IT’S FUTILESo why do we do it,

and how can we stop?

A NEW TOOLIN THE ARMOURY?

Immunotherapies have neverlooked more promising

THE FATAL ALLURE OFALTERNATIVE THERAPIES

One woman’s story of howshe lost her chance to be cured

September-October 2012 Number 50

CancerW

orld50

September-O

ctober2012

3 EditorialPersonalised medicine: a note of caution

4 Cover StorySiddhartha Mukherjee: explaining cancer

14 Cutting EdgeWe told you so: how the persistence of immunotherapyresearchers is finally paying off

22 CrosstalkFutile care: why does it happen, how can we avoid it?

28 Best ReporterIn the jungle of the miracle healers: an award-winning articleon the seductive powers of alternative therapists

37 e-Grand RoundHow exposure to a mother’s cancer treatment during pregnancyimpacts on the child

46 Spotlight OnHow bad news can be good news for cancer services

52 Impact FactorFor localised prostate cancer, does technology equal progress?Gemtuzumab ozogamicin in acute myeloid leukaemia

60 NewsroundSelected news reports

64 My WorldThe challenges and rewards of working in cancer

EditorKathy Redmondeditor@eso.net

Assistant EditorAnna Wagstaff

Editorial AssistantAlexandra Zampetti

Editorial AdvisorsJacques BernierFatima CardosoFranco CavalliAlberto CostaVincent T. DeVita

Contributing WritersBernhard Albrecht, Marc BeishonMatthew R Cooperberg, Simon CromptonJanet Fricker, Hagop KantarjianPeter McIntyre, Farhad RavandiAnna Wagstaff

Publishing AdvisorsGillian Griffith, Fedele Gubitosi

Website LiaisonAlexandra Zampetti

Art EditorJason Harris

ProductionHarrisDPIwww.harrisdpi.co.uk

Printed byGrafiche Porpora

Cover photographPeter Foley

Published byEuropean School of Oncology

Direttore responsabileAlberto Costa

Registrazione Tribunale di RomaDecreto n. 436 del 8.11.2004

All enquiries about Cancer Worldshould be made to:ESO Editorial OfficeVia del Bollo 420123 Milan, Italye-mail: magazine@eso.netTel: +39 02 8546 4522Fax: +39 02 8546 4545All correspondence should be sentto the Editor at editor@eso.net

Copyright ©2012 European School of Oncology.All rights reserved

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

1

3

ailoring a patient’s treatment tothe particular biology of theircancer holds out the enticingprospect of avoiding over-treat-ment and reducing unnecessary

toxicity – patients and cash-strapped healthsystems both stand to benefit. But deliveringthe right option for the right patient at theright time takes more than having the rightbiomarkers.And success in developing pre-dictive biomarkers and targeted drugs has sofar beenmodestwhen compared to the time,money and effort invested.

All of which gives cause for concern thatsomany people are jumping on the ‘person-alised medicines’ bandwagon and are push-ing national and European policy makers tomake this a priority.

The problem lies not with personalisedmedicine per se. Medicine has always beenabout tailoring treatment and care to apatient’s particular disease, age, comorbidi-ties and preferences. The problem is thatwhen the term ‘personalised medicine’ isused today, the focus is on one aspect of tai-lored cancer treatment – the use of targeteddrugs and predictive biomarkers.

Weknow that translating scientific know-how into clinical reality is a highly uncertainbusiness. History is littered with scientificfailures that once appeared highly promisingbut ended up on the scrap heap. So far onlyaminority of cancer patients havederived sig-nificant benefit from targeted drugs, andthat is not likely to change much in theimmediate future.Arguing in favour of put-

ting all our eggs in the ‘personalisedmedicine’basket is therefore a flawed strategy thatrisks creating unrealistic public expectations.

It also takes the focus away fromaddress-ing obstacles to delivering personalised carethat we do know how to overcome. Muchmore public funding is needed to conductthe optimisation studies that can show howbest to use the the therapies we alreadyhave. Then there is the question of deliver-ing personalised cancer care in everydaypractice.Urgent action is required to improvecancer services, so every patient receivesthe attention of the rightmix of specialists, toplan and deliver care tailored to their needs.

And finally,whilewecertainly need to vig-orously pursue the potential for developingtherapies designed using our knowledge ofcancer genetics, the current heavy focus ondrugs is too narrow.What about the potentialfor more precise tailoring of surgical andradiotherapy strategies, which currentlyaccount for only a tiny fraction of researchinto personalised therapies?

Weneed tobecareful about themessageswe sendout.Thebiggest potential for improv-ingcanceroutcomesover thecomingyears liesin redesigning health systems to give allpatients, regardless of cancer type, access tohigh-quality treatment andcare fromamulti-disciplinary team of specialists. If we call forpolicy makers to focus instead on a scientificpotential that might never reach the main-stream, we risk giving them a green light toshirk their duty to do what they must do toimprove the delivery of cancer services.

4

ust who is SiddharthaMukherjee? Thisis thequestionmanyveteransof thecan-cer community asked as a book by thisunknown author began to win criticalaccolades and prizes last year, including

the Pulitzer Prize for non-Fiction and the GuardianFirst BookAward, earningMukherjee a place amongTIMEmagazine’s 100most influential people.Less than two years since publication, The

Emperor ofAll Maladies:A Biography of Cancer hassold between half a million and a million copies, isbeing translated into20 languages, andcontinues togenerate around50emails to the author aday. “Iwascompletely overwhelmed by the generosity of theresponse,” says Mukherjee, currently a practisingoncologist specialising in haematological cancers atthe Columbia University Medical Center in NewYorkCity. “By thesizeof it, byhowdiverse it is, byhowdiffuse it is. From students and general lay readerswho said ‘I was never interested in this question tillI read thebook,’to scientists at theNational Institutes

of Health who write thanking me for providing anoverview. Different people come at it in differentways.For somepeople it gives themsolace, for someit activates them.Youngmen andwomenwrite andsay ‘I nowwant tobea scientist, a cancer researcher’.This happens literally everyday.”His celebrity statusis such thathewasevenapproachedbyagroupof stu-dents while on a trip with his kids toDisneyland.ReadingMukherjee’s ownbiographical noteswill

tell you that he reached his current position as assis-tant professor ofmedicine atColumbiaUniversity, inchargeof a translational research labat theUniversity’sIrvingCancerResearchCenter, throughanacademicresearch route,with the clinical practice comingonlylater.Bornandeducated inNewDelhi, India,hewenton tomajor in biology at StanfordUniversity,Califor-nia, where he worked in Nobel Laureate Paul Berg’slaboratory defining cellular genes that change thebehaviours of cancer cells. A Rhodes Scholarshiptook him to Oxford, where he earned a DPhil inimmunology. Only then did he train as an MD at

With our new-found understanding of cancer biology comes the opportunity to explain

a disease that for centuries has confounded doctors and engendered stigma and

superstition. Siddhartha Mukherjee took that opportunity and turned it into a best seller.

5

HarvardMedicalSchool,wherehecompletedhis res-idency in internal medicine followed by an oncologyfellowship atMassachusettsGeneralHospital.His research focuseson the linksbetweennormal

stem cells and cancer cells, specifically probing themicroenvironmentof stemcells –particularly blood-forming stemcells. It has attractedgrants frommanysources including a coveted Challenge Grant fromthe National Institutes for Health, and generatedpapers published in journals includingNature,Neu-ron and the Journal of Clinical Investigation.Mukherjee, then, couldbe summedupasoneof

the newgeneration of translational researcherswho

is exploringoneofmany interestingavenues thatmayoffer newopportunities for intervening in processesthat generate and fuel certain typesof cancer growth.None of this, however, offers a clue as to why he

ended up being the first person to explain to a massgeneral readership thenatureof this frightening,mad-deningly elusive,multifacetedenemy that formillen-niahashaddoctors, cancerpatientsandsocietyat large P

ETERFOLEY

asking: what is this thingwe are up against?For Mukherjee, however, the real question is

why no one else had already done it. “When I wastraining as a fellow in cancer medicine what wasamazing tomewas that suchabookdidn’t exist.Hereis a family of diseases that will affect one in two orthree of us, and we don’t have a sense of whatbrought us to this point andwhatwemight bedoingnext.So that ishowthebookbegan tobewritten.Butmyapproach to thiswasn’t towrite a600-pagebook.Really Ibegan tokeepa journal; itwas a verypersonaljourney forme to start with.”It didn’t take him long to realise that his need to

understandwas shared, evenmoreurgently, bymanyofhispatients, and thebook thenalso tookon the taskof trying to respond to their needs.“Every time you treat a patient in the hospital,

onceyou’ve allowed themtogetused to themadnessthatmodernmedicine is, the first question patientswant to know is:Why do I have this?What is goingon?Whatdo Idonext?That is their firstmechanismof grapplingwith the disease, long before diagnostictests and therapeutics kick in.”If people don’t get an answer they can make

sense of, says Mukherjee, they reach out forother explanations,whichcan range fromnihilism–

cancer is too complex, too evasive; nothing can bedone – to conspiracy theories. He recalls a talk hegave at a healing retreat for womenwith breast can-cer, involvingyogaandmeditation, as “oneof themosthostile environments” he has ever been in. “Theconversation went like this: ‘Is it not obviously clearto you that there are abundant environmental car-cinogens that you knowand that I knoware causingbreast cancer?And if youknowandIknow,whyhavewe not been able to change the world and removethese environmental carcinogens?’”Heoftenencounterspatientswhoare convinced

that pharmaceutical companies are hiding the realcureandare incahootswith thegovernment, or therearealternative therapies thatwill cureall cancers, butno one wants to invest in them and refine them.“These theories really aboundacross a swatheof thisand other countries.”Understandably, saysMukherjee, these percep-

tions corrode the relationship between doctors andpatients that is so essential to practicemedicine. “AsI point out in my book, there is reason to be suspi-cious.The relationshiphasbeencorroded in thepast.But Ihope thebookprovides aperspective across thecenturies about the complexity of theproblem, howit has been tackled, correctly and incorrectly, what

6

PETERFOLEY

beendecoded.The virologistswhosediscovery of theso-called “Rous sarcoma virus” in chickens lent cre-dence to the theory thatcancer is an infectiousdisease,leading to a fruitless decadeof fevered searching for asingle viral cause, which made little sense given thewider evidence.Mukherjeedescribeshis book as ‘amanifesto for

humility’, and says he wanted to show that sciencedoesn’t exist in “some kind of anArcadian realm ofperfect truth and honesty”, but is in fact a veryhuman project, “and therefore susceptible to thesamefoibles that anyhumanproject is susceptible to:egos andmistakes and attachments to theories thatthen don’t get unattached from your brain.”Every character in the book is real, he says, and

shares the benefits, but also the paralysis, of being avisionary. “Thevisionbecomesanobstruction. Imadea point of trying to identify, to isolate, thosemomentsin which the vision occurs and then the vision itselfbecomes ablock. It’s true ofmost of the characters ofthis book. They have the simultaneity of humangenius andhuman flaws. It becamea story of humanbeings trying very hard, and sometimes failing veryhard, to work their way aroundwhat is clearly one ofthe seminal problems of the 20th century.”Thebook is notwithout critics.Many researchers

question the choice of what to include and what toleaveoutof thebook. “The lodestonewasanything thatmadeadifferencedirectly in the livesofpatients,” saysMukherjee. “Someoneaskedme:What about telom-eres? I said that is a very interesting theory and it willmake itself into this book when you findme the firstmedicine that canmodify telomeres in a real humanbeing andmake adifference in their lives.Evenwhatabout Avastin? If you were writing about maculardegeneration, that bookwould have to have a centralrole for a drug like Avastin. But has Avastin reallychanged thewaywe thinkaboutand treat cancer?Notreally. Itwasawonderful theory, and thenmet theuglyfacts. Does it make a huge difference? No. Not inbreast cancer and barely in colorectal cancer.”Mukherjee has also faced criticism for choosing

