lightning” or“you are more likely to be run over bya bus” may be less informative thanthey sound (patients will have theirown ideas about how likely these maybe, and anyway both depend heavilyon circumstances), and may be mis-leading. The odds of a big win on anational lottery are said to be smallerthan the risk of being murdered, butevery week millions of people confi-

dently predict that their numbers willcome up on the lottery, without wor-rying about murder.

Many of the above findings arecontradictory (or true within somecontexts and not others), and theymainly relate to written presentations.A doctor–patient consultation givesan opportunity to discuss the risk, ina situation where the doctor canassess how well the patient under-stands these concepts, and can tailortheir approach. The examples ofRoger Wilson, a leiomyosarcoma sur-vivor, and Jan G, a CML patient,shown below, show how differentlypatients approach the question ofrisk, and how important it is to beable to tailor the information and thediscussion to the particular patient.


risk than 1 in 5, simply because theyassociate the higher number (10)with higher probability. This can beavoided by using the same denomina-tor: i.e. compare ‘2 in 10’, ‘5 in 10’ ‘1in 10’, in preference to ‘1 in 5’, ‘1 in 2’and ‘1 in 10’.

Some people find graphical pre-sentations easier to understand thanfigures. Decision trees (see opposite)can be helpful for evaluating optionsthat involve a number of successiverisks (e.g. risk that you will survive thetransplant, risk that having survivedyou may go onto relapse, etc.). Barcharts and line graphs can helpexplain benefits in survival over time.However, they can also be misleading.For instance, graphs that show onlythe top half of the survival curve (i.e.from 50% to 100% of the patientsample) can make the increase in sur-vival offered by a particular therapylook twice as great as it really is.

Relative risk is frequently a sourceof confusion for doctors and patients,and can magnify perceived levels ofrisk or risk reduction. Clearly if therisk of an adverse side-effect risesfrom 1 in 1000 to 2 in 1000, the riskhas doubled, but the odds remainextremely favourable. To give a reallife example, for women with Her2+early breast cancer, adjuvantHerceptin can decrease the relativerisk of recurrence in the first fewyears by around 50% – i.e. it halvesthe risk of recurrence. But that riskwithout Herceptin is only about 20%in the first few years, so the absoluterisk reduction is only 10 percentagepoints. The patient is much morelikely to focus on the 50% (“my risk ishalved”) than on the 10% that is rele-vant to her decision.

Avoid the abstract. People mayunderstand statistics better if they areput in human terms. “In a group of 100

APPLIED STATISTICS 1Roger Wilson: “You either will or you won’t survive”Roger Wilson is a leiomyosarcoma survivor with a back-ground in the media. When diagnosed with cancer hisresponse was to look for as much information as possible.However, he did not find statistical data very helpful in decid-ing what to do. Roger is 1 of 4 complete remissions out of 322 patients who par-ticipated in a trial six years ago comparing doxorubicin with two experimental sched-ules of ifosfamide for metastatic leiomyosarcoma. The odds against him were80–1, but as far as he is concerned, the success of the treatment in his case wasthe statistic that really mattered. “In your mind, whether the odds are 30:70 or70:30, for you it is still 1:1. It is a binary issue. You either will or you won’t.”

APPLIED STATISTICS 2Jan G: “I calculated the odds and used a decision tree”Jan G is a chronic myeloid leukaemia (CML) patient with abackground in information technology. When he was diag-nosed in 2001, at the age of 28, his response was to turnto the statistics for guidance: “I got the figures from medicalreports, Internet discussion forums and various doctors – I took the median ofthose.” Jan had two options: immediate bone marrow transplant, or joining a phaseII trial of STI-571 – now Glivec (imatinib) – and interferon. He drew up a decisiontree (see opposite) to show the likelihood of dying associated with the two options,and decided to opt for the Glivec. So far, the decision has served him well, but herecognises that many patients find this highly objective approach “too rational”,and that many would not have the statistical skills to do this for themselves.

Transplant

20%

80%

75%

15%

10%

75%

25%

Death20%

Death

Alive at 6

weeks

Mild chronic morbidity60%+9%

Relapse12%

Severe chronic morbidity

8%

Second transplant

9%

Death3%

STI-571

Transplant

60%

20%

80%

40%

Completecytogenicremission

Haematological remission

after x months

Alive at 6

weeks


centages, but the patient may find iteasier to consider ‘real-life’ risk factors

rather than figures, such as what wasfound at surgery, various

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Tip 5

Statistics: keep it personal

Statistics can seem a welcomeoasis of hard information, but

even patients who understand the fig-ures often find them unhelpful wheninterpreting their own situation.Tailoring information to the individ-ual can make a big difference. Thedoctor may view risk factors as per-

“Patients cannot and do not want to see themselves in statistical terms, andprobably find it very unpleasant and unconstructive to have to discuss theirtreatment options with a doctor who talks like that.” Rita Pilbrow Carlsson breast cancer patient

>>>

NUMBER OF RECURRENCES/100 PATIENTS

JAN'S DECISION TREE: STEM CELL TRANSPLANT VS STI-571 PLUS INTERFERONProbability of death 23% (20%+3%)

probability of a desirable outcome 69%(60%+9%)

Probability of death 9.2%(40%x23%)

probability of a desirable outcome87.6%(60%+27.6%[40%x69%])

38No hormonal adjuvanttreatment

19Tamoxifen adjuvanttreatment

10Adjuvant treatmentwith an aromataseinhibitor

Decision trees canbe helpful forexploring complexoptions such as thiscomparison betweentwo alternativeseries of risks.The figures werebest guesses on theinformation availablein 2001. Survivalrates for bothoptions are highernow

Many patients find visual information easier to relate to than numbers. This image shows how hormonal treatments can affect the risk of breast cancer recurrence

GrandRound

pathological reports and scans, andrelevant medical history.

Some doctors find Adjuvant!online (www.adjuvantonline.com)useful. This is an Internet programmefor breast cancer assessment, whichdraws on information from variousdatabases and the literature. Availableto health professionals (and designedto be used by the health professionaland patient together), it calculates therisk of negative outcomes, the reduc-tion of risks afforded by therapy, andthe risks of side-effects, once a doctor(or nurse) feeds in data from thepatient’s pathology reports and med-ical history. Estimates are printed outin graphical and text formats, for dis-cussion with patients.

It can be helpful to use words aswell as numbers to indicate risk levels.Although phrases such as “highlyunlikely”, “not very likely” or “fairlylikely” are unspecific and open tointerpretation, studies have foundthat they actually do a better job ofrepresenting true feelings thannumeric scales using odds or percent-ages, due to the way most peopleprocess information.

It is also important to recognise thatpatients interpret statistical risk accord-ing to their own preconceptions,

experiences, emotions and so on. Events that are more serious are

often perceived as being more likelyto happen. Thus a chance of 1 in 8seems objective, but feels more likelyto a patient when applied to moreserious outcomes, such as metastases,than to less serious outcomes such asneuropathy.

People also think that somethingthat has already happened to some-one they know is more likely to hap-pen to them. Thus, two women withidentical breast cancers may havevery different views about probableoutcome, if one had a mother whodied from the disease, while the otherhas two friends who both survived it.

Doctors should therefore be awarethat the statistical message they aregiving may be different from the onethe patient receives. This is why it ishelpful early in the discussion to talkabout what experiences and prior infor-mation the patient already has. Asking,“What do you know about the

cancer/proposed treatment?” is oneway of doing this. This can help thepatient to reveal the experience that isinfluencing their judgment. The doc-tor may then have an opportunity toexplain: “From what you say it soundsas if your mother was diagnosed whenthe cancer was already quiteadvanced. Luckily your cancer hasbeen picked up quite early, whichmeans there is a much better chancethe treatment will be successful.”

The immediacy of the risk canalso affect perception. Faced with acancer diagnosis, a patient may panicand only be able to think about therisk of the disease and getting rid of itas soon as possible. They may find itimpossible to focus on the longer-term implications of treatmentoptions. Encouraging a patient to taketime to talk through the risk of side-effects may help them to balance onerisk against another. For example theymight consider how a risk such asinfertility or impotence would impacton their mental health, their relation-ships and their plans for the future.Patients may later become very bitterabout such outcomes if they feelthey had no opportunity to discussthem when they were deciding ontreatment.


FROM MORE THAN ONE ANGLE

Genetic counselors tend to use absolute figures (e.g. your risk of developing colo-rectal cancer during your lifetime) and relative figures (e.g. you are three times

more likely to develop colorectal cancer than an average person of your age). Theymay also offer 5- and 10-year probability figures (your risk of developing colorectalcancer within the next 5/10 years). Giving data that present a different angle onthe same issue may confuse some patients, but will help others to formulate amore complete picture in their mind.

“Asking survey respondents to place a numeric probability on the occurrenceof a health outcome and then comparing their answers with objective data isone of the least meaningful and least reliable measures of risk understanding.” Neil Weinstein (JNCI 25:15–20)

“What does help is to assist the patient to understand that the treatment theyare recommended is tailored specifically to them as an actual person.”Kath MacLachlan and Lynn Dowde specialist breast nurses


GrandRound

Lack of time is the single constraintmentioned most often by doctors

as hampering communication withtheir patients. But time has to betaken. The issues are complex, and thepatient can be overwhelmed by the sit-uation and the amount of information.Faced with a cancer diagnosis, patientscan panic and reach for a snap deci-sion. In most cases, the patient losesnothing by giving themselves a week ortwo to decide how to proceed. Theystand to gain a great deal by takingstock of their situation, and talkingthrough options with their doctor,friends and family. Trying to rush a con-sultation can be a false saving.

Make best use of time with thepatient. A lot of time in consultationsis wasted going over information thepatient already knows, while thingsthey need to talk about are barelytouched on. Asking patients what theyalready know saves time. Reading thepatient’s notes avoids asking the samequestions two or three times (a com-mon complaint from patients). Focuson the information most relevant to thedecision that has to be made.

Around 70% of information pro-vided when the patient is first given a

It is hard for one doctor to fulfil all apatient’s needs for information and

for discussion. Patient and doctor canboth benefit from the involvement ofspecialist cancer nurses, psycho-oncol-

ogists and other members of a team.There is great scope in much ofEurope for making better use of nursesand other health professionals. Nurseswho are part of a cancer team normal-

ly have more contact with the patient,and know more about the family situa-tion and their emotional state, and maybe better placed to talk things throughwith a patient at his or her own

cancer diagnosis is not retained.Retention can be improved if thepatient brings a member of the familyor close friend as a second pair of ears,

and if they take notes. See also theadvice under Tip 8 (Signpostingthe patient) about how to reinforceinformation.

Tip 6

Take enough time – use it well

Tip 7

A team approach

“I tell the young urologists that you need to give more time in the firstconsultation and you will gain it back in all the subsequent consultations.” Louis Denis urologist

“Take time for explanations after the diagnosis. Re-explain if the patientdoesn’t understand. Give them the impression there are no silly questions.Offer them the chance to come back after they have made up their mind, andask questions again. If this time is invested in the beginning, it will makethings much easier in the course of the treatment.” Jan G CML patient

LISTENING SAVES TIME

“One of the feelings some doctors have is that consultations willtake much longer if they have to do all this touchy feely stuf f, but

an Australian study looking at oncologists’ reactions to cancerpatients’ verbal cues (Butow et al. Psycho-oncology 11:47–58) hasshown that this isn’t the case. What can happen when people aren’treally getting what they want or when they don’t feel they’ve been heardor understood is they star t asking the same question over and overagain, sometimes in slightly dif ferent ways, and the doctor can getquite frustrated thinking: ‘I’ve already given them the information, whyare they asking again?’ It tends to be an indication that some under-lying emotion is not being recognised.” Clara Gaff Genetic Counselor

>>>

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pace. Patients often feel morerelaxed with nurses, and it is com-mon for patients to open up and askmore questions after the doctor hasleft the room. However, it must bethe doctor who plays the critical rolein discussing and helping the patientdecide on treatment options.


Doctors can supply their patients witha short list of the clearest and moreaccurate resources on the Internet thatare designed for patients. This willhelp them to access good-quality infor-mation and make it less likely that theywill visit sites with poor-quality or mis-leading advice.

There are many independentsources of support and information tohelp a patient build a picture of theirdisease and treatment options. Manycountries have support agencies withfree help lines staffed by health profes-

sionals who can be an additionalsource of information and advice.Some hospitals have a cancer informa-tion centre or a psycho-oncology serv-ice that takes referrals.

All these options provide sources ofsupport and information, whichpatients can access in their own time.

Cancer units should compile a listof all these resources and should makethem available to patients. Though thismight seem an obvious point, doctorsare not always natural networkers, andoften omit to mention patient groupsor cancer information centres, eventhose attached to the same hospital!

Doctors can also encourage apatient to seek a second opinion. It canbe reassuring for a patient to hearanother specialist talking in similarterms, even if the second opinionvaries slightly from the first.Suggesting a second opinion and offer-ing a list of names gives an importantsignal that the patient is being encour-aged to make an informed decision,rather than following recommenda-tions out of blind faith.