wrong roads we went down, and how we workedourselves back.”Thechallengeof explaining suchcomplexities to

a lay audience may be one reason why no one hasattempted such a book before, and this one cer-tainly does not lack ambition. It took Mukherjeeseven years from start to finish and it is no ‘Idiot’sGuide’. Among its more scientific passages, forinstance, is a highly accessible, but nonethelessdemanding, description of themechanism of retro-viral transcription. But by that point in the book thereaderhas alreadybeendrawn into adramatisedhis-toryof thebreakthroughsand false trailsbywhich thetrue nature of cancer was being revealed, in fits andstarts, glimpse by glimpse, through a diverse paradeof protagonists from specialisms ranging from epi-demiology tobiology, pathology, surgery,haematology,internalmedicine, radiology, virology and genetics.These individual stories arewoven together into

a tragic-heroic detective story, an odysseywhere thetrail frequently diverts up blind alleys, led there bygifted, dedicated and courageous specialists whoareoften toocertainof their ownvision topickupandinterpret clues that should have turned them inanother direction.The surgeonswho insisted for decades, andwith-

out evidence, that theonly reason for recurrences andmetastatic spread following breast cancer surgerymustbe that theyhadused too small amargin, and theonly remedywas tochopoutever largerchunksof theirpatients’ upper torsos. Themedical oncologists who,after the great initial breakthroughs using multidrugregimens to treat acute leukaemia andHodgkin’s dis-easewenton toapply the sameprinciples to advancedbreast cancer, treating up to 40,000 women withextremely toxic therapies before discovering that theonly evidence of benefit was generated from a fraud-ulent trial in Johannesburg. The geneticists who dis-covered the structure of DNA, which was to provesuchan important part of thepuzzle, but insisted thatNixon’s proposedwar against cancerwouldbea futileexerciseuntil every last geneof thehumangenomehad

“I made a point of trying to identify moments in which

the vision occurs and then the vision becomes a block”

7

to call the book a biography, on the grounds that itanthropomorphises cancer, attributing to it charac-teristics of ananimateenemy rather thanabiologicalphenomenon. “It’s createdquite abacklash,” he says,“though there isnosentence in thebook thatdoesanyof thatexceptwhenquotingpeople talkingabout theirillnesses in very human and personal terms.”And while the book has certainly been widely

welcomed by the oncology and science community,there may also be a hint of regret among some whowere centre stage during many of the most excitingyears, that this extraordinary tale ofhumanendeavourended up being told by someone who had not beenthere at the time. “My take on this is that you had tobeanon-expert towrite thisbook. It is crucial.Youhavetohave the vulnerability towritewithouthaving to sayyouare thebig expert.”Hepoints out thatmanyof themostmoving and seminal books inmedicine recentlywerewrittenbypeoplewhoare relatively young to thefield. “AtulGawande,writing in theNewYorker aboutsurgical error,wrote that as a young resident in surgery,just after his fellowship, because he could see thatworld for what it was, with fresh eyes.”Ironically, perhaps, thebookMukherjeewrote as

a ‘non-expert’haspropelledhimonto theA-list of invi-tees to speakat countless seminars andconferences.Havingoutlined soelegantly thehumanobstacles tomakingprogress, surelyhecanoffer somesolutions?He does not duck the challenge. The big issue

rightnow, saysMukherjee, is converting the tremen-dous gains of scientific research into human medi-cines. “The level of diversity that has been revealedevenwithinonecancer let aloneacross cancers, andthe level of evolutionarypressures that are operatingin a single cancer cellwouldhave left someone fromthe 1950s shocked. So we have all this knowledge,

and thepublic is asking, andweare all asking:whereare themedicines that come out of this knowledge?“I talk in the book about this metaphor that sci-

ence inevitably produces a boil that lets itself out assteamthrough technology.But if youare living in theworld of cancer, there is a lot of boil, especially fromthe basic science world, but there is little steamwhichwouldmake theenginemove.So thequestionwe are asking ourselves is:Where is it?Howcanwetransformbreast cancer so thatwecan treat, say, triplenegativebreast cancer inaway thatwecouldnotevenhave imagined four or five years ago.”One problem, he argues, is a lack of innovation

from the pharmaceutical industry. “I’m waiting forgood exemplars of this change in which the drugemerges from research performed primarily bybiotechorpharmacompanies. I’veyet to see that.Thereality typically still remains investigator-initiatedtrials or protocols. The drug company possessessome IP [intellectual property rights] around amol-ecule and investigators around the world go to thecompanyand say, look youhave thismolecule, allowus to test it in a particular disease. Then if there issomething real there it catches fire.But the initiativestill lies with the clinicians and translationalresearchers, even today.”Comparisons that have been made with other

industries with a similar focus on turning academicknowledge into marketable technologies – the ITindustry for example – Mukherjee finds unillumi-nating. “It reduces theproblemofcancer toa systemsanalysis and information systems problem, which itisn’t. It is vastly more complex.”And he doesn’t buyinto the idea that progress is being strangledbecausecommercial secrecy is tying up vital information. “Itwould be possibly if therewere dozens of things out

“My take on this is that you had to be a

non-expert to write this book. It is crucial.”

“We have all this knowledge, and the public is asking:

where are the medicines that come out of it?”

8

looks stable. There’s something there.’ In the olddays of chemotherapy, youwould say, ‘This is a non-sense intuition.’Thiswouldbeprecisely thedrug thatyouwould discard.”The BOLERO trial of Afinitor used in patients

with advanced hormone-receptive breast cancer,who are resistant to endocrine therapy alone, is oneof the few thatMukherjee admits could turn out tobe ‘transformative’.Callingupagraphcomparing pro-gression-free survival between thoseonanendocrineinhibitor aloneand those additionally given themTor

there tobesecretiveabout. It’snot clear tomethatwehave that level of innovation yet. Pharma keepstelling us it has things up its sleeve that are deeplytransformative. I haven’t seen them.”He concedes, however, that these things can

take time. “The claim is that a lot of innovation isgoingonwithin thepharmauniverse,butwecan’t seeit becauseby its verynature it’s hidden.Fair enough.Let’s say it happens in about adecade.Theclockhasjust begun.Wewill find out if it is true or not.”Moreanddeeperunderstandingof cancerbiology

will of course continue tobe important, but this is notwhere the blockage lies. What is needed now, saysMukherjee, is tobringmore talentedchemists into thefield to help answer the question of how to intervenein the potential targets that have already been identi-fied.Heexpects a strongcontribution to this effortwillcome from the pool of expertise that is developing inIndia andChina, among other emerging economies.“Hopefully they will bring a whole new wealth ofideas, chemical ideas.”Ironically perhaps, theother areaof expertise that

Mukherjee argues is becoming increasingly impor-tant in developing newdrugs comes from the tradi-tional skills of the clinical practitioner. “You needbetter old medicine to understand new drugs. Yourclinical skills have to be more astute than ever,because the variables have become so complex.That was not the case when you were giving cyto-toxics.Nowyouare interveningonextremely specificaspects of humanphysiology and youneed to knowhow to follow those.” He cites the example of thedoctors who first began to notice a correlationbetween rash and response in the EGFR-inhibitorErbitux (cetuximab). “Youneed a very astute physi-cian to pick that up and say, ‘There is somethinghere. This rash out of the hundreds of rashesthat happen to people on chemotherapy,seems to have something to do withresponse.’This has initiated awhole newfield of understanding.”Thedevelopmentpathof themTor

inhibitor everolimus (Afinitor) isanother good example, he says. “Thephase Ipeoplewho first tested thedrugonpatientswithkidneycancer said ‘It’snotas if thedrugweremelting the tumouraway,butwesee thesepatients comingback,they feelbetter, they lookbetterandtheirdisease

9

PETERFOLEY

from now we will conclude that this is not the bestway to go. But you cannot go somewhere else with-out being here now.”Mukherjeehimself seems to accept no limits on

his intellectual curiosity. In midApril theNewYorkTimesmagazine carried a feature piece he wrote onthe science andhistory of treating depression, titled‘Post-ProzacNation’, where he applies his detectivewriting skills to trying tomake senseof another jour-ney of scientific discovery that has beenmarked bygreat hopes of a magic bullet followed by disap-pointment, conspiracy theories and distrust.At the same time, hehas taken great care to sus-

tain his hands-on clinical practice, though this hasbeen tricky in thewakeofhisnew-found fame, to theextent thathe finds it veryhard tokeephisclinical andresearch agendaon track.Overloadedwith requestsfrom people wanting second, third, fourth or evenfifth referrals, he tookapragmaticdecision to removethat pressure. While he takes his turn caring forpatients on the ward, he hasmoved his entire clini-calpractice to the ‘fellows’clinic’,which is run forpeo-ple with no medical insurance and often no properlegal status. “Not because I’m a saint,” hehastens toadd, “but because it wipes the slate clean of all theaccess issues.”Mukherjeedoesnot encouragediscussionof his

backgroundor family, though thewideuseof literaryallusionsand thegeneral accessibility of the structureand style of his writing has, rightly or wrongly, beenat least partially credited to the influenceofhis artistwife Sarah Sze, and he clearly revels in intellectualstimulus fromalmost anydirection.He talks of him-self as having multiple lives, “or at least dual lives,”centred around patients. “Every time I think aboutanything that is relevant, for instance trying tounder-stand how we ended up with this hypothesis ofdepression in2012, andwhat thenext steps are, I goback topatients. So this life is very important forme.It keepsmealive and it keepsmybrain alive in awayIhave toprotect, otherwise I cannotkeepworkingonothermore abstract things.”

Remembering the lessons of his own book,

Mukherjee is careful not to get too carried away

inhibitor, heputs his finger between the twocurves.“It fits the famous ‘BobMayer rule’[namedafter theeponymous Harvard professor at the Dana-FarberCancer Institute]: if youcanput a fingerbetween thetwo arms it is real, if not youmight aswell discard it.Weneedmore of these things that reallymake a bigdifference in survival.”He is also excited about GlaxoSmithKline’s trial

combiningBRAF therapywith immunological ther-apy againstmelanoma. “This is anobvious idea, see-ing what will happen if you can combine targetedtherapy andmicro-environment-directed therapy orimmunology-directed therapy. Presumably theimmunology-directed therapy will have completelydifferent pathways and be non-redundant with tar-geted therapies that are autonomous to the cancercell. This is the kind of stuff that really excitesme.”Remembering the lessons ofhis ownbook, how-

ever, Mukherjee is careful not to get too carriedaway. As he says, the reality is that there are morewomen who have been cured or benefited from“boring old chemotherapy” for early breast cancerthanany targeted therapy for any cancer. “Theques-tion is: where are we going?Havewemade anothermistake?Arewewrong in thinking that theway for-ward is to target the cancer cell? Maybe five years

10

PETERFOLEY

14

system to fight cancer have com-manded sporadic interest but onlylimited success, a flood of recentresearch findings have earnedtheir place in top journals andASCO presentations, with promisingtrial results and a big pipeline ofnew agents.

class of therapy that haslong held promise fortreating cancer patientsmay finally have come ofage. Immunotherapy, or

biological therapy to give the broad-est term, can use the body’s immunesystem in a wide variety of ways, by

directly attacking tumours, control-ling factors that allow tumourgrowth, using vaccines to preventbut also to treat cancers, helpingrepair damage from other treatments,and more. Now, after more than acentury in which the tantalising pos-sibilities for harnessing the immune

With two novel immunotherapies approved and many more in the pipeline, is it time

to announce that a new treatment modality has emerged?