“Doctors often feel they have to provide every bit of support and informationto a patient. They don’t have to do it all themselves. They need to be aware ofwho is around and who can help.” Kath MacLachlan and Lynn Dowde specialist breast nurses

“It is extremely important that doctors do not work against the patient’srequest for a second opinion. It should be encouraged and not met with thearrogance I received from one consultant [specialist] in a UK hospital. His exactwords were: You can either believe me or choose another consultant.” Rita Pilbrow Carlsson breast cancer patient

Tip 8

Signposting the patient

There are many avenues to helpingpatients to take in information,

understand their condition and judgeavailable options. Some doctorsencourage their patients to tape theconsultation, so they can listen to itagain where and when they want.Written information should be providedfrom the start, and the patient shouldbe asked to read it before they attendtheir next consultation. Patient groupsare very willing to check written infor-mation to ensure that it is appropriate,relevant and easy to understand.

Doctors should offer their patients a list of good-quality relevant Internet sites. This comprehensive list of French-language sites was compiled on the initiative of Rouen University Hospital


GrandRound

groups are often also experts – andhave good reason to be.

Most European countries havepatient groups for many cancers, localor national or attached to a particularhospital. Patient websites and chatgroups can also provide informationand put patients in touch with people

facing similar situations, although lan-guage may be a limiting factor for non-English speakers.

Working with patients to set up apatient group where they do notalready exist is an important way thatspecialists can help patients learn whatthey need to know.

“If you really do believe in partnership with patients and joint decision making, I cannot see how youcan work effectively without a patient group. [Helping set up a group for stoma patients] was the bestthing I ever did in my life. It takes a lot of patience and time to get them organised. But once they areorganised, if you are lucky they work on their own and are certainly not dependent on your opinion,they form their own opinion, because then they have contacts.” Louis Denis urologist

“I think quite often one of the biggest influences on a patient’s decision isanother patient who has been through that decision before. You get some sortof ‘decision inheritance’ that works in an untraceable way.” Roger Wilson leiomyosarcoma patient

“Some patients have said ‘no thank you’ to a recommendation ofanti-hormonal medications such as tamoxifen or aromataseinhibitors. Others have refused chemotherapy. These patients shouldbe informed fully about the statistics and treatment guidelines,with material they can take home to read, but most of all their deci-sion should be respected. Some patients have felt threatened intohaving the recommended treatment, although their inner voice sayssomething quite different.” Rita Pilbrow Carlsson breast cancer patient

Tip 9

Patient groups

Tip 10

The right decision?

Many patients say that the insightsand information they found

most useful came from other patients.It can be easier to discuss painful andfrightening issues with someone in thesame situation, who talks from person-al experience. Patients in patient

Doctors have a responsibility toensure, to the best of their ability,

that a patient’s decision is based on anaccurate picture of the medical facts.Talking through with the patient howthey reached their decision may revealmisunderstandings or logical flaws thatneed to be explored further. However,afterwards, it is never possible to saywhether a decision was right or wrong.There is no telling whether arecurrence might have happened withor without adjuvant chemotherapy.

There is no knowing which patientsgained tremendous benefits fromtreatment, and who suffered side-effects needlessly. Patients withsimilar diagnoses make differentdecisions based on a myriad offactors, including different priorities

and preferences, and differingfeelings about their chance of beingone of the lucky (or unlucky) ones.

The patient lives or dies with theconsequences of a decision, and it isnot for a doctor to say whether it wasright or wrong.

DrugWatch


Innovative approaches to drug dis-covery and disease treatment arethe basis of the biotechnology

industry. However, it is a rare eventwhen a new technological approachleaps straight from the lab bench intothe market. Invariably, by a process ofiterative refinement, a conceptevolves through multiple generationsbefore a marketable product is creat-ed. A prime and well-recognisedexample is monoclonal antibodytechnology, which is in its third andfourth generations. There are nowover 100 potential antibody productsin clinical development.

A similar evolution is emergingwith the development of nucleic acidtherapies. The use of a string of DNAnucleotides to bind and block mes-senger RNA function was firstreported in 1978 and, since then,many companies have applied theantisense principle to make oligo-nucleotide drugs with the aim ofswitching off the expression of a spe-cific disease-associated protein – thedrug blocking or destroying themessenger RNA responsible for theprotein’s synthesis. The first such

drug to be marketed was IsisPharmaceuticals’ Vitravene, a topicaltreatment for human CMV(cytomegalovirus) retinitis, whichwas approved by the EuropeanMedicines Agency (EMEA) in 1999and the US Food and DrugAdministration (FDA) in 1998.Through a series of chemicalimprovements, antisense drugs havebeen refined substantially since thenand breakthroughs have been madeby a number of companies.

In particular, the discovery ofRNA interference – a natural anti-sense mechanism in plants andanimals – has led to the emergenceof companies such as AlnylamPharmaceuticals and SirnaTherapeutics, who are developingsynthetic double-stranded RNA ashigh-potency antisense drugs knownas short interfering RNA (siRNA).More recently, the recognition thatsiRNAs are unwound within the cellby a mechanism known as RNA-induced silencing complex (RISC),and that only one of their two RNAchains (the antisense strand) bindsand inactivates the target mRNA, has

swung the pendulum back to thepotential potency of RNA analogues,such as locked nucleic acid (LNA) assingle-stranded high-affinity anti-sense drugs. The latest generation ofnucleic acid therapeutics in the clinictherefore encompasses both double(siRNA) and single (LNA) oligo-nucleotide compounds.

FIRST GENERATION OF RNAINHIBITORSThe first generation of antisensecompounds were made from synthet-ic DNA monomers, modified only inso far as they contain a sulphur sub-stitution in place of oxygen in thephosphate linkages betweennucleotides. This so-called phospho-rothioate modification has been usedin most clinical oligonucleotides todate, since it goes some way towardsenhancing the stability of the drug inthe presence of tissue nucleases, andalso improves plasma half-life. BothVitravene and the Genta drug,Genasense – currently the subject ofa re-submitted NDA – are DNAphosphorothioates. The main prob-lem for such drugs is their relative

➜ Keith McCullagh*

RNA-bound: the future of antisense drugs

The use of nucleic acid therapies to block RNA function was first described in 1978. The

latest generation of these compounds, LNA antagonists, is now overcoming the main obstacle

to the success of its predecessors, through a greater ability to bind to RNA.

* Keith McCullagh is CEO of Santaris Pharma, based in Hørsholm, DenmarkThis article was first published in the March 2006 issue of Scrip Magazine (issue 154). It is republished with permission from Informa Healthcare, a division of Informa UK.© 2006 Informa


DrugWatch

lack of potency because of weakbinding affinity to their target RNAand continuing inadequate resistanceto nuclease digestion. Acute toxici-ties of DNA phosphorothioatesreported in primates have also limit-ed the doses at which such drugs canbe administered systemically tohuman patients.

Most experts in the field agreethat the first-generation antisensedrugs are simply not potent enoughto achieve statistically robust effica-cy. To date, phase III trials of six sep-arate DNA phosphorothioates havefailed to meet their primary endpoint.

Only the seventh – Genta’sGenasense in a chronic lymphocyticleukaemia (CLL) phase III trial –met its primary endpoint and the drugis being reviewed by US regulators. Inthe face of such poor results, manycompanies have sought to developimproved products.

Thus evolved the second genera-tion of antisense compounds, alsopioneered by Isis, which acquired alicence for Novartis’ 2’-O-methoxyethyl(2’MOE) chemistry. Oligonucleotidesconsisting wholly or partially of2’MOE-derivatised monomers haveincreased resistance to plasma and

tissue breakdown. Isis is applying thistechnology in several areas, includingdiabetes and cardiovascular disease,and has sub-licensed development offurther 2’MOE drugs to Oncogenexand Antisense Therapeutics. However,although they have improved stabilityover DNA oligonucleotides, 2’MOEcompounds show only marginalimprovements in the affinity withwhich they bind RNA.

Other second-generation modifi-cations, such as 2’OMe (pioneered byHybridon, now Idera Pharma-ceuticals) or morpholino-compounds,developed by AVI BioPharma, appearto have no greater potency or benefitthan 2’MOE. This lack of potency,particularly when phosphorothioated,is likely to restrict the use of the sec-ond-generation antisense compoundsto diseases of the liver or kidney,where they achieve relatively high tis-sue concentrations.

ENTER THE THIRD GENERATIONThere is current excitement in theRNA inhibition field because it isnow possible to synthesise com-pounds with two-to-three orders ofmagnitude greater RNA-bindingaffinity. These third-generation anti-sense drugs fall into two categories:double-stranded siRNA and single-stranded LNA oligonucleotides. Inthe presence of transfection reagentsin cell cultures, both of these third-generation compounds produce sig-nificant reductions in target mRNAand proteins at concentrations belowone nanomolar. This is dramaticallyhigher than any previous antisense

To date, phase III trials of six DNA phosphorothioates

have failed to meet their primary endpoint

SCIE

NC

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DrugWatch

OVERVIEW OF OLIGONUCLEOTIDE COMPOUNDS IN DEVELOPMENT IN 2005

Name of compound Target Indication Phase Nucleotide Companychemistry

First generation antisense: DNA phosphorothioates (low metabolic stability, low potency)Vitravene CMV CMV retinitis Approved DNA ISISGenasense Bcl-2 Malignant III DNA Genta

melanoma (NDA withdrawn)Bcl-2 Chronic lymphocytic III DNA Genta

leukaemiaAlicaforsen/2302 ICAM-1 Ulcerative colitis II DNA ISISGTI 2040 RNR R2 Renal cell II DNA Lorus Therapeutics

carcinomaGTI 2501 RNR R1 Prostate cancer II DNA Lorus Therapeutics

Second generation antisense: 2'-O-methoxyethyl phosphorothioates (high metabolic stability, moderate potency)ISIS 113715 PTP-1B Diabetes II MOE ISISISIS 301012 ApoB-100 Cardiovascular II MOE ISISATL-1102 VLA-4 Multiple sclerosis II MOE Antisense Therapeutics

– licence from ISISATL-1101 IGF-1R Psoriasis I MOE Antisense Therapeutics

– licence from ISISOGX-011 Clusterin Prostate/breast/ II MOE Oncogenex – licence from

non-small-cell ISISlung cancer

LY 2181308 Survivin Cancer I MOE Lilly – licence from ISIS

Other second generation antisense: 2'-O-methyl, and morpholino analogues (high metabolic stability, moderate potency)AEG35156 XIAP Local and metastatic I 2’OMe Aegera – licence from

solid tumours HybridonResten-NG C-myc Cardiovascular I/II Morpholino AVI Biopharma

restenosisResten-MP C-myc Cardiovascular I/II Morpholino AVI Biopharma

restenosisAVi-4020 West Nile virus West Nile virus I Morpholino AVI BiopharmaAVI-4126 C-myc Bladder cancer I Morpholino AVI BiopharmaPD3 Multitargeted? Chronic obstructive Preclinical FANA Topigen

pulmonarydisease (COPD)

Third generation – double stranded: siRNA (low metabolic stability, very high potency)Cand5 VEGF Wet AMD II siRNA Acuity Pharmaceuticals

Diabetic Preclinical siRNA Acuity PharmaceuticalsretinopathyDiabetic Preclinicalretinopathy

Continued on page 29


technology and predicts enormousclinical potential, provided the drugscan get to their site of action in vivo.

Unfortunately, unmodifiedsiRNAs are inherently unstable inthe body, with the duplexes unwind-ing and being degraded by nucleasesin the circulation. This may be less ofa problem for topical applicationsand, indeed, Acuity Pharmaceuticalshas the most advanced siRNA clini-cal programme with Cand5 – a localophthalmic drug to treat wet age-related macular degeneration(AMD), which is in phase II. Theproduct is designed to silence thevascular endothelial growth factor(VEGF) genes that promote the reti-nal neovascularisation that leads to

loss of vision in AMD. Similarly,Alnylam’s siRNA drug ALN-RSV01,currently in phase I studies for thetreatment of respiratory syncytialvirus (RSV) infection, is delivereddirectly into the lungs.

By contrast, the RNA analogue,LNA, when coupled by phosphoro-thioate linkages, is remarkably resistantto nuclease cleavage and has a pro-longed tissue half-life. In addition,LNA oligonucleotides bind to RNAwith extraordinarily high affinity. Thesecharacteristics are critical, and result insubstantial increases in potency in vivocompared to first- or second-genera-tion oligonucleotides. Santaris Pharmareported data at the American Societyof Hematology meeting last December

showing that an LNA drug directedagainst HIF-1a (hypoxia-induciblefactor 1) mRNA appeared significantlymore effective in reducing tissuehypoxia and VEGF protein levels aftersystemic administration to mice thanthe best siRNA directed against thesame gene – the comparison was madeusing the siRNA against HIF-1adescribed by Yu et al (Lab Invest 2004).HIF-1 is a transcription factor thatfunctions as a key regulator of VEGFand VEGF receptor expression and istherefore important in tumour angio-genesis. Additionally, HIF-1a also playsimportant roles in other cancerprocesses, such as cell proliferation,apoptosis and cell invasion.