How the persistence of immunotherapy researchers is finally paying off

15

There are two reasons whyimmunotherapy has now gainedsuch traction, says ChristianOttensmeier, professor of experi-mental cancer medicine at theUniversity of Southampton in theUK. “We’ve had a poor understand-ing of how the immune systemworks– but that is changing rapidly withwork on chronic infectious diseasessuch as malaria, TB and HIV, as wellas cancer – they are cross-fertilisingand similar questions are being asked.Second, our tools are much better –we had quite rudimentary ways oflooking at immune response, but inthe past 10 years there has been anexplosion in what we can deliver formeasuring immunity. Being able tomeasure in more detail the differentfacets of the immune system, and inways that others can reproduce, is amajor contributor to the field.”As a result, he adds, we are now

in a better position to study one ofthe least explored approaches thathave the potential to improve out-comes for cancer patients. “There isalso a rapidly accumulating body ofevidence to indicate that immuneattack on cancer is critical, and look-ing at it just numerically in the tissueis a very powerful tool for predictingoutcomes – so there is a strong argu-ment that improving outcomes canbe achieved through improvingimmune responses. And there is a

Investment analysts, never slow tospot trends, suggest we might beapproaching a tipping point – thenumber of ASCO abstracts on thistopic more than doubled over thelast two years, reaching more than300 this year. Researchers nowtalk of the ‘end game’ being insight for immunotherapy, thoughthere is still a long way to go.The excitement that is buildingwas triggered in no small part bythe approval in 2010 by the USregulatory body, the FDA, of thefirst vaccine therapy, sipuleucel T(Provenge) for advanced prostatecancer, followed last year by ipili-mumab (Yervoy) for metastaticmelanoma, which is an ‘immune-tar-geted’, or stimulatory, antibody agent.Meanwhile the wider public are

being primed about the possibility ofa major breakthrough. This April,The New Yorker, a literary magazine,carried a story titled ‘The T-cell army’,in which writer Jerome Groopmantraces the early history of immuno-therapy back toWilliam Coley, a sur-geon in New York, who stumbled ona case where a streptococcal infec-tion seemed to help a sarcomapatient eliminate his cancer, andthen tried to replicate it.T cells – a type of lymphocyte, or

white blood cell, found in theblood andother parts of thebody–workmainly byproducing proteins which allowimmune system cells to communicatewith each other, and which can alsoattack foreign or cancerous cells. It isthe discovery of one type of T cell thatproduces a protein called cytotoxicT-lymphocyte antigen-4, or CTLA-4,

“In the past 10 years there has been an explosion in

what we can deliver for measuring immunity”

Harnessing the immune system. Far left: T cells homein on a cancer cell. Left: Melanomas like thisone were the focus of much of the earlyimmunotherapy research, but trials arenow ongoing for a range of cancers

thatGroopmandescribes in detail, as itled to the development of Yervoy.The breakthrough moment came

when Jim Allison, head of tumourimmunology at Memorial Sloan Ket-tering, and colleagues, spotted thatthe mechanism worked in the oppo-site way to what had been believed –CTLA-4 had to be blocked, not stim-ulated. It then took a while beforethey finally persuaded a drug com-pany to take up the approach.Drug companies could be forgiven

for being cautious, given the longhistory of difficulties. Interleukin-2(IL-2) and interferon-α – the main-stays of attempts at improving immuneresponses introduced in the 1980s –both have significant toxicity and lim-ited evidence for overall survival. Thepast few years have also seen high-profile failures of companies such asCancerVax andCell Genesys. But thisunpromising picture has changed dra-matically over the last two years. SC

IENCEPHOTOLIBRARY

16

rapidly growing number of ran-domised phase II and III studiesthat show this is actually the case.The field has changed in just twoyears from having little to offer tobeing a ‘grown up’ treatment.”Joost Lesterhuis, amedical oncolo-

gist and researcher at Radboud Uni-versity Nijmegen Medical Centre, inthe Netherlands, says that the basicresearch community had not lost faithwith immunotherapy. “Therehavebeen

a lot of papers in preclinical and trans-lational research journals – therewas adifference in perception about whatimmunotherapy can do between clini-cians and laboratory scientists.”A stringof high-profile negative trials, in par-ticularwith vaccines, has not helped ofcourse, but there has been steadyrefinement of animal models and aflowof small human studies that pavedthe way for the impact we see now,with the standout sector being thenovel

immune-targeted agents such asYervoy,says Lesterhuis.He outlines some of the key advan-

tages of immunotherapy. “It can bevery specific – T cells can be directedagainst tumour cells, in theorywithoutcausing any damage to surroundingtissue. The immune system also has amemory, so if you induce a response, ingeneral it is long-lasting and can bequite potent – we’ve seen instances inpeople with high tumour burden,although peoplewith less tumour tendto respond better.“And immunotherapy is additive –

the old idea was that you should go forone treatment or another – now wearemoving in the near future to givingimmunotherapy with or on top ofother therapies.”

Strategies in immunotherapyImmune checkpoint blockadeAmong the big news stories at ASCOthis yearwere trials of two agents in theclass of immune stimulatory antibodies,targeting the PD-1 (programmed celldeath) and PD-L1 (programmed celldeath ligand) proteins. The aim is toblock pathways that shield cancer cellsfrom the immune system, and theagents have been trialled not only inmelanoma and kidney cancer, whichhave long been candidates for immuno-therapy, but also in non-small-cell lungcancer (NSCLC), with promisingresults in these hard-to-treat advancedtumours. Both agents aremadebyBris-tol-Myers Squibb (BMS), which alsomakes Yervoy.The reason Yervoy has gained so

much attention is straightforward, says

“The field has changed in just two years from having

little to offer to being a ‘grown up’ treatment”

IMMUNE CHECKPOINT BLOCKADE

Ipilimumab CTLA4-blocking Melanoma Approved

Prostate cancer Phase IIIand NSCLC

Other tumours Phase I–II

MDX1106 (Medarex/ PD1-blocking Melanoma, RCC Phase IIBristol-Myers Squibb) antibody and NSCLC

CT011 (CureTech) PD1-blocking Melanoma and Phase IIantibody haematological

malignancies

VACCINATION STRATEGIES

Sipuleucel-T Autologous APC vaccine loaded Prostate cancer Approved(Dendreon) with prostate acid phosphatase

Dendritic Cell (DC)- Autologous DCs loaded All cancer types Phase I–IIIbased vaccines with tumour antigens

MAGE3 ASCI MAGE3 protein NSCLC Phase III(GlaxoSmithKline)

PROSTVAC Poxvirus-based Prostate cancer Phase III(Bavarian Nordic) PSA-targeted vaccine

T-VEC (Amgen) Attenuated herpes simplex Melanoma Phase III(developed by type 1 virus encoding and HNSCCBioVex as OncoVEX) human GM-CSF

Source: All tables are adapted from W Joost Lesterhuis and Cornelis J A Punt (2012)Harnessing the immune system to combat cancer [poster]. Nature Rev Drug Discovwww.nature.com/nrd/posters/cancerimmuno © 2012 Nature Publishing Group

antibody(Bristol-MyersSquibb)

17

Lesterhuis: it is the first drug to showsurvival benefit in a phase III trial inadvanced melanoma (although theBRAF inhibitor, vemurafenib, hascompeted for attention, and the twoare being trialled together now). “Itwasn’t thatmost patients were cured –they weren’t – but it was the first posi-tive story to tell about melanoma, andthere were dramatic responses in aminority, and itwas the spark thatmadea lot of people enthusiastic again.”This type of immunotherapy is pro-

gressing very rapidly, he adds, becauseclinical data are becoming readily avail-able, and because it is not a patient-tailored approach. “It’s just an antibodyagainst a surfacemolecule on T cells.”

Therapeutic vaccinesOttensmeier points out that thereare well-established immune treat-ments, such as bone marrow andstem cell transplantation in haema-tological malignancies, but the spec-trum of treatments is opening upwidely now. In addition to agentssuch as Yervoy, he considers that ther-apeutic vaccines such as Provengeare becoming valid treatment options.His opinion is shared by Lester-

huis, who co-wrote a review paperpublished August 2011 in NatureReviews Drug Discovery, where theyargue that therapeutic vaccines aremore widely applicable than preven-tive ones, asmost human cancers haveseveral causal agents. Such vaccinescan be developed in a variety of ways,

Lab-grown T cellsAnother interesting approachmentionedby Lesterhuis is adoptive T cell therapy.While the immune-targeted therapiesandvaccines aim to induceorboost thebody’sexisting responses to tumours, adoptiveT cell therapies culture large numbers –potentially billions – of tumour-specificTcells in the lab, and infuse these into thepatient.This strategywasdeveloped in theUS (for example in a trial in 2002 withadvancedmelanoma, althoughearlyworkgoes back to the 1980s), and has nowstarted to become available for a fewmelanomapatients inEurope, at centressuchas theAmsterdamCancer Institute,CopenhagenUniversity/HerlevHospitalin Denmark, and the Christie in Man-chester, UK. The T cells can also bederived from blood or can be geneticallymodified, but in the main melanomatrials they come from the tumour – atreatment known as TIL (tumour-infiltrating lymphocyte).

The role of chemotherapyThe case is now being made thatimmunotherapy deserves to be classedas a distinct treatmentmodality, to rankalongside chemotherapy, hormonal

using viruses, proteins, DNA, pep-tides, dendritic cells and so on. Someof these strategies are showing prom-ise, they say, but most have failed.One important lesson they highlightfrompastmistakes is that enough timemust be allowed to judge the potentialimpact of a vaccine in early-stage trials.Despite the many setbacks, there

is now a pipeline of candidates inphase III, such as GlaxoSmithKline’sDERMAandMAGRIT trials for non-small-cell lung cancer and melanomathat target theMAGE-A3 antigen, andAmgen’s talimogene laherparepvec(T-VEC), an engineered herpes virusthat also targets melanoma. Ottens-meier adds that there are at least fiverandomised vaccine trials for lungcancer that are well worth watching.

ADOPTIVE CELL TRANSFER

Adoptive transfer Polyclonal T cells Melanoma Phase IIIwith TILs against multiple tumour-

associated antigens

Adoptive transfer Monoclonal T cells Melanoma Phase IIwith TCR-transduced with high-affinity TCRT cells against single tumour-

associated antigens

NON-SPECIFIC IMMUNE STIMULATION

IL2 (Novartis/ Recombinant Melanoma Approved for melanomaPrometheus) human IL2 and RCC in some and for RCC in

most countries

IFNα (Schering- Recombinant Melanoma Approved for melanomaPlough/Roche) human IFNα and RCC (adjuvant) and RCC in

several countries

Denileukin Recombinant IL2– Persistent or Approved in US; orphandiftitox (Ontak) diphtheria toxin recurrent cutaneous drug designation in EU(Eisai) conjugate T-cell lymphoma

Other tumours Phase I-II

Imiquimod TLR7 agonist Basal cell Approved for basal cell(Meda/Graceway carcinoma, VIN carcinoma; in Phase III/iNova) and CIN for VIN and CIN