A daunting technical hurdle for

DrugWatch

Sirna-027 VEGF Age-related I siRNA Sirnamacular Therapeutics/partnereddegeneration (AMD) with Allergan

IL4/IL4R Asthma PreclinicalIL13/IL13R Asthma Preclinical Partnered with LillyVEGF Solid tumours PreclinicalHBV/HCV Hepatitis Preclinical

ALN-RSV0 RSV Respiratory I siRNA Alnylamsyncytial virus(RSV) infection

NN HVC Hepatitis C virus Preclinical BenitecNN HIV AIDS lymphoma Preclinical

Third generation – single stranded: LNA-based RNA antagonists – LNA phosphorothioates (high metabolic stability, very high potency)SPC2996 Bcl-2 Chronic leukaemia I/II LNA Santaris PharmaSPC2968 HIF-1α Renal cancer & Preclinical LNA Santaris Pharma

myelomaSPC3042 Survivin Chemotherapy

in cancer Preclinical LNA Santaris Pharma

Name of compound Target Indication Phase Nucleotide Companychemistry

LNA oligonucleotides bind to RNA

with extraordinarily high affinity


siRNA is uptake into cells in the body.SiRNAs are large double-strandedmolecules which do not pass readilyacross cell membranes. Alnylamreported in 2004 that liver uptake, atleast, could be enhanced by conjuga-tion of the siRNA with cholesterol.Santaris has matched that by data,presented at a recent Keystone sci-ence conference, showing thatunconjugated LNA oligonucleotidesdirected against ApoB100 in the liverare effective in reducing ApoB syn-thesis and plasma cholesterol levels inmice at doses eight times lower thanthose required by Alnylam’s choles-terol-conjugated siRNA, synthesisedas described by Soutschek et al(Nature 2004). LNA may transformthe opportunity for oligonucleotidesas drugs. The much higher bindingconstants of LNA to complementary

RNA sequences, compared to con-ventional DNA analogues, is suchthat LNA oligonucleotides can beconsidered a new class of drug.Santaris has coined the term ‘RNAantagonists’ to describe such drugs inrecognition of their high-affinity bind-ing and target specificity.

NUCLEIC ACID THERAPIESTHE FUTUREAs is clearly demonstrated in thefield of antibodies, the early murineantibodies showed great promise,and some progressed onto the mar-ket. However, a rapid evolution of thetechnology followed. Murine anti-bodies soon became chimeric (partmouse, part human). The secondgeneration of antibodies weredescribed as humanised – in effectrecombinant mouse antibodies

tweaked to closely resemble humanantibodies. The third generation ofantibodies were fully human, andnow we have further developmentsinto antibody fragments, domainantibodies and nanobodies.

In addition to the 100 in devel-opment, this class of compoundsnow has 20 products on the market.

The evolution of nucleic acid ther-apies has much in common with theantibody market. Few of the early gen-eration of drugs reached the market,but these are being closely followed bythe next generations. Third-generationproducts based on LNA and siRNAare now in the clinic. As theseprogress, much will be learned and,before too long, we are likely to see aburgeoning series of more effectivenucleic acid-based targeted therapeu-tics hit the market.

DrugWatch

The evolution of nucleic acid therapies has much

in common with the antibody market

LNA-based RNA antagonistsLocked nucleic acid (LNA) drugs appear to be well tolerated in animals. Santaris has completed GLP (good laboratory prac-tice) toxicology studies with three separate LNA compounds and has observed no clinical, haematological or pathologicaladverse affects in either rodents or monkeys at clinically relevant doses. Santaris’ lead product, SPC2996, is being developedto treat chronic lymphocytic leukaemia (CLL) – the second most common type of cancer of the blood, characterised by a pro-gressive accumulation of long-lived, functionally incompetent lymphocytes.SPC2996 acts by inhibiting the synthesis of Bcl-2, a key sensor protein that protects cells against apoptosis. The protein isexpressed in most cancers but is especially high in CLL where the level of over-expression also correlates with poor outcome.In primate pharmacology studies, SPC2996 has been shown to effectively down-regulate Bcl-2 mRNA and protein wheninjected intravenously at low doses. The compound is currently being evaluated in an international phase I/II multicentre clin-ical study at haematology centres in Denmark, France, the UK and the US.Santaris has two further preclinical candidates in development. The first, SPC2968, was selected from a small library of LNA-based RNA antagonists of HIF-1a mRNA. The other compound, SPC3042, is a potent LNA-based RNA antagonist of sur-vivin mRNA. The latter plays a vital regulatory role in apoptosis, by inhibiting activation of lethal caspases.In addition, survivin plays a pivotal role in normal mitotic progression and cell division. Survivin is over-expressed in manycancers and in endothelial cells engaged in angiogenesis. However, it is almost absent in normal adult differentiated tissue,thus making it a prime target for cancer therapy.


The international systemfor classifying cancer bytumour size and location,regional lymph nodeinvolvement and distant

metastases (the TNM staging sys-tem) has served oncologists well formore than 50 years. But now ques-tions are being asked about its use-fulness in the 21st century. Whilesome people believe that it can andshould survive, albeit with someadaptations, others are already writ-ing its obituary.

Chief amongst its critics is HarryBurke, Associate Professor ofBiochemistry and Molecular Biologyat the George Washington UniversitySchool of Medicine, Washington DC,USA. In 1993, when he was a con-sultant to the American JointCommittee on Cancer (AJCC), heproposed that a computer-basedsystem for cancer prognosis should

replace TNM. His reasoning was thatsuch a system could include molecu-lar factors, such as oestrogen andprogesterone receptor and HER2status, and it could provide individualpatient recurrence and survival pre-dictions for specific therapies. Hisidea was rejected, but since then hehas kept up the pressure with variousarticles on the subject, and mostrecently he participated in a debate atthe European Breast CancerConference 5 (EBCC-5) in Marchthis year, entitled “This house believesthat TNM is a waste of time”.

The TNM system is a cancerstaging classification system that isused around the world as a commonlanguage to classify anatomic diseaseextent in tumours and give indica-tions as to the course of the disease.The French surgeon, Pierre Denoix,developed the TNM Classification ofCancer Stage at the Institut Gustave-

Roussy, France, and proposed it tothe International Union AgainstCancer (UICC), which adopted it in1953, with the AJCC following suitin 1959.

Since then there has been anexplosion in knowledge about cancer.TNM was created before any of thegenes implicated in the onset of vari-ous cancers had been discovered,before the role of hormones had beenrevealed, before routine screeninghad been introduced which enablescancers to be discovered at muchearlier stages in their development,and before the introduction of neo-adjuvant and molecular therapies.Biomarkers have been discovered forcancers such as breast and prostate,which enable physicians to have amore detailed view about what treat-ments would be best for a particularcancer sub-type and the likely courseof the disease, yet they are not

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➜ Emma Mason

Has TNM been overtaken by science?

The biology of a cancer is a key factor determining prognosis and prediction of response.

So should we still be characterising it by the size of the tumour and spread of the disease?

In a debate at the European Breast Cancer Conference in Nice, a packed hall of delegates

was, reportedly, evenly split on the question.


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incorporated into TNM and are notpredicted by it.

Burke argues that, in an age ofincreasingly personalised medicine,TNM is unwieldy, outdated andshould be replaced by a system thatincludes tumour size, lymph nodestatus, metastases, and other predic-tors of outcome, including powerfulnew biomarkers, in order to providethe most accurate predictions ofwhich therapy would be best for anindividual patient. Other oncologistspoint out that, while TNM may nolonger provide all the informationthat needs to be known about somecancers such as breast and prostate,there are still many cancers wherebiomarkers have not been discoveredor developed, and where cancer stag-ing gives valuable information aboutnot only the extent, but also the like-ly course of the disease. In addition,they argue that the developed worldowes a duty to the developing worldto maintain an international classifi-cation system that is simple to under-stand and to use.

Burke told CancerWorld: “TNMis basically dead. It cannot takeaccount of the fact that screening isnow detecting cancers at much earli-er stages when they are smaller; itcannot incorporate new biomarkers;and it cannot incorporate new thera-

pies. So it is clinically misleadingrather than informative.”

When the TNM system started,all that was known about a cancerwas the size of the tumour and theextent of its spread; the existence ofclinical symptoms was the only wayof detecting it. The system was basedon the fact that the larger the tumourand the greater the extent of thespread, the less likely the patient wasto survive the disease. TNM organ-ised this spread into ‘stages’ of thedisease, with a higher stage having apoorer prognosis.

However, in October 2004 apaper published in the Journal of theNational Cancer Institute on coloncancer survival rates revealed thatthere was an outcome cross-overbetween stage IIIa and IIb patients,with the IIIa patients, who accordingto the TNM system should have aworse prognosis, having better sur-vival rates than the IIb patients. Thelikely reason for this cross-over wasthat the IIIa patients had received aneffective chemotherapy that the IIbpatients had not received and thistherapy resulted in improved survival– survival that was not taken intoaccount by TNM.

In an accompanying editorial,Burke stated that this proved thatTNM was not taking account of new

treatments, nor was it taking intoaccount the biology of the disease,and that this was the final nail in thecoffin of the TNM staging system.

Burke explained: “The TNMstaging system relies on the surgicalremoval and pathologic description ofthe anatomic characteristics of thetumour and of any associated lymphnode involvement, so that it tells youthe prognosis of patients if theyreceive surgery (whereas some can-cers only receive radiation therapy,for example, prostate cancer).Further, what if patients receiveother treatments such as chemother-apy or molecular therapy (e.g.Herceptin)? How does it take thesefactors into account in terms of itsprediction of prognosis? It is clearthat, today, the staging system ismaking predictions that are not accu-rate because other treatments arechanging the patient’s survival andthe staging system doesn’t tell youabout that. That’s a fatal flaw in theTNM staging system.”

Supporters of TNM responded tothe cross-over in a way that Burkesays has shocked many clinicians.“The leaders of the AJCC and UICC,in response to my editorial, wrotethat it was all right to have outcomecross-over in the staging system,because it’s not a prognostic system,

“Let’s base prognosis on the biology of the disease,

not on how big it is when it is discovered”

“TNM is basically dead... it is clinically

misleading rather than informative”

it’s an anatomic, extent-of-diseasesystem,” said Burke. “But once youdisconnect prognosis from the stag-ing system, that’s the end of the sys-tem. Clinicians are totally shockedwhen I tell them that the staging sys-tem is nothing to do with prognosisnow.” He said most clinicians did notknow of the disconnection betweenstage and outcome and continueusing TNM. Yet this approach, usingthe stages to determine therapy,could mean that some patients werebeing denied an effective therapythey needed, while others were beingtreated unnecessarily.

While supporters of TNM saythat it is possible to adjust the systemso that it can either take account ofnew developments or can be used tocomplement prognostic tools such asmolecular biomarkers, Burke saysthat this is impossible because youwould end up with hundreds, ifnot thousands, of different categoriesthat cross over each other, thusdefeating the main purpose of TNM– that it is a simple, easy to under-stand and use, outcome system.

However, Burke feels that the realissue with the use of TNM is what hecalls “biological determinism”. “Theessential question is: are we going tocontinue to treat our patients basedon an anatomic extent-of-diseaseapproach, or are we going to use whatwe have learned about the biology ofthe cancer to defeat the tumour that isgrowing in the patient?”

Seconding Burke at the EBCC-5debate was Frédérique Penalut-Llorca, a pathologist at the Centre

Jean Perrin, Clermont-Ferrand,France. She highlighted the irrele-vance of TNM in breast cancer com-pared with the far more relevantinformation that is now known aboutthe role of oestrogen and proges-terone positive and negative markers(ER and PR), and HER2 status.

“We need prognostic and predic-tive intrinsic tumour parameters ofresponse to treatment that can beobtained by understanding thetumour biology. These are not in theTNM!” she said.

While not all cancers are as faradvanced as breast cancer with theidentification and use of biomarkers,Burke says that there needs to be aparadigm shift.

“We need to recognise that can-

cer is a biological disease and let’sbase prognosis on the biology of thedisease, not on how big it is when it isdiscovered. If we know about ER, PR,HER2 and p53 status, then we knowabout the prognosis. And survival isvery different, even for patients with-in the same TNM stage of disease.Your destiny is determined by thebiology of your disease. This is thedefinition of biological determinism.”

He believes that a computer-based prognostic system, such asthe one that he developed for theAJCC, that can take account ofall the patient’s biomarkers is stillthe best way forward, and he hasestablished a model for this atwww.cancerhome.com.

Mary Gospodarowicz, Professor

“Clinicians are shocked when I tell them that

the staging system is nothing to do with prognosis now”


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Harry Burke: TNM is unwieldy, outdatedand should be replaced by a systemthat includes biomarkers and other predictorsof outcome

Frédérique Penalut-Llorca: oestrogenand progesterone receptors and HER2status are all far more relevant thanTNM stage in breast cancer


and Chair at the Department ofRadiation Oncology, University ofToronto, Canada, and MedicalDirector at Princess MargaretHospital, Toronto, disagrees withBurke and opposed him in theEBCC-5 debate.

She is a member of the UICCCore Committee of the UICC TNMProject, which maintains the TNMclassification and has introduced arigorous process for continuousimprovement of the TNM system.

She told CancerWorld thatnobody was pretending that TNMwas a perfect system. “We live in aworld that is imperfect. What isimportant is that we understand theprinciples of what we are doing,observing and reporting.”

The importance of the basic princi-ples of the TNM staging system stillremained, she said. “In order to makedecisions in cancer you always needto know the anatomic extent of thedisease and it always has diagnosticimportance. It may be that in select-ed cancer centres where all thepatients have very small tumours(stage I disease), other tumour char-acteristics are more important thanthe disease extent for making treat-ment decisions. But TNM provides aworld-wide framework for consider-ing the extent of the disease across allcancer sites.”

Although other prognostic mark-ers, such as molecular biomarkers,were constantly being developed,these tools should be used in addi-

tion to, not instead of, TNM, sheargued. “TNM is useful whether ornot you have access to biomarkers.It’s not perfect, but it’s useful.”