BCG Intravesical Urothelial cancer Approvedadministration ofBCG as adjuvant

18

therapy and the new targeted thera-pies. But as usual with cancer, thingsare not so clear-cut. Take chemother-apy – as Ottensmeier says, “We arelearning that both old and newchemotherapies that are not immuno-logical in nature do produce immuno-logical effects. Some think thatchemotherapy is going to immuno-suppress the patient, but that’s nottrue for all drugs. For example, thereis a recent paper in the JCO thatfound the number of immune cells inbreast cancer predictedmore benefitfrom chemotherapy. It means thatwhen we have been focusing only onthe cytotoxics in terms of poisoningcancer cells, it may be much morecomplex than that.” The benefit fromboth chemotherapy and radiotherapy,he adds, may be related to immuno-logical factors and not primarily tothe toxic effects.This is pointing to new directions

for investigation with conventionaltreatments andwith targeted therapiesto find out whether they can work inconjunctionwith immunological treat-ment. “Some are particularly good andsome really bad – we need a case-by-case analysis to understand the prin-ciples,” he says.Investigating the effects of plat-

inum-based chemotherapies in com-bination with immunotherapy isLesterhuis’s own field and he’s recentlyreturned from a spell as a visitingscientist at the tumour immunologygroup at the University of WesternAustralia. “I’ve found that there arebeneficial effects in induction ofimmunity, such as by activating

much longer to respond to treatments,and tumours may grow for a while.Benefits may not emerge for monthsor possibly years, which can leaveoncologists and patients facing diffi-cult decisions about whether to con-tinue with treatments. Lesterhuis alsonotes that there can be unexpectedside-effects, such as the high rate ofacute renal failure that occurred in atrial of a combination therapy for kid-ney cancer. Generally, side-effectscan be severe in immunotherapy, asfound in trials of Yervoy, and canrequire fast medical action.Inevitably, there are cost and regu-

latory issues concerning the newagents. When Provenge hit the head-lines, it was on account of its price tagasmuch as anything else. Yervoy is notfar behind, at about €85,000 for onecourse of infusions in theNetherlands,for example. A recently establishedcancer drugs fund in the UK is cover-ing costs there, but at a ‘tear-inducing’price, says Ottensmeier.As with other therapies, there is a

need to identify patients who willbenefit. His own group presented aposter at ASCO on early work on abiomarker for gauging whomight ben-efit fromYervoy for melanoma. Usinga proprietary panel of tumour-associ-ated antigens, they found that amongpatients treated with the therapy,those with pre-existing antibodiesagainst two or more antigens weresignificantly more likely to survive.They concluded that the melanomasin these patients “are immunologi-cally more visible”, and so more likelyto respond to activation of immunity.

dendritic cells, making tumour cellsmore susceptible to immune attack,”he says. “It feels counterintuitivebecause one of the side-effects ofchemotherapy is immune suppressionwith decreased immunity to bacteria,but in recent years we have evidencethat immune response to tumour anti-gens is not decreased and may alarmthe immune system towards cancer.”He points to another study, a phase

II trial that has attracted interest,where Yervoy was combined withchemotherapy in non-small-cell lungcancer. “It showed longer progression-free survival depending on the sched-uling of the two drugs, and phase III isnow starting. The other exciting thingis that it is in lung cancer, which wasthought to be a non-immunogenic dis-ease.” The anti-PD-1 agent has alsoshown some good responses in lungcancer, he adds.

Towards the end game?But the successes so far should not dis-guise the many obstacles for makingmore progress in immunotherapy.While investigation and tools are devel-oping fast, major gaps in knowledgeremain regarding, for example, optimaldosage, scheduling and how to meas-ure response. The rulebook for cyto-toxic drugs is no good here; asLesterhuis and colleagues point outin their reviewpaper,maximal tolerateddose and tumour response rate haveproved not to be valid as markers forimmunotherapies, and there is muchless – if any – correlation between drugexposure and efficacy and/or toxicity.In particular, patients may take

“Benefit from both chemotherapy and radiotherapy

may be related to immunological factors”

19

Ottensmeier says that the current focusis mainly on treating established dis-ease, but attention will also turn moreto prevention of recurrence, and pri-mary prevention and prevention of dis-ease development – the HPV vaccinefor cervical cancer being an obviousexample of a primary prevention.

“And the excitement about anti-CTLA-4 is not only that it works in asmall number of patients, but alsothat there is a group of patients who donot have recurrence after you’ve fin-ished treatment, and it’s a paradigmshift that I think we will see with vac-cines and T cell transfer as well.

“It is a result of the memory of theimmune system, both in B cells,which make antibodies, and T cells.They hang around for decades –probably for life. If they are enabledto see the tumour, then they cando what our current drugs have notbeen able to do.”

henHein Jambroers, a47-year-old event coordinator fromRoemond,acity in thesoutheast of theNetherlands, founda small mole on his leg that was growing, he went to his

doctor, whosent him to the local hospital, where it was found to bemelanoma.He thenwent to theuniversity hospital inMaastricht foroperations onhis spleenand lymphnodes – but one year later, thecancer returnedwith tumours on his leg. Thiswas summer, 2010.“I went back to Maastricht and they said they couldn’t help meas the cancer was now in my blood. I went to Rotterdam tooand was told again there was no treatment. So Istarted Googling.”Jambroers found the story of a Belgianwoman who had been treated with ipili-mumab in Brussels, and tracked herdown on LinkedIn. After talking toher, and her oncologist, he wasadvised to see John Haanen attheNational Cancer Institute (NKI)in Amsterdam,whowasworking onthe latest melanoma trials.“I was first put on vemurafenib[Zelboraf], the newBRAF inhibitor,and that worked well at first – aspot on my liver vanished andothers shrank to a pea. But then itstopped working and tumours inmy leg grew again, to egg size, within one month.” He was thenoffered Yervoy, which hadworked in other patients in Amsterdam.“I had four infusions but it didn’t do anything – it is thought it couldwork after several months but there was no change in my bloodwork at all. I was told they were not expecting an anti-PD-1 trialbefore 2012.”He had already asked about adoptive T cell lymphocytes (TIL) in2010, but had been told there were no plans to try it. Thankfullyhe then got a call inviting him to be one of the first three patientsin the Netherlands to undergo the treatment, under Haanen.

Jambroers says that TIL is a major procedure involving severalstages and people need to be physically fit. “First I had an oper-ation to remove some tumour to get the antigen-specific T cells,but I got an infection and had towait anothermonthwhile that wastreated. I then went back to have white cells removed from myblood and had a week of chemotherapy.” That process – calledlymphodepletion – is needed to eliminate competing lymphocytes

and regulatory T cells. Meanwhile, thespecific T cells were cultured for infusion– there were about 196 billion in hiscase, which he received in October lastyear. “I was told that 196 billion is anextremely high number of cultured

cells – the results of all the world-wide TIL trials show anything over150 billion gives a good chance ofcomplete remission.”But the treatment was not over –he also had four infusions of IL-2,and had to go into intensive careas his liver and kidney began tofail. A week later, he was wellenough to go home. A checkrevealed the tumours had shrunkby 25–30%, and hewas soon backat work. “After another two weeks

therewas a50%shrinkage, and by Christmas therewere no activetumours – just one lumpwith fluid. By April this year it looked likeI was cured – there was only scar tissue and nothing inmy blood.”Jambroers, pictured herewith his wife Varadi and daughter Jenna,has become an advocate formelanoma patients, telling his storyon websites and in Dutch newspapers. There is much moreabout the latest treatments now available, but he feels that, evennow, many doctors are still unaware of where to refer people.“I know how hard it is if you can’t find information and I’m happyto tell my story whenever I can.”

ENLISTING 196 BILLION T CELLS TO HELP FIGHT STAGE 4 MELANOMA

He feels that, even now, many doctors are stillunaware of where to refer people

22

hy are cancer patients being givenmedically futile treatment in thelast weeks of their life?Wehear thisquestion raised time and again atinternational meetings and in jour-

nal articles, provoking polarised views and occa-sional acrimony.A recent editorial in the Annals of Oncology

(2011, 22:2345–48) posed the question: “Why arewe not ceasing chemotherapy when it is useless,toxic, logistically complex and expensive?” It drewattention to studies showing marked global varia-tions in approach between countries, with as fewas 8% of patients in England receiving chemother-

apy in the last month of life, compared with 37%in Portugal. And it commented that “Medicaloncologists have overly optimistic predictions and,sometimes excessive, treatment-prone attitudes.”Is this a fair point?Are toomany patients being

offered aggressive treatments with unpleasantside-effects when palliative approaches would bethe better option for their remaining days? Is thequest for new life-prolonging treatments over-riding the best interests of individual patients?

Cancer World’s Simon Crompton asked twoexperts – one amedical oncologist, the other a pal-liative care specialist – to debate the issue, and seeif they could agree on a way forward.

23

It’s well known that there are variationsin treatments and the way certain situa-tions are handled in different countries,but I have my doubts about generalisingfrom such international comparisons,which are based on very diverse studies.While it is true that attitudes may dif-

fer, it is not only the oncologist who dic-tates what happens – the attitude of thepatient and their family is also crucial,and this may vary from country to coun-try. I think the idea that medical oncol-ogists are pressing ahead with treatmentsto the last minute in the full knowledgethat they are futile is false. It is notalways easy to determine what a ‘futile’treatment is, or indeed when a patient

will be ‘at end of life’. In some cases weobserve a rapid and surprising deterio-ration in the patient’s status over days ora few weeks, often after a period whenthe disease has been progressing slowlywith the patient remaining very fit. Is it‘futile’ to try to find a new treatment forsuch patients?If so, we should give up on treating

endocrine-responsive breast or prostatecancer when it progresses following thefirst endocrine treatment. And we shouldnot treat colon cancer that progressesbeyond the first line of chemotherapy.And what about disease which may pos-sibly be refractory to chemotherapy, asdramatically illustrated in the

It has been said that the intensity of cancertreatment may be related to culture, andthis is backed by data that seems to indicatethat culture influences the use of chemo-therapy during the last two to four weeks ofa patient’s life. I believe this data needs to beevaluated and debated.We can identify different cultural

approaches to treating patients nearing theend of their life in different societies. Somemedical oncologists offer end of lifechemotherapy to asmany as 15% – even upto 50% – of dying patients. Not all medicaloncologists workingwithin the same culturalsetting will take the same approach, andthe proportion of patients given futile treat-

ment may vary between institutions andevenwithin large institutions. Societies needto assess the cultural approach governingdecisions about when to stop active treat-ment, from an ethical, clinical, practicaland economic point of view, because thetreatment being offered to patients is futile.One factor may be that we do not have

good enough indicators to select the righttreatment for patients during the last threeto six months of life. Improvements mightbe achieved by research focused on unse-lected cohorts of cancer patients duringthis part of their disease trajectory. Hereoncology and palliative care would need tocollaborate closely.

Stein KaasaPalliative care expert and head of the Cancer Clinic at Trondheim UniversityHospital, Norway

�

Matti AaproMedical oncologist and director of theMultidisciplinary Oncology Institute at theClinique deGenolier in Genolier, Switzerland

24

This isn’t just about medical oncologists.Two other groups, in particular, are driversin this issue, and the way in which theyinfluence what happens to patientstowards the end of life should be assessedby themselves and by society.First, there is the pharmaceutical

industry, which sells very expensive drugsto the patients via media advertising,talking about new ‘breakthroughs’. Theseheavily marketed drugs have a marginalimpact, if any, on patients who are in theirlast weeks andmonths of life, even thoughthey might have remarkable effects whengiven to the right patient at earlier stages.Second, there are the basic scientists

who, via clever media coverage, createthe impression that personalised treat-ment with new drugs and technologieswill soon revolutionise cancer care. The-oretically they may be right, but there isa long way to go before we see a majorinfluence on care for patients during thelast three to six months of life, and sys-

tematic, large-scale clinical research onthe use of these treatments in this settingis needed. Until then, the greatest poten-tial to improve decision making aboutend of life care will come from moreextensive and systematic use of goodclinical indicators, including patient self-assessment of function, symptoms andpsychological factors.It is true that personalised treatments

generally have fewer side-effects thanchemotherapy, and bring good responserates and life prolongation to the rightpatients when used early in a non-curativedisease trajectory. But there is an argu-ment that patients are being encouragedto use these medicines for too long.Patients find it very hard to know what isbest for them as their illness progresses,and I believe that medical oncologistsneed to be more careful than ever in mak-ing these decisions towards the end oflife. It is very important that we raise theprofile of this issue.

Annals of Oncology editorial? We know,for example, that many patients withnon-small-cell lung cancer who have apoor performance status will not benefitfrom chemotherapy. But is that a suffi-cient reason to deny them a chance?The poor performance status may not beindicative of a major refractory tumourburden, and adequate support can helpthese patients survive longer, as wasshown in a paper by Temel et al. (NEJM2010, 363:733–742)Oncologists recommend treatment

in the full belief that it will bring positiveresults to the patient. It may not workout that way in practice, and may ulti-mately prove ‘futile’, but it is often

impossible to know in advance.One also has to accept that futility,

while a statistical term, is not perceivedin the same way by everyone. The dis-tinction between treatment and pallia-tive approaches can be false. Cancertreatments can also palliate pain, forexample, even when they are not activeagainst the disease. If you go through theliterature on infused 5-FU chemother-apy, it is clear that in many patients thetreatment reduces pain – an effect thatmight otherwise be achieved only withmedicines that are less well tolerated.There are many other examples wheretreating the tumour reduces pain andother symptoms.

25

Industry is always blamed, but I am not surethat is fair. Poor journalismcancertainly be atfault –which iswhyencouraginghigher stan-dards in reporting is so important.Noonecandeny that some recent developments in can-cer drugs are of great value. But it is also truethat statistically significant survival benefit ofonly a few days is of no clinical value.As for the basic scientists’proclamations

about revolutionary personalised treatments,it may well be that some scientists are“clever” in promoting themselves. But whatabout those clever drugs: imatinib, ritux-

imab, trastuzumab, everolimus and others?Might not the new tools available todayallow significant progress to bemade in theindividualised approach? It took years forsome oncologists to accept that patientswith endocrine-responsive breast cancerwould derive little or no benefit from stan-dard chemotherapy. Maybe the new toolswill showwhich patientswith non-endocrineresponsive cancers will benefit from one oranother drug class, beyond the classic deter-mination of a HER-2 receptor for breastand some other tumours.

Oncologists want to offer optimal treatmentfor their patients, but they are subject to thepressure of marketing from industry, and atthe moment I think the balance is wrong.There is no doubt thatwhat physicians com-municate, and how they do it, has a majorinfluence on the decisions patients and theirfamilies take when approaching the end oflife. We need a greater sense of realismapplied to these decisions.I think we need to go back to the individ-

ual patient, and ask ourselves who wouldreally benefit fromreceiving this treatment. If

you lookat the inclusioncriteria in the relevantclinical studies,most patientswill have had agoodphysical performance status. So if a per-son’s performance status starts to drop and/ortheir subjective symptoms increase,weshouldconsider stopping treatment.I believe you have to follow the patient –

not just by their CT scans, but by followingtheir symptom patterns and their physicaland psychological performance patterns overtime. I’mnot sure thatmedical oncologists aredoing that systematically, ordocumenting it, atall stages of the cancer.

Rather than stigmatising the physicians andthe treating teams, we need to open a frankdialogue about the limits of our understand-ing of the true value of different treatments,for different diseases and in different clinicalsituations. I believe themost important thingis to offer continuous care to the patient,from the start to the end of their cancer jour-ney – and even after the end, in supportingfamily and friends. I think that dividing can-

cer care into ‘active’ and ‘palliative’ is wrong.In aneditorial just published in theAnnals

of Oncology (23:1932–34), I discuss theimportance of continuity and of supportivecare, which should include the needs of ter-minally ill patients.We should not differenti-ate supportive andpalliative care fromactivetreatment.Good cancer care is a continuum,and sending the patient to a ‘death home’ isnot ideal.

26

High-quality and continuing supportivecare, as recommended by the EuropeanSociety for Medical Oncology and othermedical organisations, is definitely of pri-mary importance. It could be that in somecountries, and in some settings, oncolo-

gists are led toomuch by test results, ratherthan thinking about the real benefits topatients of offering approaches that inte-grate the best active treatment with thebest supportive care. If that is the case,there needs to be a change.

I agree with Matti that we should notlook at palliative care as a separate systemfrom active treatment. I also agree weshould not stigmatise physicians, butinstead have an open discussion aboutthese issues. The expertise of palliativecare and symptommanagement should becontinuously integrated with tumour-directed treatment. It’s about offering thecorrect treatment at the right time, and

patients have to understand that they arepart of a large team including medicaland radiation oncologists, palliative carephysicians, specialist nurses, communitynurses and so on. As patients approachthe end of their life, this team will changeand the focus will be more on home carethan hospital care. Oncology expertise isalso needed in home care situations andwithin palliative care teams.

Beneficial or futile? It is oftenhard to predict how an

individual patientwill respond

SAMOGDEN/SCIENCEPHOTOLIBRARY

t was on a Monday threeand a half years ago thatRenateMulofwa* first gavein. “I can’t cope any more,”she said to gynaecologist

Angela Kuck as she bared her breast.“I’m sure you’ve never seen anything asbad as this!” And she burst into tears ofembarrassment.

Threedaysearlier thenaturopathwhowas treating her had jumped back inalarmasbloodcame spurting out at him.The tumour was as large as a grapefruitandwaspushingoutwards as though try-ing toescape fromherbreast. Ithadeatenawayher skin, so thatMulofwadescribedwhat remained as a “glacier landscape”.

Renate Mulofwa was then 47; shehad known for almost two years that

she had breast cancer. Surgery wassomething she had never wanted. Shewas a woman who had always attendedher mammography appointments, eversince shehad first felt a hardening in herbreastwhen shewas28. Shehadhadherthree children immunised and allowedthem to be prescribed antibiotics whentheywere ill. Shehadnever had anythingagainst conventionalmedicine – at leastnot until that phone call in June 2006that changed everything. For RenateMulofwa, that day saw the start of anodyssey through the strange world ofalternativemedicine. For four years shehad been pursuing that pathway, leavingit only once – briefly – in 2008.

Mulofwa had been visiting a friendwhenhermobile phone rang. The caller

was the resident gynaecologist from theneighbouring village. He had recentlyarranged for a tissue sample to be takenfromher left breast. She had cancer, thedoctor told her curtly, and he had madean appointment for her to go into hospi-tal the followingweek for surgery.At anyrate, that was how she remembered it.

The gynaecologist now says that itcannot have been like that – his profes-sional ethics would not permit him todeliver such a serious diagnosis over thephone. The truth of the matter can nolonger be ascertained, but Mulofwamaintains that from theoutset she foundthis doctor cold, uninterested and arro-gant. She saw him as representing theheartlessness of conventionalmedicine,and thenshe imagined thechemotherapy

It was her own fault that she lost her chance to be cured. Or was it?

This article, which was first published in the German weekly news

magazine Der Spiegel, and won its author a Best Cancer Reporter

Award, explores what makes people choose alternative over

conventional treatments.

An award-winning article on the seductive powers of alternative therapists

28

‘I was stubborn’“I don’t want to push the blame ontoothers. I was stubborn and had got itintomyhead that Iwould showeveryonethat there were other ways of doing it,”she now says. She shakes her head, onwhich, after five cycles of chemotherapy,nothing but fuzz is growing. On theshelves inher small living room is aphotoof her twenty years ago,with longblondehair and a beaming smile – she is doingthe splits on a tree trunk that is bridginga stream.Now she thinks that she looks

more like “a newly hatched vulture”.But is it all ‘her own fault’?Her fault

because she let herself be seduced bythe promises of the wonder doctors?To what extent are the seducers them-selves to blame?

Renate Mulofwa now recognisestraits in herself that make her an idealvictim of that ‘alternative’parallel world.She sees herself as easily influenced,she takes decisions on the basis of gutfeeling, and if a charismatic healer claspsherwarmly by bothhands andproclaimsin a tone of complete confidence, “Wecan crack it!”, that goes down betterwith her than the ruthless realism ofconventional doctors.

And so she entered the jungle ofalternative medicine, where no one

showed her how to distinguishbetween genuine treatmentmethods and life-threateningquackery.

The first tip came from herbrother – he knew of a farmerwho had cured a colleague of

a persistent allergy through laying onof hands. Mulofwa drove in her greenVolkswagen camper to the Allgäu insouthern Germany. A friendly elderlymanwith a red face and a large stomachwelcomedher intohis living room. In thecorner stood an altar, surrounded bystatues of Mary of every conceivablesize. His hands on her shoulders werewarm; it felt good to feel the energyflowing.And the farmerwasmodest; hemade nomention of payment.Mulofwagavehim€100. She stayed aweek, sleep-ing in the camper van and enjoying theoutdoors and her freedom.

Once shemet another cancer patient

– the hair loss, the vomiting into thetoilet. No! She decided not to give con-ventional medicine a look-in.

And so, regrettably, she did not findout how good her prospects were: nolymph nodes were affected, the cancerwas less than five centimetres acrossand was ‘moderately differentiated’.Chemotherapy would probably nothave been needed at all, she couldhave been treated effectively with hor-mone inhibitors. Her chances of a curewere good.

She saw him as representing the

heartlessness of conventional medicine

Don’t do what I did.Providing insight intowhy people choosealternative therapies,and what theconsequences canbe, helps readersavoid falling intothe same traps

29

Could she have abandoned her approach at this point,

brought down to earth by this failure?

there, who secretly advised her, “I’vehad surgery and chemo as well – youshould do the same! Just don’t say any-thing to him about it; he doesn’t like it.”Mulofwa learned that with healers it’sjust like with doctors: if you want themto try to help you, you have to do whatthey say.

A small book with a yellow coverrevealed the next step to her. Pub-lished in 1978, it still ranks amongAmazon’s top 10 cancer guides. Underthe title Advice for the Prevention andNatural Treatment of Cancer, Leukemiaand Other Seemingly Incurable Dis-eases, the author – also a farmer – leadspeople to believe that cancer can be‘starved out’ by a 42-day diet: a wide-spread misconception that flies in theface of all the insights of cell biology.The theory is preceded by numerousaccounts of cancer patients who haveallegedly been cured by the ‘Bruessdiet’ – even without surgery.

Mulofwa stuck rigorously to the diet:for sixweeks shehadnothing but tea andfruit juice,with thin onion soup at lunchtime. She lost 14 kilos, her hair fell out inclumps, but the lumps in her breast gotno smaller.

A chance for a rethinkCould shehave abandonedher approachat this point, brought down to earth bythis failure? “My mother is very strong.You can talk to her, but in the end shedoeswhat shewants,” says her daughter,a qualified nurse with experience ofworking on cancerwards. Since she rep-resents conventionalmedicine, she says,hermotherwould not have followedheradvice in any case.

Vera Hermann, her alternative thera-pist and friend, also avoided conflict.Atfirst, choosing her words carefully, shetried to encourage Mulofwa to havesurgery – after all, the alternative routewas still an option after that. “But youwere wearing blinkers; you only took inthings that fitted with your world view,”she now says, and Mulofwa ruefullyacknowledges, “You’re right. If you hadspoken to me forcefully like other peo-ple did, I would have stopped comingto you!”

By this time Mulofwa had alreadyaccumulated two shelves of books abouther cancer. What all of them have incommon is that they accuse conven-tional medicine of only treating thesymptoms, not the cause, and they sug-gest an apparently simple way out ofthe problem. Sometimes the solution islarge doses of vitamins, sometimes infor-mation about the healing properties ofAloe vera that has supposedly been sup-pressed by scientists, sometimes yousimply have towork on your relationshipwith yourmother.Under seductive titlessuch asChemotherapyHealsCancer andthe World is Flat (another longstandingbestseller), authors of dubious standingskilfully attack conventionalmedicine atits weakest point.

In a book about Germanic NewMedicine,writtenby the formerGermandoctor Ryke Geerd Hamer, who hasbeen charged and convicted on a num-ber of occasions, Mulofwa read aboutthe ‘iron rule of cancer’, according towhich tumours are the result of psycho-logical conflicts. With a purple high-lighter she marked the passages statingthat conventional doctors put cancer

patients in a panic. “Knowing patients”have no fear because they know thatmetastases do not exist.