The basis for making decisions incancer rests on several factors:• the tumour• the type of cancer (i.e. site, histology,

genetic, phenotypic and molecularcharacteristics) and the extent of thedisease (i.e. stage, size, number oflesions, sites of metastasis)

• the patient (i.e. age, race, generalhealth, etc)

• the environment (i.e. what toolsand treatments are available for thephysician to use, quality of care,and access to appropriate care)

and TNM gives valuable informationon several of these. “Everyone inoncology in the world uses the extentof the disease as the main part oftheir prognostic design,” saidGospodarowicz. “Even in breast can-cer, if you have a small cancer, withno lymph node involvement and nometastasis, you know that the patientmay not need to have chemotherapyor radiotherapy. On the other hand, ifthe tumour has spread then youknow that the patient does needmore treatment.”

The aims of the TNM stagingsystem, she argued, were to aid theclinician in planning treatment, togive some indication of prognosis, toassist in the evaluation of the resultsof the treatment, to facilitate theexchange of information betweentreatment centres and to contributeto the continuing investigation ofhuman cancer.

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Mary Gospodarowicz: The TNM system is undercontinuous review by several expert groupsand is able to respond to the challengesof the 21st century

Lars Holmberg: Lymph node status is stillthe major prognostic divider. Even if anothersystem is developed, we still couldnot abandon TNM

“Other prognostic markers should be used

in addition to, not instead of, TNM”


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“TNM is simple and affordable. The developed world

has a responsibility to keep the system in operation”

Because TNM had been running as auniform system for more than 50years, it was now possible to trackchanges in cancers over a long periodof time, even though some detailsof staging classification had alteredto keep track with developments(Burke disputes this). This, saidGospodarowicz, made it possible toconduct epidemiology studies, inves-tigate the natural history of cancer,and share information from clinicaltrials.

“Cancer registries need a systemthat provides a framework for record-ing and considering all cancers. Theyneed the uniformity provided byTNM,” she said.

TNM is subject to a process ofcontinuous review and improvementby several groups of experts around

the world. Gospodarowicz believesthat this system is capable ofresponding to the challenges thatTNM faces in the 21st century.

“TNM provides a common lan-guage for classifying cancer so thatpeople know what they are talkingabout. There would be total chaos ifeveryone used different methods fordescribing different cancers,” she said.

Lars Holmberg, Professor ofClinical Cancer Epidemiology at theRegional Oncologic Centre inUppsala, Sweden, also spoke infavour of TNM at the EBCC-5debate.

“TNM needs to be maintainedfor epidemiological cancer surveil-lance,” he told CancerWorld. “It isimportant to know how many peoplehave localised cancer, cancer with

regional metastases and cancer withdistant metastases. World-wide it haslarge public health implications. Inmany parts of the developing world,cancer is becoming the most impor-tant disease, once other causes ofdeath such as starvation, infections,malaria and tuberculosis have beendealt with. It’s very important to havethe TNM system to record and clas-sify the cancer burden here.

“There’s the issue of publichealth planning. TNM is an indicatorof the scale of resources that coun-tries will need for cancer treatment,because if you have a large propor-tion of patients diagnosed when theyhave distant metastases, that’s quitedifferent to people diagnosed withlocal tumours in terms of theresources needed to treat them.

Partial pictures. Proponents of TNM say itis simple, provides vital epidemiologicalinformation, and requires relatively low-techimaging techniques, such as bone scan(above). Opponents argue that informationon molecular biology, such as HER2 statusas revealed by the FISH test (right),should be at the heart of any modernstaging system


“The developing world will not beable to afford modern, elaboratesystems of surveillance of cancerepidemiology and cancer mana-gement for a long time to come.TNM is simple and affordable. Thedeveloped world has a greatresponsibility towards developingcountries to keep the TNM systemin operation.”

However, Burke argues thatTNM has become extremely complex(for example, the determination ofsentinel lymph node involvement)and is itself too complicated fordeveloping countries to use. Hementioned a much simpler system,which predated TNM and is stillbeing used by the US NationalCancer Institute, of “local, regionaland distant disease spread”, andsuggested this would be a bettersystem for developing countries touse, especially where patients mightnot even be able to have surgery.

Holmberg said: “TNM reflectstumour-host balance and tumourburden, none of which is wellcaptured by known biological tumourmarkers. The cancer burden in onepatient is still biologically importantand relevant. The surgeon has toknow what size a tumour is andwhether there is lymph nodeinvolvement.

“It is a naïve over-estimation ofour progress to believe that tradition-al staging rapidly will be outdated.Lymph node status is still the majorprognostic divider. Even if anothersystem is developed, we still couldnot abandon TNM.”

Although molecular biomarkers arebeing developed for cancers such asbreast, prostate and testicular cancer,there are many other cancers with noknown biomarkers as yet. “Breastcancer has been at the forefront formany years in terms of biologicalmarkers. But if you look at lung cancer,bowel cancer and gastric cancer forinstance, it’s more obvious that TNMis still needed,” said Holmberg.

While he conceded that therewas some validity in the argumentthat increasingly tumours were beingdetected earlier, at stage I, and thatthis consequently affected prognosis,he pointed out that this was far fromthe norm. “This is a correct argumentwhen we get to the stage whereeveryone has a small localisedtumour, but we are not even there inbreast cancer. We still need to knowin different countries how many peo-ple have what stage of tumour, andthere are still many countries, even inEurope, such as Eastern Europe,Turkey, Croatia, where a significantproportion of patients have distantmetastases.

“When you look at sophisticatedmarkers that show how a tumour willprogress, the actual anatomic burdenin one patient at the time of diagno-sis is reflecting something of the biol-ogy. You need to know the tumourburden to know how much the dis-ease has over-powered the patient, aswell as a number of other factors, andTNM reflects this.”

Medicine tends to be a conserva-tive field and there is always resist-ance to change. While this can be

good in that it reduces the risk of fadsand transient phenomena, it canstand in the way of progress. Thecrux of the debate at EBCC-5 was:do we determine prognosis and ther-apy based on the biology of the dis-ease or do we remain with theanatomic extent-of-disease system,perhaps with some adaptations? Inthe event, the chair, Aron Goldhirsch,declared the vote to be split down themiddle. There is no doubt that thedebate will continue, which is goodfor science and for patients.

Further reading, listed by date of publicationHB Burke, DE Henson (1993) Criteria for prognosticfactors and for an enhanced prognostic system. Cancer72:3131–35FL Greene, LH Sobin (2002) The TNM system: ourlanguage for cancer care. J Surg Oncol 80:119–120J Benson (2003) Overview of the TNM system. LancetOncology 4:56–57I Mittra (2003) Failure of the TNM System. LancetOncology 4:59HB Burke (2004) Outcome prediction and the futureof the TNM staging system. J Natl Cancer Inst96:1408–09MK Gospodarowicz, D Miller, et al (2004) The processfor continuous improvement of the TNMclassification. Cancer 100:1–5JB O’Connell, MA Maggard, CY Ko (2004) Coloncancer survival rates with the new American JointCommittee on Cancer sixth edition staging. J NatlCancer Inst 96:1420–25SB Edge, LH Sobin, DL Page, MK Gospodarowicz, FLGreene, DP Winchester (2005) Re: Colon cancersurvival rates with the new American Joint Committeeon Cancer sixth edition staging. J Natl Cancer Inst97:463–464HB Burke (2005) Re: Colon cancer survival rates withthe new American Joint Committee on Cancer sixthedition staging. J Natl Cancer Inst 97:464–465S-Y Jeong, DB Chessin, D Schrag, WD Riedel, JGGuillem (2005) Re: Colon cancer survival rates withthe new American Joint Committee on Cancer sixthedition staging. J Natl Cancer Inst 97:1705–06HB Burke (2005) Re: Colon cancer survival rates withthe new American Joint Committee on Cancer sixthedition staging. J Natl Cancer Inst 97:1707D Weaver (2005) Benefits of the revised TNM system.Lancet Oncology 4:57–58U Veronesi, G Viale, N Rotmensz, A Goldhirsch(2006) Rethinking TNM: Breast cancer TNMclassification for treatment decision-making andresearch. The Breast 15:3–8

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“It is a naïve over-estimation of our progress to believe

that traditional staging rapidly will be outdated”

Masterpiece

The Moscowsmokebuster

There are smokers in Russia alive today thanks to David Zaridze and the lead he took in

halving tar levels 20 years ago. He has a long history in cancer prevention, but believes the

biggest gains may lie in early detection. Will the country that discovered the first liver cancer

marker give the world the first proteomic marker for lung cancer?

Lung cancer deaths have been in decline inRussia since the mid 1990s, which is per-haps surprising given that 35 million

Russians smoke and show few signs of giving upthe habit (70% of young men and 25–30% ofyoung women are current smokers).

Mortality from all cancers in Russia is stillhigher than in the US and other Western coun-tries. Lung cancer deaths in Russian men are athird higher than in Western Europe.

Yet after rising steadily between 1965 andthe early 1990s, the age-standardised death ratesfrom lung cancer levelled out and then began tofall. David Zaridze, Deputy Director of the N NBlokhin Cancer Research Centre in Moscowand Director of the Institute of Carcinogenesis,traces the turning point to the first meeting onsmoking prevention in what was then the SovietUnion, in 1985.

Zaridze organised the meeting in conjunctionwith the International Agency for Research onCancer (IARC) and the renowned OxfordUniversity epidemiologists Richard Doll andRichard Peto. The meeting was attended by influ-

➜ Peter McIntyre


ential Russian doctors and senior officials fromthe Ministry of Public Health and other agencies.

Behind the scenes, there was a dispute.Zaridze and Peto both saw the high levels of tar inRussian cigarettes as being the priority. LorenzoTomatis, then director of IARC, believed that thisshould be secondary to a “stop smoking” message.

The Moscow–Oxford alliance held. The con-ference adopted a resolution which said:“although elimination of tobacco consumptionshould be the final goal, an upper limit such as,perhaps, 15 mg, on cigarette tar deliveries shouldbe introduced as quickly as possible.”

Zaridze believes that was right. “At that timeSoviet cigarettes had tar levels of 30 plus, so thiswas a proposal to reduce the tar levels by half. Wehave seen since the middle of the 1990s a reduc-tion in the incidence and mortality of lung cancer.The only explanation of this decline is that meas-ure we took in the middle of the 1980s, becausesmoking levels in Russia have not changed.”

The Soviet Union introduced tobacco regula-tions within three years of the meeting. Since thestate had a monopoly on cigarette production,

Masterpiece


putting it into effect was easy. The reduction inlung cancer mortality will continue for manyyears because of the effect on lifetime smokers.More recently, the International CigaretteVariation Group compared packets of Camel,Lucky Strike, and Marlboro cigarettes purchasedin 29 countries. The cigarettes were analysed inMoscow where they found similar amounts of tarand nicotine, but great variations in the amountsof two nitrosamines, NNK and NNN, carcino-gens which are probably responsible for theincrease in adenocarcinoma of the lung.

Zaridze has written to the chief physician at theMinistry of Public Health to call for regulations toreduce the level of these carcinogens in cigaretteson the market. But he recognises that in themarket economy of modern Russia, this timethere will be a fight with the tobacco companies.

“The high content of nitrosamines in thesetobaccos has different causes, but the tobaccocompanies don’t care and they don’t want toinvest.”

Some campaigners fear that if cigarettesbecome “safer” that will dilute the “stop smoking”message. Zaridze does not see these policies asmutually exclusive. “The main slogan of anti-smoking campaigners, myself included, is thatthere are no safe cigarettes. Safe cigarettes don’texist and never will be produced. But if we canmake cigarettes less carcinogenic, less harmful,less noxious, we have to do this.”

Zaridze does not seem perturbed at theprospect of having to take on the tobacco compa-nies while keeping anti-tobacco campaignersunited. In the course of his career, he has pro-moted public health within a variety of politicalsystems and social policies, while keeping stronginternational contacts. He has learned to respectthe data, rather than the current orthodoxy.

In 1969, Zaridze was accepted as a postgrad-uate fellow in pathology at what was then theInstitute of Experimental and Clinical Oncology,headed by Nicolai Krayevsky. As chief pathologistof the Soviet Army during World War 2,Krayevsky had been responsible for identifyingthe remains of Hitler and Eva Braun in Berlin.Zaridze says he was “a very nice man and a firstclass pathologist”.

And this was what Zaridze himself wantedto be. Over the next decade, he carried out hun-dreds of autopsies and biopsies on all kinds oftumours, with a special interest in thyroid can-cers and morphological peculiarities. Thishands-on approach, examining tumours

“Safe cigarettes don’t exist. But if we can make

cigarettes less carcinogenic, we have to do this”

Masterpiece


physically, gave Zaridze a grounding. “Knowledgeof the body is essential and I had ten years of veryvaluable experience. I do not want to insult mod-ern pathologists, but in recent years there arefewer and fewer autopsies. And some molecularbiologists for example have no idea what happensabove molecular level.”

Nikolai Blokhin, a former wartime surgeonand a leading traumatologist, became the firstDirector of the Cancer Research Centre inMoscow. “He was really a brilliant personality.The cancer institute was just a hospital before hetook over and the research part was really hischild, based on his interests. He was interested inbasic science, and understood and took part indiscussions and arguments in this field. He wasfascinated by basic research into cancer and byepidemiology which was a very new, young disci-pline for chronic disease.”