Vindicated?Mulofwa saw herself vindicated.Was itnot this very panic that was paralysingher? She therefore avoided all conven-tionalmedical advice or newspaper arti-cles and turned off the television as soonas a talk show mentioned her illness. Inher books, on the other hand, Mulofwalearned that she herself was responsiblefor her cancer. Had she not left her twofaithful ex-husbands, one after the other,after many years of happy marriage, inorder to eventually marry a youngerAfrican man in 2003? “Although manypeople didn’t understand me then, itwas deep love at first sight, and now hestands faithfully by me,” says Mulofwa.But she believed that the cancer was apunishment for what she had done.

She chased tirelessly from healer tohealer. She had her bowel cleansed oftoxicwaste, was injectedwithmistletoeextract and tried out dubious proceduressuch as snake venom therapy and auto-haemotherapy. She took part in themasshealings of aNigerian priestwhoworkedhimself up into a frenzy on the stage, andin Tibetan group yoga events.

Today some of these experiencesbring tears of laughter to her eyes. Onealternative practitioner pushed her inthe back, to test her aura. She thenheard him rummaging in a toolbox anddoing something behind her. A “repairto the aura”, carried out with hammerand screwdriver, he explained. “Obvi-ously I thought, ‘this is pure humbug’–part of me isn’t stupid. But I also

30

thought, ‘it won’t do any harm.’”At the start of 2008, in the months

beforeher capitulation, shebelieved thatshe was in the best possible hands withthegeneral practitionerDrNorbertVogel.The imposingpracticewithbright rooms,now managed by a successor, lies in anexclusive quarter of Zurich, opposite ahospice for the terminally ill. Mulofwaremembers Dr Vogel as asmall man in his late 50s,in old-fashioned pleatedtrousers, who kept talkingabout Jesus Christ.

By then her breast can-cer had already grown con-siderably. She was havingto stuff more andmore tis-sues into the bra cup ofher right, healthy breastto stop people noticinganything. The tumoursecreted a yellowish dis-charge, and it bled.

Dr Vogel had promisedher great things from themiracle product amygdalin– an extract of apricot ker-nels that alternative practi-tioners also refer to asVitaminB17. She had readthat scientists and thephar-maceutical industry wereconspiring to suppress information aboutthe effectiveness of this substance,because it could not be patented.Mulofwahadpaid out 4000Swiss francsin cash for her daily injections of thewonder drug. Vogel, who has since emi-grated to SouthAmerica, leaving only anemail address, did not respond to anenquiry from Der Spiegel.

Yet the results of themonthly blood testsfiled away by the doctor show that underhis care shewas becoming steadilymoreanaemic – to an extent that was poten-tially life-threatening. Three days later,when Angela Kuck admitted Mulofwato the Paracelsus Clinic in the Swiss

The doctor’s handwritten notes fromthat time consist of one page of spiderywriting.On18.4.2008he noted, “exulc.tumour significantly grown bleeding” –on this very day he had seen the bleed-ing breast andMulofwahadbeggedhimto refer her after all to a hospital. “I hadsuch a bad conscience – after all, he hadtried so hard to help me,” she said.

town of Richterswil, the gynaecologistassessed the patient as too ill to be oper-ated on, at that stage, on account of herpoor blood values. She was given bloodtransfusions, and the hospital chaplainheard her confession.

It took three days for Mulofwa’scondition to improve enough forthe operation to be carried out. The

medical report states thatfive out of eleven lymphnodes in her armpit wereaffected at this time, andthe cancer had spread toher pectoral muscles.

The patient next toMulofwa in the three-bedroomwasBarbara. Barbarawas the sameage, had colo-rectal cancer, and likeMulofwa had not wantedto have surgery. In conver-sation, the two kindredspirits discovered that theyhad been treated by thesame healers. Mulofwarecovered quickly fromheroperation, but her newfriend was soon writhingwith the pain of hertumours. Thenursemovedher toanadjacent room.Thefollowing night Mulofwa

heardher screaming, and in themorningshe was dead.

That evening, with tears streamingdownher face, she sat besideBarbara inthe basement, where the corpse, sur-roundedby flowers,was laid out – in linewith theusual anthroposophical practicein the clinic.Mulofwawas shocked. Sheresolved to accept whatever the doctors

“Obviously I thought, ‘this is pure humbug’ – part of

me isn’t stupid. But I also thought, ‘it won’t do any harm’”

Alternative therapies. You must do as you are told

31

BLIC

KW

INKEL/M

CPH

OTO

S,H

EIK

OW

OLFRAU

M,A

LAM

Y,M

AN

FRED

RU

CKSZ

IO

offeredher: radiotherapy, hormoneblock-ade with tablets, three-monthly slow-release injections. Chemotherapy wasthe one thing that she still refused.

Over the followingmonthsMulofwagained strength for a new life.After ninemonths she felt well and stopped takingthe hormone inhibitors – which sheshould have taken for five years. Then,more than a year after the operation, alump appeared for the first time in theother breast. The doctor who examinedher ordered a full-body PET scan.

Too late for a cureThe tomography image showsherwholebody scattered with dots. These aremetastases – in thebones, the lymph sys-tem, the liver and the lungs. They are notcurable, thedoctor toldher, but palliativechemotherapy might keep them incheck for a few months or years.

Weeping, Mulofwa confided in hersister-in-law. She knew what to do: analternative therapist in Zurich – a friendhad given a glowing report of him.Thereitwas again, the temptation.Before long,Mulofwa was once more having coffeeenemas, soaking in alkaline mineralbaths and swallowing ahandful of herbalcapsules every day.

Mulofwa could feel her strengthdwindling. Her weight was falling dayby day. “Everyone dies sometime,” shesaid to her friends. Her youngest sonand her daughter no longer needed her;they would make their own way in theworld. Her husband would probablygo back to Gambia. She was grateful tohim; he had been just right for her dur-ing those years. The illness didn’t spellthe end of their physical relationship.Her husband had told her that for

Africans the breast was not sexy – its jobwas to suckle babies.

Mulofwa’s concern, though,was herelder son, who still lived with her. Shehad never spoken to him about her ill-ness, but she knew that hewas suffering.More or less on the day of her canceroperation he had given up his job at anelectrical superstore; since then he hadbarely got himself together at all. Forhim, she thought, she must hang on.

Her dry coughwas becoming obstru-sive, but the worst thing was her short-age of breath.Mulofwa felt as thoughherlungs were wedged into her ribcage.This time her alternative therapist senther to “a doctor that he trusted”: JoachimChrubasik, a man with the impressivetitle of “Prof Dr med” attached to hisname.

Reassured by a titleFor a second time the doctor titleinstilled inMulofwa a sense of security.She believed that Chrubasik combinedconventional and complementaryapproaches.Now she says, “Hewas thevery personwho once again broughtmeto the brink of death.”

Until 1996Chrubasikwas an anaes-thetist in charge of a pain clinic in Hei-delberg – a prominent researcherwith along list of publications to his credit. Yetprevious colleagues recall that, eventhen, hewas allegedlymanipulating hispatients and using questionable treat-ment methods. Then on account ofirregularities hewas stripped of his offi-cial status. His boss at that time, EikeMartin, comments, “I was glad that theproblemwas solved in thisway, becausewith his obsessiveness and his exagger-ated opinion of himself Chrubasik had

repeatedly put patients at risk.”Chrubasik peddles himself and his

work at alternative ‘mind body spirit’events. The booklets available on hisstand at the ‘First experience fair’, heldnear Zurich, sported titles such as TheCreation of the World and Cosmopsy-chobiology. According to his businesspartner, Chrubasik has often cured can-cer patients at an advanced stage ofthe disease.

The professor is a sturdy, pink-facedman with artistically styled grey hairand a beard. At the fair he denouncesthe pharmaceutical industry and inthe next breath talks about how after50 years he no longer needs glassesbecause he regularly takes rosehip pow-der. While he is speaking, pill boxesand juices are being circulated amongthe audience; many of them bear thewords “based on Prof Chrubasik” aspart of the product name, while otherscome from a pharmaceutical companythat uses his address.

Mulofwa is familiar with many ofthese products. She says thatChrubasikgave her two large bagfulls that he hadpacked in the back room of a Zurichpharmacy.

Looking back, says Mulofwa, shefell for the professor’s charisma in aninstant.Heprescribed gel-padded shoesand herbal painkillers for her hip pain(which was caused by the metastases).Todayhe explains his strategy: “Themostimportant thing is to get cancer patientsfree of pain. Then they live longer.”When she told him about her coughingand shortage of breath, he listened to herchest and said her lungs were clear.Even now he emphasises, “Her lungswere always good.”

“With his obsessiveness and exaggerated opinion

of himself he had repeatedly put patients at risk”

32

The turning pointMiklos Pless, who treated her shortlyafterwards, remembers things quite dif-ferently.At that time Mulofwa’s condi-tionwas life-threatening, the oncologistsays. As a result of the cancer, largequantities of water had accumulated inher chest and her lungs could no longercope with the resistance they encoun-tered. Mulofwa nevertheless believedChrubasik. It was not until she was athome and her son broke his silencethat her conviction began to waver.Weeping, he begged her, “Please,Mum,have the chemo!” Thatwas the turning point. Ina flash I realised what Ihad done to my life withmy obstinacy.

Pless, the oncologist,had prepared himself wellfor his first consultationwith his new patient.From the alternativetherapist he had alreadylearned thatMulofwa haduntil then always rejectedconventional medicine.The majority of patients,he says, are afraid that inhospital theywill bedrawninto a spiral in which onetreatment invariably leadsto another. And this anxi-ety is not unjustified, inPless’s view. “I thereforepromisemypatients that Ishall always respect theirautonomy,” he says.

He knows little about complementarymedicine, he admits, but he recom-mends therapists whom he trusts ifthat’s what patients want. The fact thathe was not in principle hostile to alter-natives was what won Mulofwa over.

The records show that Pless wasexpecting an emaciated woman whowould probably be in awheelchair. Sohewas surprised to see her walk into hisadmission room. He didn’t say, “Howcould you let it come to this?” He didn’tsay, “You are incurably ill.” Instead hiswords were: “Your general state is still

very good. If you give yourself a chance,you could soon be feelingmuch better.”

He first sentMulofwa to a lung spe-cialist, who spent several sessions punc-turingher life-threatening effusion.ThenMulofwa said ‘yes’ to chemotherapy. Theresults astounded even Pless: thetumours shrank, the pain disappeared,Mulofwa could breathe freely again,although the cough remained. Threemonths later the lung specialist reportedwith surprise how well her lungs werefunctioning.

A second lifeIn January 2011 Mulofwa celebratedher 50th birthday and, as the invitationput it, her ‘second life’. Today, a yearlater, she has five cycles of chemother-apy behind her. Apart from the hairloss she has had no major problems,she says. “No vomiting, no nausea,each time I just feel a bit weaker thanusual for two days.”

She seems stronger than she didthen, saysHermann, the alternative ther-apistwho is still at her side. She is one ofthree complementary therapists whomMulofwa still trusts.Her clear verdict is,“My life has been saved twice, and bothtimes it was conventionalmedicine thatdid it,” and she deliberately courts pub-licity: “I want to spare other womenwhat I have been through.”

Mulofwa still hopes that she canbeat the cancer, with the help of herself-healing powers,with globules, herbs– and chemotherapy.

* The patient’s name has been changed.This article was first published in Der Spiegelon 27 February 2012, and is published withpermission © Bernhard Albrecht 2012

“My life has been saved twice, and both times

it was conventional medicine that did it”

Mulofwa receiving chemo-therapy. “I was stubborn”

33

Knowing what needs to be done is one thing. Making it

happen is quite another. Well-informed media stories that

highlight shortcomings and failings can help focus minds

on the need for urgent action.

hemedia plays a critical rolein creating politicalmomen-tum for change to improvehealth services, accordingto the UK’s National Can-

cerDirector,MikeRichards.He speaksfrom personal experience, as it was acombination of evidence-based statisticsandhuman interest stories that, in 1999,triggered the then PrimeMinister TonyBlair to appoint him as what the mediaquickly dubbed ‘the Cancer Czar’.Richards would prefer not to be in

thepublic eye, but says thatmedia atten-tion is essential if things are going tochange. “Myappointmentwas greeted asgood news for about 24 hours and afterthat all the bad news stories came outabout people not getting treatment andabout late diagnosis. We were delugedwith bad news and I got experience very

quickly in dealing with the media.“Letmebehonest, I have ambivalent

feelings towards the media. I measuremy success byhow rarely I have to do the[BBC Radio] Today programme. I don’tneed thepublicity – I amnot trying to getelected. But I know that we need thosebad news stories. If all the journalistsstopped criticising and said cancer iswonderful, my ability to move thingswould be diminished.”Richards was speaking to broadcast-

ing and print journalists at an ‘Off theRecord’trainingcourse, ‘CanEuropecopewith the rising burden of cancer?’ organ-isedby theEuropeanSchool ofOncology(ESO) and the European BroadcastingUnion (EBU) on June 18 and 19.The EBU has a record of high-

qualitymedia briefings for broadcastersinEurope, but thiswas the first time that

they had tackled a critical health issuesuch as cancer.ESO,whichprovided theexpertise and content for the trainingevent, has organised a number of initia-tives to bring together cancer specialistsand journalists in various settings andparts of the world, but this was the firsttime it had focused on broadcast jour-nalists. The event was organised as partof ESO’s contribution to the EuropeanPartnership forActionAgainstCancer. Itwas co-financed by theEUHealth Pro-gramme and was held in conjunctionwith the Partnership’s Second OpenForum, which was hosted by Italy, andheld in theMinistry ofHealth inRome.

46

ESO’s primary focus is on giving doctorsand other health professionals accessto the knowledge that they need to givepatients the best possible treatment andcare. But Kathy Redmond, editor ofESO’s magazine Cancer World, seesworking with journalists as a significantpart of the ESO brief to educate andexplain the complexities of cancer and toimprove public understanding of the

disease. “There needs to bemuchmoreengagement between the cancer com-munity and the mass media. There is adisconnect between what the mediausually highlights andwhat people need

to know.Whether itmeans to or not, themedia shapes public attitudes, beliefsand knowledge about cancer and has aresponsibility to ensure that what itwrites or broadcasts is correct.”The journalists who attended the

event in Rome came from broadcastingorganisations and from print and on-line outlets, and they were looking forways tomake their reportingmore effec-tive. Many felt there is often a lack ofaccessible data to give a solid basis forreports on issues such as screening, earlydiagnosis and treatment.Tetyana Melnychenko, a reporter

and presenter forUkraineNational Tel-evision said, “I understandweneed to beabridgebetween thepatient and thepol-icymakers. I would like better statisticsto be available in the Ukraine, particu-larly about survival.”Also present were journalists from

the Czech Republic, Bulgaria, Estonia,Romania, Spain, Greece, Portugal, theUK, France, Denmark, Latvia, Lithua-nia, Poland, Slovenia, andSweden. Thislist includesmanyof the countrieswherehealth services are being squeezed byausteritymeasures, and this was clearlyan issue for the journalists and theexperts. “If I had to choose a word Iwould remember this course by, it wouldbe ‘money’,” said Jasmina Jamnik, fromRTV Slovenia. “Money is a problemeverywhere. But this age of austeritycould be a chance for prevention.”

Who is listening?Money was not the only constraint.Claudia Laslo from Radio Romaniapointed out that her country had had 30different Ministers of Health over the

“I understand we need to be a bridge between

the patient and the policy makers”

A bone marrowregistry for Romania.The power of goodreporting to galvanisedemand for actionwas demonstrated byPro TV’s Paula Herlo,pictured here at theMinistry of Health inBucharest, giving asample of her bloodto join the bonemarrow registry thatwas set up followingher series of hard-hitting reports.Below: Paula witha young leukaemiapatient who appearedin one of her reports.The full story canbe found in CancerWorld Jan–Feb 2011

47

CRISTINANICHITUS

DALILADULGHERIU

past 20 years and it was hard to getpoliticians to listen.Richards urged her not to give up.

“Youwould be surprised at howmany dolisten to your stories. I think we have amajor problem of changing perspec-tives and beliefs. You can influence thepolitical system. It takes time. It tooktime in the UK. Unless the politiciansare presented with a problem, they willleave it alone. They have lots of otherdemands on their time and onresources.”He said that the UK had been in

denial about the poor state of cancerservices, despite the mortality figuresfor theUKbeingworse than otherwest-ernEuropean countries. Evenwhen thefirst EUROCARE statistics showedmortality rates lagging behind “we dis-

missed them as unreliable and the doc-tors said they cannot be true.”Things began to change as cancer

experts, cancer charities and patientgroups became concerned. “Who waslistening? Very importantly the mediawas listening and I am sure you all knowthe power of the individual story backedup by statistics.“What influenced Tony Blair over a

period of three, four or five yearswas you,the journalists, writing stories. The badnewswas there and you could not ignoreit and journalism had a big part to play.”The UK has improved its record on

cancer, although it is still behind theleading countries. “What changed is thatit became a political issue,” Richardssaid. “Perhaps the singlemost importantthing is building the community that

says we must have better survival oroutcomes for cancer. We need to getclinicians, academics, managers, civilservants, patients, politicians and char-ities pulling together.”TitAlbreht, from theSlovenian Insti-

tute of Public Health, led a workinggroup to survey national cancer plansacrossEurope, to be published later thisyear.He said that themedia had a role toplay in removing an aura of shame thatexists in some countries around cancer.In Slovenia themedia had helped to

raise the response rate for colorectalcancer screening from 28% to 71%, sothat it is now amongst the best inEurope. In all about 800 stories hadbeenwritten, and he recalled one abouta man who had delayed sending in hisstool sample, but had then spoken outafter screening discovered cancerouspolyps, which were then removed.Albreht responded positively to a

suggestion from Olaf Steenfadt, theEBU project manager who chaired thesessions, thatmedia strategies should beincluded in national cancer plans. “Wewill definitely work on it,” he said. “It isnot part of the current template, but it isextremely important.”Journalists received briefings from

cancer experts about the latest statisticsand discussed ways in which they canbroadcast and write more clearly aboutcancer prevention, screening, treatmentand the social issues that surround can-cer. Silvia Francisci from the IstitutoSuperiore di Sanità, the leading scientificpublic health body in Italy, showed jour-nalists how statistics available on theinternet could be used to compare out-comes and value for money acrossEurope. Elke van Hoof, head of the

Journalists saw how statistics available on the internet

can be used to compare outcomes across Europe

� EPAAC is a European Union initiative set up in2009 to enable member states to work inpartnership with one another and withprofessional, charitable, campaign andadvocacy organisations involved in theanti-cancer effort.

� It aims to close the gaps between the bestand the worst performers across Europe bycutting down on the duplication of effort andpromoting transfer of knowledge and best practice.

� The partnership pursues a variety of initiatives in prevention, early detection,treatment and care, research, data and information, and cancer plans.

� The Off the Record ESO/EBU journalists training course, ‘Can Europe cope withthe rising burden of cancer?’ formed part of the Partnership’s action to communicatewith a wider audience, and took place at the second EPAAC Open Forum, held inRome, June 2012.

� The third and final Open Forum will be held in Brdo pri Kranju, Slovenia, inNovember 2013. The initial phase of EPAAC will come to an end in February 2014.

A PARTNERSHIP FOR ACTION

48

tion and I think I need to do this.”MayaDancheva, the health reporter

at Bulgarian National Radio, felt shewas now better equipped to use statis-tics for comparative analysis of the can-cer picture in Bulgaria with otherEuropean countries.Meelis Süld, a producer and reporter

onEstonianPublicBroadcasting, saidhewould askmore critical questions abouthowpatients can get the best treatment,but that it was also important not tomake cancer a scary subject. “Iwill try tofocusmore on the patients, not to scarethem away, because people are scaredabout illness.”For Olaf Steenfadt, such training

courses are part of the EBU and publicservice broadcasting commitment toquality journalism in difficult times.“Fewer resources and cuts on the onehand and more complex and inter-related topics on the other challengeeach editor, journalist and correspon-dent.An in-depth understanding of themain issues, such as the rising burden ofcancer, can promote safer news judge-ment and contextualisation for thebenefit of large mass media audiences.“Theprofessional exchangesbetween

mainstream news journalists and spe-cialist science writers proved extremely

Belgian Cancer Centre, talked aboutthe strengths andweaknesses of screen-ing programmes for cancer.A hard-hitting panel discussion

includedCora Sternberg, head ofmed-ical oncology at the San Camillo-Forlanini hospital in Rome and JaimieBrown, head of communications forNovartis Oncology in Europe. Andalthough the journalists pulled nopunches in quizzing Jaimie Brownabout the pricing policies of drug com-panies, they were delighted to havesomeone from the industry there.Mette Weber, who writes for theDanish Cancer Society, remarked“Excellent that you invited a rep fromthe pharma industry was well. A nicebalance of perspectives!”

New approaches, new perspectivesIt was clear from feedback at the end ofthe course thatmany of these journalistswill increasingly link their stories onindividual cases to statistical data andwill have a greater awareness of the bal-ance of risks and benefits in issues suchas screening. There was also increasedinterest in focusing on cancer survivors.Silja Paavle, a reporter on the Estoniannewspaper SLÖhtuleht, said, “Nobodyin Estonia has written about rehabilita-

useful for both sides. While producingcontent for different target groups, theyshared the common task of identifyingtrends and finding new angles to reporton cancer.”Using the experience gained in its

media training work over the past years,in 2013 ESOwill produce a journalists’guide to reporting on cancer. AnnaWagstaff, assistant editor of CancerWorld, who has led much of this work,says that journalists want to be able toput their stories into context, and tohave a greater understanding of whatreally makes a difference in treatmentand care. “Many journalists say theyare tired of doing endless stories aboutindividual patients who cannot get thetreatment they need, and of being toldthat the problem is lack ofmoney. Somebroadcasters even involve their jour-nalists in fund-raising initiatives, butthat is not what journalism is about.Journalists want to be in a position tohelp the public understand cancer, andtheywant the information and insight tohelp them ask the right questions ofpolicy makers about shortcomings incancer services and how these can beaddressed. When journalists do theirjob well, patients are more likely to getthe treatment and care they need.”

PROMOTING QUALITY COVERAGE OF CANCER

� In addition to the training course in Rome, ESOhas provided courses on cancer reporting tojournalists in Cairo and Damascus, and at the twomost recent gatherings of the World Conferenceof Science Journalists.

� ESO’s media team has worked with EUROCHIPto provide training to professionals involved incancer screening and cancer registries.

� ESO has run an annual Best Cancer ReporterAward since 2006. A total of 22 journalists from10 countries have received awards so far. Theirwinning articles can be read at CancerWorld.net(go to the Media menu)

49

Off the Record journalists’ course, Rome 2012

ALEXANDRAZAMPETTI

For localised prostate cancer,does technology equal progress?

Recent evolution of prostate cancer treatment reflects technological armsraces driven by economic incentives rather than high-quality evidence – asexemplified byproton-beamradiation, recently foundmarkedly inferior to farless expensive alternatives.Another study foundpromise for focal treatment,but much research is required before this could become a standard option.

fforts are constantly ongoing tointroduce alternatives to stan-dard treatments for localised

prostate cancer that offer equivalent orbetter oncological efficacy, togetherwithreduced side-effects. However, therecent history of treatment evolutionhas beendrivenmore bymarketing hypeandmisaligned financial incentives thanby high-quality evidence. Two studieshave generated a great deal of attentionin the media, and are illustrative ofbroader ongoing trends in the field. Thefirst study, by Sheets et al.,1 analysed

data from the Surveillance, Epidemiol-ogy, andEndResults (SEER)Medicare-linkeddatabase to compareproton-beamtreatment with other forms of external-beam radiation therapy (EBRT) –namely intensity-modulated radiationtherapy (IMRT) and conventional con-formal radiation – between 2002 and2006, using both standardmultivariableanalysis and propensity weighting.