When Blokhin met Richard Doll – the pio-neer on work relating smoking to lung cancer –something clicked. He was determined that hiscentre would base research and treatment on thebest epidemiological evidence. He looked forsomeone to train in this new art. Of his team,

Zaridze had the best English. Zaridze went to Oxford in

1977 on a fellowship from IARC.“I joined the department whereRichard Doll was Regis Professor.This was a brilliant team. Doll him-self, Richard Peto (today Professorof Medical Statistics &Epidemiology at OxfordUniversity), and his brother JulianPeto (now Cancer Research UKChair of Epidemiology) and manyother brilliant people.”

He was only in Oxford for 10months but his collaboration andfriendship with Doll and RichardPeto has been lifelong. After acrash-course in epidemiology andstatistics at the London School of

Hygiene and Tropical Medicine, Zaridze wasappointed to work at IARC in Lyon.

For six years, he headed the group on diet andcancer. He also worked on colorectal and prostatecancer. In the early 1980s Zaridze and PeterBoyle (now Director of IARC) published the firstpaper that explained the rise in incidence ofprostate cancer in the US.

“Today, what we said is commonplace. PSAscreening was discovering a lot of indolent carci-nomas which, thank god, the urologists have nowunderstood should be followed, not treated.Urologists in the United States pushed this testinto the screening programmes without testing itas an instrument for screening. It was misused.”

In 1985, Blokhin invited Zaridze back toMoscow to head the unit of epidemiology, a smallgroup who did not then even have a computer.

One of his early efforts was on diet and can-cer. It was becoming obvious that diets rich ingreen vegetables are protective against cancer.Zaridze had been instrumental in setting up anintervention trial in Uzbekistan, where a studygroup was encouraged to take vitamin supple-ments in the form of pills – beta-carotene for vita-min A, riboflavin (vitamin B2) and vitamin E.However, the results were disappointing, as weretrials in other parts of the world. Vitamin supple-ments appear to offer no protection.

“Empirically we could see the beneficial

PE

TE

R M

CIN

TYR

E

Lighting up. Zaridze and his assistant Olga Gorbacheva at the tobaccosmoke analysis kit in the Institute of Carcinogenesis in Moscow. This machine can ‘smoke’ 20 cigarettes at once – and it doesn’t like what it finds in any of them

effects of beta-carotene, vitamins B, C & E andascorbic acid, but we do not know their complexinteractions. Twenty years ago, we were sureabout the story of diet and cancer; we knew morethen than we know now! Today, we know the ben-eficial role of a diet low in calories and high in fruitand vegetables, but it is a complex interaction.”

By the time Zaridze returned to Russia,Gorbachev was President and social and politicallife was beginning to loosen up. However, a partyapparatchik from the central committee was stillin charge of the Institute of Carcinogenesis.

Zaridze says: “People started to say what theythought and they were fed up with this guy.Finally, he was sacked. Then the staff met andeverybody voted – not a scientific council but all350 people who worked here. I was probably thefirst and the last director of a research institutewho was elected by popular vote.”

Zaridze was a member of the executive boardof the Organization of European CancerInstitutes, and he helped its chairman, WalterBodmer, to plan a meeting in Moscow on CancerPrevention in Central and Eastern Europe. Thedate was set for 2 September, 1991. On 19 August,a group calling itself the State EmergencyCommittee launched a coup, holding Gorbachevin the Crimea and surrounding the Parliamentwith tanks.

Zaridze recalls how nervous they all felt thatthe old guard would return. His staff took theirphotocopiers and paper to the Parliament, so thatthe anti-coup forces could print out their ownleaflets and orders. After a week, the coup col-lapsed and Gorbachev was back, although nowYeltsin was effectively in power.

Despite the crisis, Zaridze decided to goahead with the meeting, warning those comingthat they had better bring their own paper. “Wehad a beautiful meeting here – a historic meeting.Everybody arrived with a pack of paper. The daywas devoted to visiting the barricades in Moscow,

Masterpiece


and we worked at night-time. I have a lot of mem-ories of this meeting because people who werecoming from the West were delighted to visit bar-ricades in central Moscow.”

The economic crisis in the former SovietUnion coincided with a fall in life expectancy.From 1991 to 1995, premature mortality rosesteadily. In 1998 a further economic crisis sawthe death rate climb again.

Zaridze and his colleagues worked on ahypothesis that the high background mortalityrate in Russia was mainly to do with smoking,while fluctuations in the 1990s were mainly to dowith high levels of alcohol consumption.

At the close of the decade the Institute ofCarcinogenesis in cooperation with OxfordUniversity and IARC set up a huge two-partstudy in three Russian cities – Tomsk, Barnauland Novgorod – a retrospective mortality studyand a longitudinal study, following the lifestyleand health status of 200,000 healthy people.

Results from the mortality study are not yetpublished, but will show a much greater thanexpected role of alcohol. In Barnaul, researchersexamined records of 25,000 forensic autopsiescarried out on those who died outside hospital orthe home. They found that an incredibly highproportion of men had high levels of alcohol intheir blood.

“About 20% of those people who had a post-mortem diagnosis of cardiovascular diseasein fact died from alcohol poisoning. Russia ingeneral is a very heavy drinking country and allnegative situations are washed down by vodka.There is also a lot of spirit that people makethemselves. With the fake product on the market,even lower levels of alcohol may be lethal.”

Alcohol and smoking together multiply therisk of cancers of the pharynx, larynx, oesophagusand stomach. Surveys show an interrelationbetween habits that can damage the health ofyoung people. A teenager who smokes has a

“The day was devoted to visiting the barricades

in Moscow, and we worked at night-time”

Masterpiece


greater chance of drinking alcohol, taking drugsand becoming involved in crime.

Zaridze believes there should be strongerpublic policy to alert the public to the dangersof hard drinking and illegal spirits, but policy iscurrently poorly related to evidence. In April2006, Russia banned imports of wine from twoneighbouring republics, Georgia and Moldavia,with whom it is having political disputes, on“health grounds”. No action was taken againsthome-brewed vodka.

The Institute of Carcinogenesis is responsi-ble for basic research as well as population-basedstudies. Its current focus is on the need for earlydetection of lung cancer.

Zaridze points out that even countries withscreening programmes really only succeedin preventing cervical cancer, while mammogra-phy prevents only 25% – 30% of deaths in thescreening group. He believes they can do betterand that the most urgent need is for early

detection of lung cancer. “Screening means that you

discover the disease beforesymptoms, before clinicalmanifestation of cancer. Lungcancer is different because peo-ple who smoke have a lot ofproblems like coughing, bron-chitis, emphysema and so on.We need early biologicalmarkers that can help us todetect disease at an early stage,because disease detected atearly stage is curable.”

“I am working for the devel-opment of highly sensitive and

highly specific cancer markers. We have collect-ed a huge database, epidemiological databaseand blood serum bank for about 1,000 cases oflung cancer and 1,000 controls. All these casesare very well documented. We know the type ofcancer, squamous, adenocarcinoma, small celland so on.

“Using mass spectrometry, we are looking forproteomic patterns in blood which distinguish theplasma serum of lung cancer patients from theplasma of healthy individuals. When these pro-teins are discovered and characterised we willproduce diagnostic chips that can be used forearly detection of lung cancer, and for monitoring,before and after an operation.

“We have seen four or five peaks which dis-tinguish the blood from lung cancer from theblood of healthy people. We don’t know whatthese proteins are; we have not characterisedthem yet, but sensitivity is about 96% and speci-ficity is about 94% and this is already quite good.We are going to try to make them more sensitiveand more specific, and to identify the proteins.

“The next step will be to test it in epidemio-logical studies as a screening tool for lung cancer.You screen heavy smokers – those who smoke one

Neither he nor Russian science ever made

a penny out of their discovery

The famous 1991 meeting in Moscow that took place amidst thebarricades. Amongst the audience are (foreground from left),Maurice Tubiana from Paris, Richard Peto from Oxford, IARC editorElizabeth Heseltine and Rodolfo Saracci, director of epidemiology in Pisa

Masterpiece


pack plus, because you know that in this high-riskgroup, 17% develop lung cancer in their lifetime.

“We have only a small group interested inproteomic patterns but I don’t think that we aremuch behind internationally. They started earlierin the US, but they made a lot of mistakes whichwe learned from.”

Keeping up with cutting edge research is dif-ficult when so much talent is lost.

“A lot of young people go to the US. We losea terrible amount both in molecular biology andin epidemiology. We just cannot keep the bestyoung people. This is not a question of personalincome, but mainly of being able to do somethinggood. When you are young, you have to work andhave facilities. I don’t know if I would come backmyself, if I were their age.

“Frankly if I did not have a lot of grants fromdifferent parts of the world I would not be able todo anything.

“Now, like the Americans, I spend half of myworking time writing up grant applications. I hopefrom next year we will have quite reasonablegrants for different bits of research.”

One research gap he would like to plug is toinvestigate what makes some cancers indolentwhile others progress rapidly. “That has fascinat-ed me for several years. Prostate cancer is proba-bly the best example, but breast cancer incidenceis increasing partly because indolent breast can-cers are discovered by mammography. They areprobably different. If not discovered on screening,they would not manifest themselves clinicallyduring the person’s life span.”

Perhaps it would help the research pro-gramme if Russian researchers could exploit theirdevelopments as their US and European counter-parts do. But there is no tradition of taking theirwork to market. The liver cancer marker, alpha-feto protein, was discovered in the Institute ofCarcinogenesis by Gary Abelev 35-years ago.Abelev still works at the Institute. Neither he nor

Russian science ever made a penny out of theirdiscovery.

Nor is there a tradition in Russia of those whohave made money putting something back intoresearch. Zaridze compares unfavourably theRussian billionaires who made their money bytaking over the assets of the old Soviet state, withBill Gates, whose foundation now funds researchall over the world.

As President of the Russian Cancer Society,Zaridze sees how the money trickles in.“Contributions are mainly very small sumsoffered by old people from their pensions, 10, 20,or 30 roubles – less than US$ 1. These peoplefeel something and want to do something. Theyare different from those billionaires.”

In all the changes in Russia there have beengains and losses – wealth for some, poverty forothers. Few want to turn back the clock, butsome services have been abandoned in a rathershocking manner. The former screening systemfor cervical cancer (based on check-ups every twoyears) was cancelled in the early 1990s, sincewhen deaths of young and middle-aged womenfrom cervical cancer have been on the increase.

The role of Zaridze’s institute is partly to pro-vide evidence to help policy makers protect thepopulation – by curbing smoking, reducing alco-hol intake and appropriate screening. But Zaridzeis frustrated that cancer is still not being given thepriority it deserves. AIDS and avian ’flu, he says,are the subject of intense debate at high-levelpolitical meetings, while cancer, which kills300,000 people a year in Russia, is scarcelymentioned.

“Our duty is to inform people that if cancer isdiscovered at an early stage you are saved. Forexample if breast cancer is discovered at an earlystage, a small operation is done which is not muti-lating. The main message should be that cancer,if discovered at an early stage, is a curabledisease.”

“They started earlier in the US, but they made

a lot of mistakes, which we learned from”

ImpactFactor


tality so far appears to have come fromscreening measures, with colonoscopicpolypectomy preventing cancer insome individuals undergoing aggressivescreening.1 Economic models havesuggested colonoscopy alone to bemore cost-effective than most othercancer screening measures, and havefound lower efficacy and higher costsfor aspirin chemoprevention comparedwith endoscopic screening, mainlybecause of the need to treat complica-tions of its use. If aspirin were alreadyin use, for example for cardiovascularprotection, then the addition ofcolonoscopy would yield a life-yearssaving greater than either measurealone.2 The field of colorectal cancerchemoprevention has become veryactive in recent years, with much inter-est in NSAIDs, including aspirin.3

A key question is whether thebenefit of long-term aspirin, high-dose aspirin, or both warrants recom-mendation for its use as prophylaxisagainst colon cancer. Randomisedprospective trials utilising aspirinhave demonstrated a reduction in

adenoma recurrence in subjects witha previous adenoma or cancer.4,5

Interestingly, despite the major differ-ences in endpoints and study design,the magnitude of risk reduction inthese studies is very similar to thatseen in the study of Chan et al. Takentogether, these studies provide a con-sistent body of evidence in favour of aprotective effect of aspirin.

Of course a number of questionsremain unanswered. Why is a protec-tive effect not seen in the rectum?Why is there a reduction in early-stagebut not later-stage colon cancers? Is atleast some of the risk reduction relatedto bleeding from tumours induced bythe anti-platelet effect of aspirin? Isthe protective effect of non-aspirinNSAIDs global or are there differencesin magnitude of benefit gaineddepending on which agent is taken?Do we sufficiently understand the bio-chemical pathways by which aspirinexerts its protective effect? Might fur-ther work enable more-effective, less-risky agents or combinations of agentsto be developed? Notwithstanding the

The recent update of theNurses’ Health Study (seeopposite) provides data on the

relationship between aspirin use andcolorectal cancer occurrence. In thisreport, a lower risk of colon cancerwas observed in regular aspirin users(≤2 x standard 325 mg tablets perweek) than in women who did notregularly use aspirin. Dose and dura-tion of use were important; if awoman consumed 2–5 standardaspirin per week, the RR was mod-estly reduced, while at higher doses(>14 tablets per week) the riskreduction after 10 years was highlysignificant (P<0.001). The aspirinprotection was limited to the colonand was seen for early-stage (stage Iand II) but not for later-stage (stageIII and IV) colorectal cancers. Non-aspirin NSAIDs were also associatedwith dose-dependent cancer riskreduction in the colon, but not in therectum. No protection was affordedby regular use of paracetamol.

The greatest potential impact oncolorectal cancer incidence and mor-

➜ Patrick M Lynch*

Does regular use of aspirinreduce the risk of colorectal cancer?

Use of at least two standard aspirin weekly, for 10 years or more, reduces colon cancer risk in

women. Subject to certain caveats, aspirin should be considered for colon cancer prophylaxis.

*Patrick Lynch is Associate Professor of Medicine at the Department of Gastrointestinal Medicine and Nutrition, the University of Texas MD Anderson Cancer Center, Houston,Texas, USA. This article was first published in Nature Clinical Practice Oncology 2006 vol. 3 no. 4, and is reproduced with permission. www.nature.com/clinicalpracticedoi:10.1038/ncponc0459, ©2006 Nature Publishing Group


need for further study, it must be con-cluded that aspirin reduces risk of inci-dent and recurrent colon neoplasia.Whether the individual clinicians arewilling to prescribe aspirin prophylacti-cally will depend on whether theybelieve, in the absence of a specificindication from the FDA, that suchuse is warranted, and on the potentialcardiovascular risks and benefits forthe individual. Subjects prescribedaspirin prophylaxis would have to bemonitored carefully for other adverseevents, especially gastrointestinal

bleeding, and appropriate colorectalcancer screening examinations shouldstill be performed. This study, althoughnot really designed to rigorouslyaddress such matters, did not showany substantial excess in bleeds amongthe long-term or high-dose aspirinusers.

References

1. SJ Winawer, et al. (1993) Prevention of colo-

rectal cancer by colonoscopic polypectomy: the

National Polyp Study Workgroup. N Engl J Med

329:1977–1981

2. A Sonnenberg (2002) Cost-effectiveness in

the prevention of colorectal cancer. Gastroenterol

Clin North Am 31:1069–1091

3. E Hawk, et al. (2004) Colorectal cancer

chemoprevention – an overview of the science.

Gastroenterology 126:1423–1447

4. JA Baron, et al. (2003) A randomized trial of

aspirin to prevent colorectal adenomas. N Engl

J Med 348:891–899

5. RS Sandler, et al. (2003) A randomized trial of

aspirin to prevent colorectal adenomas in

patients with previous colorectal cancer. N Engl

J Med 348:883–890

ImpactFactor

SynopsisA Chan, E Giovannucci, JA Meyerhardt, et al. (2005) Long-term use of aspirin and nonsteroidal anti-inflam-matory drugs and risk of colorectal cancer. JAMA 294:914–923Background. Regular aspirin use for 1–3 years reduces the risk of recurrent adenoma in patients with a history of colo-rectal adenoma or cancer, but it is unclear whether aspirin similarly reduces risk of incident colorectal cancer and whethernonsteroidal anti-inflammatory drugs (NSAIDs) have similar anticancer effects in these patients. Objective. To prospectively examine whether long-term use of aspirin and NSAIDs might prevent the development ofcolorectal cancer.Design and intervention. Women participating in the Nurses’ Health Study were prospectively studied biennially formedication use from 1980 to 2000, using self-completed questionnaires, the content of which was adjusted with time toreflect changes in lifestyle, diet and medications. The questionnaire included a validated assessment of diet and patternsof use of aspirin and NSAIDs. Participants were requested to record the weekly number of pills taken and the number ofyears of use. Reports of cancer were confirmed by medical records and by death reports from the National Death Index,and cancer stage was classified according to the sixth edition of the American Joint Committee on Cancer’s Cancer StagingHandbook. Individuals with a history of inflammatory bowel disease, cancer, familial polyposis syndrome or hereditary non-polyposis colorectal cancer were excluded from analysis. Outcome measures. Incident colorectal cancer was the primary outcome measure.Results. During 1,592,017 person-years, there were 962 cases of colorectal cancer among the 82,911 eligible women. Aftercontrolling for other potential risk factors, the risk of colon cancer was lower in regular aspirin users (≤2 x standard 325 mgtablets per week) than in women who were not regular aspirin users (<2 standard tablets per week; multivariate relative risk[RR] 0.77; 95% CI 0.67–0.88). A reduction in risk did not occur until at least 5 years of use, and this effect strengthenedafter 10 years of use (multivariate RR 0.67; 95% CI 0.54–0.85; P<0.001). The effect of aspirin was dose-dependent, with thegreatest reduction in risk achieved with cumulative doses of more than 14 standard tablets per week (multivariate RR 0.68;95% CI 0.49–0.95; P<0.001). The relative risk was modestly reduced in women taking 2–5 standard aspirin tablets per week(RR 0.89; 95% CI 0.73–1.10). A protective effect of aspirin was seen for early-stage cancers (stage I and II; multivariate RR0.67; 95% CI 0.55–0.82), but not for later-stage colorectal cancers (stage III and IV; multivariate RR 0.86; 0.71–1.05), or forrectal cancers (multivariate RR 0.94, 95% CI 0.72–1.23). Other, non-aspirin NSAIDs were also associated with a dose-dependent risk reduction for colon cancer but not for rectal cancer. Regular use of paracetamol had no protective effect.Conclusions. Long-term, regular use of aspirin or NSAIDs was associated with a significant reduction in the risk of incidentcolorectal cancer in an average-risk population.Acknowledgement: The synopsis was written by Petra Roberts, Associate Editor, Nature Clinical Practice

ImpactFactor


These shortcomings might also explainsome puzzling results. For example,histology (follicular vs mantle cell) didnot emerge as a factor prognostic forevent-free survival (EFS). Similarly, itis unclear why a lower baseline lym-phocyte count predicted good re-sponse, but a higher lymphocyte countafter induction therapy was associatedwith a better EFS. Whether this resultis due to the smaller number of patientsincluded in the EFS analysis, or the dif-ferent processes used for patient se-lection, remains open to speculation.

For patients with indolentlymphoma, for whom an aggressivetreatment would not be suitable,single-agent rituximab might be avalid option. This study shows thatrituximab might be particularlyworthwhile in patients with a lowtumour load and normal blood counts;however, it is exactly this patientpopulation that might as well befollowed using a ‘wait-and-watchtherapy’. Indeed, studies comparingthe single-agent rituximab and watch-and-wait treatment strategies in this

favourable subpopulation of patientsare ongoing. The prediction scoresuggested by Ghielmini et al. might beuseful for identifying patients whoshould not be treated with single-agent rituximab, but it does notprovide information on how to treatsymptom-free patients who have lowtumour burden.

While the results obtained withprolonged treatment with rituximabare regarded by the authors aspromising, the interpretation of theclinical relevance of the study isdifficult. Early treatment with single-agent rituximab aims to delay thetime until chemotherapy is required,and possibly to lengthen overallsurvival time; however, it is unclearwhether either of these goals can beachieved by prolonged rituximabtreatment. Most importantly, from aclinical point of view, both theprevious1,2 and current paper on thetwo subtrials suffer from a relativelyshort observation time and a lack ofdata reported regarding overallsurvival.

The major merit of a recentstudy of Ghielmini et al. (seeopposite) is that it provides the

first evaluation of prognostic factorsemerging after rituximab monothera-py. Moreover, it is reassuring that,while prolonged rituximab therapyresults in sustained immune suppres-sion, it does not cause an increasedrate of infections. There are, howev-er, considerable problems with theinterpretation of the study. The studypopulation included both untreatedand pretreated patients, and the cur-rent analysis of predictive factorscombined the results from two sub-trials in follicular lymphoma (FL)and mantle cell lymphoma (MCL).1,2

Quite importantly, it is unclear howmany patients who really neededtherapy were included in the trial.

The results of the univariate analy-sis of prognostic factors must be inter-preted with caution. With 33 factorsincluded in the analysis and with noadjustment made for multiple testing,some factors might have emerged as hav-ing prognostic value merely by chance.

*Michael Pfreundschuh is Professor of Internal Medicine at Saarland University Medical School, Homburg, Germany. Competing interests: Pfreundschuh is a member of the advisoryboard for Mabthera (Roche). This article was first published in Nature Clinical Practice Oncology 2006 vol. 3 no. 4, and is reproduced with permission. www.nature.com/clinicalpracticedoi:10.1038/ncponc0457, ©2006 Nature Publishing Group

➜ Michael Pfreundschuh*

Factors predictive for responseof follicular and mantle celllymphoma to rituximab

A recent analysis of prognostic factors may help identify which follicular and mantle cell

lymphoma patients should be excluded from trials of single-agent rituximab therapy.


In conclusion, while adding ritux-imab to conventional chemotherapyresulted in a significant increase inremission rates, remission durationand, in some trials,3,4 lengthenedoverall survival, the value of single-

agent rituximab with respect to theseendpoints remains to be determined.Currently, the most urgent clinicaldilemmas relating to FL are whetherwe can prolong survival further, andwhether we can do so by earlier or

more aggressive treatment, or both?Unfortunately, none of these issuesare answered by this paper.

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

ImpactFactor

SynopsisM Ghielmini, K Rufibach, G Salles, et al. (2005) Single agent rituximab in patients with follicular or mantle celllymphoma: clinical and biological factors that are predictive of response and event-free survival as well asthe effect of rituximab on the immune system: a study of the Swiss Group for Clinical Cancer Research(SAKK). Ann Oncol 16:1675–1682Background. Follicular lymphoma (FL) and mantle cell lymphoma (MCL) are generally considered incurable, so treat-ment is aimed at improving symptoms in most cases. Single-agent rituximab is an option in this setting, because it causeslittle toxicity and with prolonged treatment produces remissions in some patients. Factors predictive of response of FL andMCL to single-agent rituximab are ill-defined. Objective. To identify characteristics potentially associated with event-free survival (EFS), response and toxicity of ther-apy among patients receiving single-agent rituximab for FL or MCL.Design and intervention. This randomised trial used data from two subtrials, one for FL patients and one for MCL.Between January 1998 and January 2002, 29 institutions enrolled adult patients for induction therapy with rituximab for4 weeks (375 mg/m2 weekly). Patients who had partial or complete response or stable disease at week 12 were randomisedto no further treatment (standard treatment) or treatment with infusions of rituximab (375 mg/m2) at week 12 and months5, 7 and 9 (prolonged treatment). Outcome measures. Factors predictive of response rate and EFS were identified using preliminary univariate analyses(logistic regression for response and Cox regression for EFS), followed by a stepwise regression and multivariate analysiswithout adjustment for multiple testing. A scoring system to predict benefit of therapy was constructed and tested.Results. At a median follow-up of 4.5 years, patients who received maintenance rituximab therapy had a significantlylonger EFS than those who received no further treatment (17.9 months vs 11.2 months; P=0.005). Independent predictivefactors for response were disease bulk <5 cm, follicular histology, normal haemoglobin and low lymphocyte count. Factorspredicting prolonged EFS were response to induction therapy, a maximum of one previous cycle of chemotherapy, AnnArbor stage* I–III, high lymphocyte count, disease bulk <5 cm, Fcγ receptor genotype VV and prolonged rituximab treat-ment. Using a prediction score constructed on the basis of MCL histology, bulky disease, previous chemotherapy and lowhaemoglobin, patients could be divided into groups expected to experience high, intermediate and low benefit of therapy,according to the number of predictive factors they presented with (0–1, 2–3 and 4–5, respectively). Median levels of cir-culating B lymphocytes were reduced to 20% of baseline during treatment (P<0.0001), but their numbers partially recov-ered after a median of 12 and 18 months following standard and prolonged treatment, respectively. More prolonged sup-pression of serum IgM occurred with extended as opposed to standard rituximab treatment. Incidences of adverse effectswere similar in the two arms of the study. Serious adverse events considered to be related to rituximab included 13 infec-tions, six cardiac events and five intestinal complications. There were seven deaths due to adverse events, consisting of fourcardiac, two infectious and one intestinal event.Conclusions. Clinical baseline characteristics that predicted response to single-agent rituximab therapy in FL and MCLwere defined.Acknowledgement: The synopsis was written by Michael Pfreundschuh, Professor of Internal Medicine at Saarland University MedicalSchool, Homburg, Germany* Classification of lymphoma into four stages based on the involvement of anatomic groups of lymph nodes; stage I indicates localised nodalinvolvement and stage IV indicates disseminated disease

ImpactFactor

Anovel technique that uses a fluorescentmarker to guide surgery in malignant

gliomas has been shown to enable surgeonsto remove more of the tumour and improveprogression-free survival.

Malignant gliomas have a poorprognosis. This may be because surgeonsoften have difficulty in seeing exactly wherethe tumour stops and healthy tissue starts,making complete removal difficult.Numerous new techniques have beendeveloped to try and solve this problem;however, they have not fulfilledexpectations – frameless stereotaxy (image-guided surgery) is too expensive andintraoperative MRI is too cumbersome touse in every case.

Researchers from the ALA-GliomaStudy Group investigated a new way todetect the tumours during surgery, by usinga drug called 5-aminolevulinic acid, whichcauses fluorescent compounds toaccumulate in cancerous tissue. The tumourcan then be seen with a modifiedmicroscope during neurosurgery, in asimple, economical procedure.

The study compared two groups ofpatients; one group was operated on withfluorescence-guided surgery and the othergroup received the usual surgical procedureunder white light. They found that after amedian follow-up of 35.4 months, thepercentage of patients who had their


N E W S R O U N DS e l e c t e d p r e s s r e p o r t s c o m p i l e d b y t h e E S O C a n c e r M e d i a C e n t r e

tumours removed completely was higher inthe group that received fluorescence-guided surgery than in those who receivedusual surgery (65% vs 36%).

In the fluorescence-guided surgerygroup, more people survived to 6 monthswithout progression of their tumour (41%vs 21%). Furthermore, there was nodifference in serious side-effects betweenthe groups.

“This technique is an advance overolder, traditional methods, because it issimple, cheap, can be performed in real-time, and has now been put to a trulyprospective test,” claims coordinatinginvestigator Walter Stummer.

In an accompanying article, FredBarker, of the Massachusetts GeneralHospital, Boston, USA, welcomed the trial,but added that, “this study alone cannotdefinitively establish that the moreextensive removal, and not some otherunanticipated effect of the drug, led to theimproved clinical results.”

Although the drug is not yet availablecommercially worldwide, he concludes thatthe trial is likely to “encourage surgeons inpressing for more complete resections ofmalignant gliomas using the varioustechnological adjuncts that have becomewidespread over the last 10-15 years, suchas intraoperative MRI and frameless image-guided surgery.”■ Fluorescence-guided surgery with 5-amino-

levulinic acid for resection of malignant glioma:

a randomised controlled multicentre phase

III trial. W Stummer, U Pichlmeie, T Meinel, et

al for the ALA-Glioma Study Group. Lancet

Oncology 7: 392–401, published online 13 April

New research carried out by theInternational Agency for Research on

Cancer (IARC), based in Lyon, France, showsthat alcohol-related cancers are responsiblefor around 1 in 30 cancer deaths worldwideeach year.

The researchers analysed data from2002 on the prevalence of drinkers obtainedfrom the World Health Organization GlobalBurden of Disease. The information basedon relative risks of cancers of the oral cavity,pharynx, oesophagus, liver, colon, rectum,larynx and female breast was examined andthe researchers estimated the number ofcancer cases and deaths attributable toalcohol drinking.

The study found that, worldwide,almost 390,000 cases of cancer are attribut-able to alcohol drinking, this representsalmost 4% of all cancers. Among women,breast cancer appeared to make up 60% ofalcohol-attributable cancers.

The authors cautioned that the esti-mates were based on simplifiedassumptions; however, they highlight theneed for alcohol-associated cancer to betaken seriously, and raise questions aboutwhether public health recommendations onalcohol drinking need to be reviewed. ■ The burden of cancer attributable to alcohol

drinking. P Boffetta, M Hashibe, C La Vecchia,

et al. Int J Cancer, published online 23 March,

doi: 10.1002/ijc.21903

New surgical techniquefor malignant glioma➜ Lancet Oncology

Alcohol blamed for a largepart of cancer deaths➜ International Journal of Cancer


ImpactFactor

Rosin, a senior author on the paper. TheVELScope literally brings this natural fluo-rescence to light, helping dentists to answerin a more informed way a common questionin daily practices: To biopsy or not tobiopsy.”

Rosin said her group is now engaged ina larger follow-up study in Vancouver thatwill further evaluate the VELScope.“Laboratories are developing similar devicesto detect lung and cervical cancer,” saidRosin. “That means that the same basictechnology is now being used to evaluatethree tumour sites, and we can begin hope-fully to pool our data and fine-tune thecharacteristics and meaning of the changesin fluorescence.”■ Simple device for the direct visualization of

oral-cavity tissue fluorescence. PM Lane,

T Gilhuly, P Whitehead, et al. J Biomed Optics 10

April, 11:024006

Anew, simple, hand-held device may helpdentists detect high-risk precancerous

and early cancerous lesions by shining alight that causes fluorescence in oral tissue.

Tumours developing in the mouth areoften easily visible; however, determiningwhether a sore is benign or potentiallycancerous has remained scientifically prob-lematic. Early identification of high-riskdisease could greatly reduce both mortalityand morbidity due to oral cancer. This newdevice can help dentists tell whether alesion is likely to become cancerous andthus avoid needless biopsies. Oral cancersare particularly prevalent in India, where thetechnology to perform biopsies is expensiveand impractical in rural villages.

The Visually Enhanced Lesion Scope(VELScope), which was developed with sup-port from the National Institute of Dentaland Craniofacial Research, emits a cone ofblue light into the mouth that excites vari-ous molecules within the cells, causingthem to absorb the light energy and re-emitit as visible fluorescence.

Changes in the natural fluorescence ofhealthy tissue are generally caused by light-scattering biochemical or structuralchanges indicative of developing tumourcells. The VELScope allows dentists to shinea light onto a suspicious sore in the mouthand watch directly for changes in colourthrough an attached eye piece. Normal oraltissue emits a pale green fluorescence, whilepotentially early tumour, or dysplastic, cellsappear dark green to black.

The device was tested in 44 people, andin 43 of them it was found to distinguishcorrectly between normal and abnormal tis-sue, classified on the basis of biopsy andstandard pathology.

“The natural fluorescence of the mouthis invisible to the naked eye,” said Miriam

New hand-held device todetect oral cancers➜ Journal of Biomedical Optics

Children whose mothers have beenrecently diagnosed with breast cancer

need more age-appropriate informationabout the disease to cope better, accordingto a recently published study. More than aquarter of women in the Western world willhave children living at home when they arediagnosed with breast cancer. It is impor-tant for a child’s psychological wellbeing tounderstand their mother’s diagnosis andtreatment.

British researchers separately inter-viewed 37 mothers and 31 of their childrenaged between 6 and 18 years to find outabout their attitudes to the mother’s recentbreast cancer diagnosis. The study foundthat parents may underestimate their chil-dren’s needs for information in order to

protect them. Evidence from paediatric can-cer shows that giving children appropriateinformation about diagnosis and treatmentreduces anxiety. The more children are pre-pared and informed, as appropriate for theirage and development, the more it seems tohelp them cope.

Even before their mother’s diagnosis,children from seven years old were moreaware of the life-threatening nature of can-cer than their parents and other adultsrealised. Talking about cancer and deathmay help relieve children’s apprehension.Children had sometimes picked up skewedinformation about cancer through themedia, including TV adverts and soapoperas. For example, many children linkedsmoking to all kinds of cancers, includingbreast cancer, and were troubled when fam-ily members continued to smoke.

Many of the children said they wereunprepared for the consequences of theirmother’s treatment – particularly the side-effects of chemotherapy, such as the loss oftheir mother’s hair, and the length of treat-ment. Visits after surgery were also an areaof anxiety.

Children were unprepared for theirmother’s drowsiness, the number of tubesaround the bed and even the blood on thesheets and in the drainage tubes. Childrenwho had visited their mothers before theoperation in hospital and then at least twodays after the operation seemed to copebetter with visiting times.

Some of the older children expressed adesire to talk to a health professional sothat they could learn more about theirmother’s disease, and a few also expressed adesire to talk to their mother’s doctor. Olderchildren wanted a list of websites to look atfor more information.

The study recommends that parentswith newly diagnosed cancer need to besupported to think about how they will talkto their children. Some families may needtheir doctor and nurses to take part in thediscussions with the children. Familiesshould be routinely offered age-appropriate

Children needmore information to dealwith cancer in the family➜ British Medical Journal

(GIST) after failure of imatinib mesylate treat-ment due to resistance or intolerance, and foradvanced and/or metastatic renal cell carci-noma (MRCC) after failure of interferon- α orinterleukin-2 therapy. A marketing authorisa-tion under conditional approval means thatfurther evidence on the medicinal product isawaited. In the case of Sutent, this relates tothe product’s effect in terms of progression-free survival in patients with MRCC, forwhich a study is being conducted. EMEA willreview new information within one year andupdate the product information as necessary.The European Commission will now considerthese recommendations and should make adecision on the marketing authorisation ofboth products within two months.


ImpactFactor

New research from Columbia UniversityMedical Center in New York has found

that as many as 30% of patients with stageIII colon cancer who were prescribed sixmonths of chemotherapy with a combina-tion of 5-fluorouracil and leucovorin stoptheir treatment prematurely. Early termina-tion of chemotherapy for colon cancer wasshown to be equivalent to receiving no treat-ment at all. The findings add to the arsenal ofreasons why colon cancer patients, and allcancer patients, need to complete theirchemotherapy regimens whenever possible.

Previous studies have shown that notcompleting chemotherapy regimens forbreast cancer is associated with shorter sur-vival. This is the first study to look at a linkbetween mortality rates from colon cancerand treatment adherence.

“The intuitive thinking is that if youcomplete most of a treatment regimen, youshould get most of the treatment benefit.But these findings are significant because

Stopping chemo earlyhalves survival timein colon cancer➜ Journal of Clinical Oncology

The Committee for Medicinal Products forHuman Use (CHMP) of the European

Medicines Agency (EMEA) has given a posi-tive opinion to extending the use ofHerceptin (trastuzumab) to include adjuvanttreatment of early breast cancer (invasive,non-metastatic) over-expressing HER2 fol-lowing surgery, chemotherapy (neo-adjuvantor adjuvant) and radiotherapy (if applicable).

This was the first accelerated assessmentby EMEA under new EU legislation intro-duced in November 2005. The applicationwas submitted in February 2006 and a deci-sion made at the end of April. Also for thefirst time, EMEA supplied a separate ques-tion-and-answer document relating to theextension of Herceptin’s indication.

Manufacturers Roche will be asked toperform further studies on the long-termeffects of treatment with the product, partic-ularly its cardiovascular risk. Efforts will alsobe made to identify patients at higher risk ofcardiotoxicity and define monitoring require-ments. A final decision on extendingHerceptin’s indication now has to be made bythe European Commission. Normally thistakes a further 1–2 months.

Other decisions of the CHMP include apositive opinion on Bayer Healthcare’sNexavar (sorafenib tosylate) for the treat-ment of advanced renal cell cancer inpatients who have failed to respond to priorinterferon-α or interleukin-2 based therapyor are considered unsuitable for such therapy.The CHMP also adopted the first positiveopinion on the granting of a conditionalmarketing authorisation under new EU ruleson conditional approvals that came intoforce at the beginning of April 2006. It rec-ommended that Pfizer’s Sutent (sunitinibmalate) should be approved for the treat-ment of unresectable and/or metastaticmalignant gastrointestinal stromal tumours

EMEA gives positive opinionfor Herceptin➜ European Medicines Agency

Researchers from Stanford UniversitySchool of Medicine, USA, have identi-

fied a protein vital for the spread of cancerfrom one part of the body to another. Theresearch may help scientists develop newtargeted anti-cancer drugs.

Most deaths from cancer occur frommetastasis. Scientists have been trying tofind out what makes cancer cells spreadto help develop targets for anti-cancertherapies.

Cancerous tumours contain areas lowin oxygen. This seems to make the cells par-ticularly prone to metastatic growth,although scientists are unsure why. The newresearch shows that the enzyme lysyl oxi-dase (LOX) is produced at high levels inoxygen-starved human breast, head andneck tumours.

They found that patients with tumoursproducing high levels of LOX are more likelyto suffer metastases and tend to havepoorer survival.

The research demonstrated that LOXpromoted the spread of cancer cells byhelping cells invade new tissue. In a mousemodel, it was also found that inhibiting theLOX enzyme blocked the spread of breastcancer. Further research is needed to seewhether inhibiting the LOX enzymein humans would prevent the spread ofcancer cells.■ Lysyl oxidase is essential for hypoxia-induced

metastasis. JT Erler, KL Bennewith, M Nicolau,

et al. Nature 27 April, 440:1222

Potential new targetto prevent metastasis➜ Nature

information, and more literature needs tobe developed for younger children. ■ Breast cancer in the family – children’s per-

ceptions of their mother’s cancer and its initial

treatment: qualitative study. G Forrest, C Plumb,

S Ziebland. BMJ 29 April, 332:998–1003


ImpactFactor

they indicate that completing treatment is ascritical for colon cancer as it is for breastcancer – and we need to do better to ensurethat patients who can, complete treatmentas intended,” said Alfred Neugut, one of theleaders of the study.

The research team used the Surveillance,Epidemiology, and End Results (SEER)-Medicare database to identify stage III coloncancer patients who were at least 65 years ofage or older, and who received between oneand seven months of fluorouracil-basedadjuvant chemotherapy treatment.

Among the 1,579 patients who survivedeight months or longer, the 1,091 (69.1%)who underwent five to seven months oftreatment survived nearly twice as long asthe 488 (30.9%) who received only one tofour months of treatment. Patients who wereolder, unmarried and had co-morbid condi-tions, were more likely to receive less thanfive months of treatment.■ Duration of adjuvant chemotherapy for

colon cancer and survival among the elderly. AI

Neugut, M Matasar, X Wang. J Clin Oncol, published

online 17 April, doi: 10.1200/JCO.2005.04.5005

Approximately 8% of patients withmelanoma may develop an additional

melanoma within two years of their initialdiagnosis, and those with atypical molesappear to be at higher risk, according to arecent study.

Cutaneous (skin) melanoma begins incells known as melanocytes, which producethe pigment that gives skin its colour. Previousstudies have evaluated the recurrence ofmelanoma among patients already diagnosedwith the disease; most have estimated thatless than 4% of them will develop additionaltumours in the year following diagnosis.

Linda Titus-Ernstoff, of the DartmouthMedical School, New Hampshire, USA, andcolleagues, assessed the frequency of andrisk factors for recurring cancer among 354New Hampshire residents with a first diag-nosis of cutaneous melanoma. Participantscompleted a 40-minute telephone inter-view, during which they answered questionsabout medical history, demographics,eye and hair colour, sun exposure andwhether their skin tanned, burned orfreckled in the sun.

They then underwent a skin examina-tion, during which a physician identifiedand catalogued benign and atypical moles.Atypical moles have at least three of thefollowing features: a diameter larger than5 mm, redness, an irregular or ill-definedborder, a variety of colours or a portion thatis flat.

By examining pathology records, theresearchers found that 20 (6%) of theparticipants developed an additionalmelanoma within one year of diagnosis and27 (8%) developed an additional melanomawithin two years. Sixty-three percent ofthose who developed additional tumoursand 37% of those who did not had at leastone atypical mole. The more atypical molesan individual had, the more likely he or shewas to develop additional melanomas –three or more atypical moles indicated fourtimes the risk. Lifetime history of sun expo-sure did not appear to influence the risk ofrecurring melanoma.

“The importance of studying risk foradditional primary tumours within adefined population-based study group isunderscored by our findings,” they con-clude. “These findings, which indicate ahigher frequency of second primarymelanomas than suggested by previousstudies, also underscore the importance ofclose surveillance of patients withmelanoma.”■ Multiple primary melanoma: two-year results

from a population-based study. L Titus-Ernstoff,

AE Perry, SK Spencer, et al. Arch Dermatol, April

2006, 142:433–438

Some melanoma patients atrisk of additional tumourwithin two years➜ Archives of Dermatology

The World Health Organization (WHO) isurging research institutions and compa-

nies to register all clinical trials, includingphase I trials, whether they involve patientsor healthy volunteers. As part of theInternational Clinical Trials Registry Platform,a major initiative aimed at standardising theway information on medical studies is madeavailable to the public, WHO is also recom-mending that 20 key details be disclosed atthe time studies are begun.

Before making the recommendations,the Registry Platform initiative consultedwith all concerned stakeholders, includingrepresentatives from the pharmaceutical,biotechnology and device industries, patientand consumer groups, governments, medicaljournal editors, ethics committees, and aca-demia over a period of nearly two years.

Currently, there are several hundred reg-isters of clinical trials around the world. Theplanned Registry Platform will not be a regis-ter itself, but rather will provide a set ofstandards for all registers. It has not onlystandardised what must be reported to regis-ter a trial but is creating a global trialidentification system that will confer aunique reference number on every qualifiedtrial.

“Registration of all clinical trials and fulldisclosure of key information at the time ofregistration are fundamental to ensuringtransparency in medical research and fulfill-ing ethical responsibilities to patients andstudy participants,” said Timothy Evans,Assistant Director-General of the WHO.

Later this year, the WHO Registry Platformwill launch a web-based search portal where scientists, patients, doctors and anyone else whois interested can search among participatingregisters for clinical trials taking place or completed throughout the world.

WHO announcesnew standards for clinicaltrial registration➜ World Health Organization


Bookcase

➜ Raphaël Brenner

To screenor not to screen?

Conventional wisdom about cancerscreening is that all screening is

good. After all, patients and healthproviders alike have been infused withthe notion that the earlier cancer isdiagnosed, the better for all. But realityis not so simple, asserts Gilbert Welch,professor of Community and FamilyMedicine at Dartmouth MedicalSchool in New Hampshire, USA. Inhis thought-provoking book, Welchurges caution on the matter and con-tends that forgoing cancer screeningcan sometimes be a reasonable option. Screening, that is, testing asympto-matic people at regular intervals,is now a well-established practice inthe field of cancer prevention.Mammograms, blood tests for PSA(prostate specific antigen) and faecaloccult blood testing (for colon cancer)are among the most frequently giventests. However, as Welch points out,cancers that grow fast (interval can-cers) are the type of cancers whichtests are most likely to miss, since theyappear in between tests. Few ran-domised trials have been carried outfor cancer tests, and when they have,proof of effectiveness was minimal. Adetailed analysis of randomised trialscomparing groups screened withgroups not screened by mammography

or faecal occult blood testing showsonly a tiny reduction or none at all inthe overall mortality of the screenedgroup. The statistics are also mislead-ing, particularly regarding five-year

survival rates for cancer screening. Inhis fascinating chapter on the subject,Welch points out that the apparentimprovement in five-year survival ratesis often the result of diagnoses beingmade earlier. What really matter aremortality rates, and these have notimproved, at least for some cancers.Welch does not try to dissuade thepublic from screening for cancer. Heacknowledges that tests may greatlybenefit a few people, but he objects to“the emerging mindset that patientsshould be persuaded into undergoing

tests” and to the prevailing “medicalcorrectness” regarding the subject.For the vast majority of people, evenwith the most sophisticated screeningtests, the benefit is limited, and

contrary to the prevailing pre-sumption that “it can’t hurt just togather a little information”,screening for cancer can be detri-mental. Tests are imperfect andthe chances of a false-positiveresult over time are quite high –around 10% for mammograms.False-positive tests and ambigu-ous results not only cause anxietyfor patients, they can also trapthem into an endless cycle of test-ing and potentially risky biopsies. The truth is that some cancers –

collectively referred to as pseudo-disease – do not progress, or progressso slowly that they will never producesymptoms or require treatment. This isthe case with certain neuroblastoma,small kidney cancers, small prostatecancers in older men and even, saysthe author, early forms of breast cancer(ductal carcinoma in situ). For suchcancers, watchful waiting, says Welch,can be a reasonable strategy, because“the risks of treatment are greater thanthe risks of inaction.”As it happens, screening and pseudo-

Should I be Tested for Cancer? Maybe Not and Here’s WhyH. Gilbert Welch University of California Press, 234 pp, £12.95

Prédisposition génétique aux cancers:questions psychologiques et débatsde sociétéCoordinated by C. Julian-Reynier, J. Pierretand F. Eisinger John Libbey Eurotext, 128 pp, euro 30

Screening healthy people for cancer is a double-edged sword: while tests may help,

disadvantages can often outweigh the benefits. Eminent physician Gilbert Welch argues

forcibly for a less test-oriented, more human approach.


Bookcase

disease go hand in hand: the harderone looks for cancer, the more one islikely to find it. The problem, as Welchillustrates through numerous case his-tories and studies, is that “the more wefind, the more likely it is that what wefind is a pseudodisease. A downside oftesting is that you might find a canceryou would rather not know about.” Beyond establishing concretely thatscreening is a thorny and complexissue, Welch is to be praised for ques-tioning the ethos of modern medicalpractice. In what is probably the mostprovocative chapter in his book,“Understand the Culture ofMedicine”, Welch graphically demon-strates to what extent cancer screeningis promoted by the medical world: byphysicians, (because of their fear ofmalpractice suits, because of financialincentives, etc.), by the managerialhealth providers, and by medicalresearchers who have vested interestsin ‘proving’ the effectiveness of newtests. Alas the culture of medicine isalso a culture of pride and prejudice:no matter the evidence-based facts,when it comes to cancer screening,there are forces at play that precluderational discourse on the subject. Practically, Welch urges patients todevelop a healthy scepticism and par-ticipate more in decision-making: heurges them to ask questions, particu-larly whether it is worthwhile undergo-ing screening. Even if for most people,the most likely outcome of cancerscreening will be neither beneficial norharmful, Welch argues that “it is stillimportant to think about the decision,because not every choice will neces-sarily be right for you.”In addition to explaining clearly thepros and cons of cancer screening,Welch has produced an indispensablebook that injects good sense and ahuman dimension into a field of me-dical decision-making that is dominat-

ed by hype. In daring to question thedoxa of modern medicine, he hasshown that not everything that is pos-sible should be done and not every-thing that is new is beneficial. Allpatients intending to undergo specificcancer screening tests should read thisbook beforehand. So should theirphysicians, for it will permanentlychange their views on testing.Genetic testing for cancer even moredramatically raises the question: “Whatshould one do if a test proves positive?”The problem, as Julian-Reynier andher colleagues point out in their book,is that in the case of BRCA mutations(in breast cancer) as in other muta-tions, science has outpaced clinicalunderstanding of what to do with thedata. Since there are no clear-cut med-ical recommendations, once a testproves positive, genetic testing simplyopens up a Pandora’s box. NonethelessJulian-Reynier’s book strongly supportsgenetic testing for high-risk groups. Itspecifically focuses on the societal,psychological and economic issuesconnected with genetic testing forbreast and ovary cancer susceptibilityand stresses the importance of psycho-logical support for patients testing pos-itive. Interestingly, it emerges, fromstudies on how people at risk deal withthe issue when a cancer gene has beenidentified in a member of their family,that more than 20% choose not toundergo genetic testing, preferring tostay in the dark and live their livesfreely.As for broad-based genetic testing forlow-risk groups, given the uncertaintyand fear associated with a cancer diag-nosis, testing here can be more detri-mental than beneficial. The risk, asWelch notes in his book, is that “test-ing further distracts from the practiceof medicine: rather than making sickpeople well, we end up making wellpeople sick.”

Although metastases represent themost serious complication in

cancer and most metastatic cancersare considered incurable, quiteremarkable progress has been madein the quality of life of cancerpatients with bone metastases – andin our understanding of the bonemolecular and cellular mechanismsinvolved in osteogenesis and osteo-lysis and their development for thera-peutic purposes. This fact and theoptimism it has generated is the rai-son d’être of the Textbook of BoneMetastases, by Claude Jasmin et al,which highlights recent advances inall fields related to bone metastasesand provides physicians with the ele-ments needed in the clinical andtherapeutic management of patientswith bone metastases.Accordingly, the first part of the bookfocuses on metastatic disease andcovers biology, epidemiology, clinicalaspects and assessment of patients.More than two thirds of this part isdevoted to the different types oftherapy available: surgery, interven-tional radiology, endocrine treatment,chemotherapy, plus an excellentreview of the direct and indirect anti-tumour effects of bisphosphonates.

Textbook of Bone MetastasesEdited by Claude Jasmin, Robert E.Coleman, Lawrence R. Coia,Rodolfo Capanna and Gérard SaillantWiley, 582 pp, £195


Bookcase

The chapters on the biology of bonemetastases are of particular interest.They show that the detection andtreatment of micrometastatic diseasestill represent major challenges inoncology. The second part of thebook offers a global approach to thetreatment of patients, including man-agement of pain, psychological andsocial aspects and the special atten-tion needed for treating the elderlyand children. A third section coversspecific tumours, notably breast andprostate cancer, the two solidtumours which most often give rise tobone metastases.

Ilike to be surprised. “Anotherguide for people with cancer!” I

thought as I began to peruse thisbook, but quickly discovered that myinitial assumption was altogetherunfounded. The first reassuring factwhich sets this book apart is that thetwo editors consist of an oncologistand a psychiatrist, and roughly half ofthe 38 co-authors are psychiatrists.This may seem strange, but it reflectsprecisely the ethos that underscoresthe book, which is the inexorable

inter-connection between body andmind.Practically speaking, Facing Cancercombines top-tier medical informa-tion on cancer and its causes (includ-ing a comprehensive glossary), withcompassionate counselling andattention to the emotional aspects ofdealing with the illness. The bookexplores the various aspects of cancer– epidemiology, screening, diagnosis,and treatment (including alternativeand complementary therapies), tak-ing into account not only patients,but also their families and caregivers.“Families experience the same levelof distress as do people with cancer,”notes Erika Ryst, who argues thatcancer, as such, should be consid-ered more of a “familial disease” thanan individual problem. For this rea-son, the book deals extensively withthe impact of cancer on families andhow to help children cope with a par-ent’s cancer. The guide is organisedin short easily readable chapters(written in plain English but neveroverly simplistic or patronising), inwhich issues are formulated as ques-tions posed by patients. The chapteron new therapies and protocolsincludes, for instance, sections titled“What are the phases of clinical tri-als?” “What is informed consent?”and “What is a placebo and could Ireceive one?” But the originality of this book liesmainly in the emphasis it places onpsychological issues and ondeveloping coping strategies for allthose involved and at every stage –from the point of receiving adiagnosis of cancer to the stage ofloss and bereavement. Attention isalso given to understanding themeaning of cancer for children, stressreactions in caregivers, psychologicalinterventions and support groups.There are also original chapters on

how cancer is portrayed in the mediaand on the role of faith in the lives ofpatients with cancer. Through itsholistic, humane and sensitiveapproach to the disease, this trulyoriginal guide for patients and theirfamilies will help to fulfil the editors’aim “to make the [cancer] journeyless frightening, less painful, and lesslonely.”

Facing Cancer: a Complete Guidefor People with Cancer,their Families, and CaregiversEdited by Theodore A. Stern andMikkael A. Sekeres McGraw-Hill, 474 pp, $19.95

Patients diagnosed with cancer ofthe larynx or tongue often feel so

overwhelmed by what may lie aheadfor them, they are unable to absorb allthe information provided by theirhealthcare professionals. This guide-book steps in to fill the gap. It offersaccurate, practical data, with manyprecise illustrations (about anatomy,equipment and processes), on the var-ious treatments for cancer of themouth and throat and therapies forspeech and swallowing impairmentscaused by cancer and cancer-fightingtreatments. A highly useful bookwhich may help patients with this typeof cancer feel more able to cope.

Looking Forward…The Speech and SwallowingGuidebook for People withCancer of the Larynx or Tongue4th editionJack E. Thomas and Robert L. Keith Thieme, 138 pp, euro 12.95

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