The growth of IMRT has beenabsolutely explosive: from 0.15% ofEBRT cases in 2000 to 95.9% in 2008.1

Overall, comparedwith conformal radi-

ation, IMRTwas associatedwith statis-tically significant, but modest clinicalbenefits: 9% less gastrointestinal toxicity(only on the propensity-adjusted analy-sis) and fewer hip fractures (whichwereuncommon in all groups), but no differ-ence in urinary outcomes and12%moreerectile dysfunction. Proton-beam treat-ment was associated with no benefitscompared to IMRT– and in fact caused50% greater bowel toxicity, even afterpropensity adjustment. Proton-beamtreatment was also marked by trendstowards greater erectile dysfunction.1

The debate about proton-based ver-sus photon-based radiation recalls sim-ilar discussions about robot-assistedversus open prostatectomy; the discus-sion section of the present study1 in factdraws an explicit parallel to an earlierMedicare study focusing on this ques-tion.2 Indeed, there are similarities in theway these technologies have beendevel-oped and marketed.3 Both Medicareanalyses are alsomarkedby limitations intheir use of administrative billing codesas proxies for quality-of-life outcomes,which ideally should be assessed via val-idated patient-reported questionnaires.However, important differences shouldbe noted. The prostatectomy paper

This article was first published in Nature Reviews Clinical Oncology vol. 9 no.7, and is published with permission.© 2012 Nature Publishing Group. doi:10.1038/nrclinonc.2012.96

CLINICALONCOLOGY

52

analysed robot-assisted surgery datafrom many surgeons, mostly lower-volume providers early in their learningcurves.2 The proton-beam experience,conversely, was dominated by a singlecentre in southern California, whichis an experienced, high-volume (andaggressively marketed) centre for pro-ton-based prostate treatment; thisconcentrated experience should, ifanything, represent a best-case for out-comes.Also, unlike the case of proton-beam treatment, many other studieshave found clear benefits for robot-assisted prostatectomy compared withopen prostatectomy.4

Furthermore, the capital and mar-ginal costs of robot-assisted versus opensurgery are utterly dwarfed by those ofproton-based versus photon-based radi-ation. The additional costs of roboticsare absorbed by hospitals, whereas thecosts of novel radiation technologiesare borne directly byMedicare and otherpayers. Costs were notdirectly addressed inthe Sheets et al.1 paper;however, another recentMedicare study foundIMRT to be roughly 50%more expensive than 3Dconformal radiotherapy,and about twice as expensive asbrachytherapy or surgery (whether openor minimally invasive).5 Proton-beamtherapy is twice as expensive again asIMRT. A decision analysis demon-strated in 2007 that even if decreasedmorbidity allowed dose escalation up to90 Gy, proton-beam treatment stillwould not be cost effective.6

At this point, it seems very unlikelythat proton-based therapy will allowsuch dose escalation. Indeed, whilethere are theoretical radiation biologicaladvantages to proton-beam therapy, noclinical study – anywhere, ever – hasshown any clinical advantage in terms

of either oncological or quality-of-lifeoutcomes. Proton-beam prostate treat-ment fortunately remains uncommon,but new facilities are proliferating rap-idly, and because once a facility is con-structed there is a major incentive torecoup a prodigious investment, localprostate cancer practice patterns tendto shift to reflect more use of proton-beam treatment.7

The other recent paper, fromAhmed et al.,8 reported MRI-guidedfocal treatment with high-intensityfocused ultrasound (HIFU).HIFUhasbeen the subject of multiple series,mostly in Europe. The results havebeen decidedlymixed, with some seriesreporting excellent outcomes, and oth-ers finding low rates of cancer control,high rates of retreatment, andmediocrequality of life.9 Given this ongoinguncertainty, the technology remainsinvestigational in the USA.

Ahmed et al.8

reported on 42 menwith low-risk to inter-mediate-risk prostatecancer treated withHIFU targeting areasof cancer based onbiopsy and imaging.The protocol allowedup to 60% ablation

of the prostate, and required transper-ineal template prostate biopsies underanaesthesia before and after therapy.At12-month follow up, quality-of-life out-comes were generally good, althoughthere were certainly impacts on sexualand urinary function, particularly inthe short term, and in some cases inthe long term. Twenty-three per cent ofthe patients had follow-up biopsiespositive for cancer, and 10% wereretreated. Follow up was not sufficientfor assessment of long-term oncologi-cal efficacy.

What is novel about this study8 is notHIFU per se, but rather its use in a rela-

”“

tively well-constructed, prospectivestudy of focal therapy. Indeed, for focalprostate cancer treatment, the ablativetechnology is almost irrelevant. Ifprostate cancer canbe identified reliably,it can be destroyed by any number ofmodalities:HIFU, cryotherapy, intersti-tial laser therapy, photodynamic treat-ment, focal radiation and so on.Althoughthe resultsmight be considered promis-ing, many questions remain regardingpatient selection, workup, imaging, andfollow up, which must be answeredbefore focal treatment could be consid-ered for routine clinical practice.Because HIFU is not broadly available,direct cost comparisons to other treat-ments are not possible, although theimaging andpathology costs for anMRI-based focal protocol with before-and-after transperineal biopsies are likely tobe significant.

Where do these studies leave us?Regarding proton-beam treatment theanswer should be clear: at a time ofincreasingly constrained resources, it iscompletely unconscionable that weshould continue to pay exorbitant pre-miums for a technology that has notbeen proven better, and may well beless effective, than competing alterna-tives. Proton-beam treatment shouldcontinue to be studied, but paymentincentives must be revised – for bothproton-beam treatment and IMRT – to

No clinical study –anywhere, ever – hasshown any clinicaladvantage forproton-beam therapy

Key pointProton-beam therapy for prostate can-cer costs two to four times as much asstandard alternatives, and in a recentstudy has been shown to yield inferiorquality-of-life outcomes. Focal therapymay eventually offer a favourable alter-native, but much research is neededonpatient selection,workup, followup,and outcomes assessment.

53

provide reimbursement per patient, notper fraction, andneither should be reim-bursed so richly compared to surgery orbrachytherapy.

More generally, strident championsof expensive technology without sup-porting evidence run the risk of win-ning short-term, pyrrhic victories, butlosing the overall war: avoidable costandmorbidity associatedwith overtreat-ment of prostate cancer is amajor driverbehind calls to end prostate cancerscreening. Focal therapy remains anintriguing alternative, but requiresmuchmore study – and the fact remains thatformostmenwith low-risk prostate can-cer, the best treatment is active surveil-lance rather than any local treatment.10

Ultimately, what is needed in 2012for localised prostate cancer is not newtechnologies, but rather newparadigms

for routine, standardised assessmentand reporting of both oncological andpatient-centred outcomes; for riskstratification of tumours and targetingintensity of treatment to individuals’oncological risk and comorbidity; and forfull engagement of patients in shareddecision-making based on high-qualitydata on both effectiveness and cost-effectiveness of treatment alternatives.

References1. NC Sheets et al. (2012) Intensity-modulatedradiation therapy, proton therapy, or conformalradiation therapy and morbidity and disease control inlocalised prostate cancer. JAMA 307:1611–202. JC Hu et al. (2009) Comparative effectiveness ofminimally invasive vs open radical prostatectomy.JAMA 302:1557– 643. MR Cooperberg, AY Odisho and PR Carroll. (2012)Outcomes for radical prostatectomy: is it the singer,the song, or both? JCO 30:476–4784. A Tewari et al. (2012) Positive surgical margin andperioperative complication rates of primary surgical

treatments for prostate cancer: a systematic review andmeta-analysis comparing retropubic, laparoscopic, androbotic prostatectomy. Eur Urolhttp://dx.doi.org/10.1016/j.eururo.2012.02.0295. PL Nguyen et al. (2011) Cost implications of therapid adoption of newer technologies for treatingprostate cancer. JCO 29:1517–246. A Konski, W Speier, A Hanlon et al. (2007) Isproton beam therapy cost effective in the treatment ofadenocarcinoma of the prostate? JCO 25:3603–087. DS Aaronson et al. (2012) Proton beam therapy andtreatment for localized prostate cancer: if you build it,they will come. Arch Intern Med 172:280–2838. HU Ahmed et al. (2012) Focal therapy for localisedunifocal and multifocal prostate cancer: a prospectivedevelopment study. Lancet Oncolhttp://dx.doi.org/10.1016/S1470-2045(12)70121-39. H Lukka et al. (2011) High-intensity focusedultrasound for prostate cancer: a systematic review.Clin Oncol (R Coll Radiol) 23:117–12710. MR Cooperberg, PR Carroll, and L Klotz. (2011)Active surveillance for prostate cancer: progress andpromise. JCO 29:3669–76

Author affiliationsMatthew Cooperberg, Department of Urology,UCSF Helen Diller Family ComprehensiveCancer Center, San Francisco, California

Gemtuzumab ozogamicinin acute myeloid leukaemia

Gemtuzumab ozogamicin was withdrawn from the market after beingevaluated in combinationwith chemotherapy in the frontline treatment ofpatients aged 18 to 60 years with acute myeloid leukaemia (AML). More-recent randomised trials demonstrate that low doses of gemtuzumab addedto cytarabine and anthracycline-based chemotherapy benefit patients withbetter-riskAML.

reatment of patients with acutemyeloid leukaemia (AML) hasnot changed significantly since

studies in the 1980s established cytara-bine and anthracyclines as the mosteffective agents in this disease. Sev-

eral randomised trials have demon-strated that the doses of cytarabine andanthracyclines are important in spe-cific subsets of patients.A meta-analy-sis of trials comparing high-dose withstandard-dose cytarabine during induc-

tion has shown an improved relapse-free and four-year overall survival forpatients younger than 60 years with denovo AML who receive high-dosecytarabine as a part of their inductionregimen.1 This finding was further cor-roborated by a recent randomised trialdemonstrating a higher response rateand improved overall survival in patientsyounger than 46 years who receivedhigh-dose cytarabine induction com-pared with those receiving the stan-dard cytarabine dose (six-year overallsurvival 52% vs 43%; P=0.009).2 Otherdata have suggested that furtherescalation of the cytarabine dosebeyond levels that saturate intracellulararabinofuranosylcytosine triphosphateis not beneficial.3

Cytarabine dose is particularlyimportant in the treatment of patientswith the core-binding factor leukaemias,which have a more favourable risk pro-file; the administration of several

This article was first published in Nature Reviews Clinical Oncology vol. 9 no.6, and is published with permission.© 2012 Nature Publishing Group. doi:10.1038/nrclinonc.2012.83

54

courses of high-dose cytarabine as con-solidation therapy improves the sur-vival of these patients.4 In addition, ahigher dose of the anthracyclinedaunorubicin (90mg/m2 vs 45mg/m2)benefits patients younger than 60 years,with the exception of those withadverse cytogenetics and molecularaberrations (such as FLT3 internal tan-dem duplication).5

Clearly, escalation of chemother-apy dose seems to benefit patients withmore favourable risk disease includingyoung patients and those with morefavourable cellular biology determinedby cytogenetics or molecular abnor-malities. It is tempting to speculatethat the leukaemic cells in thesepatients are more susceptible to theeffects of cytotoxic chemotherapybecause of as yet unidentified mecha-nisms. Therefore, the limiting factorin such patients will be the limits oftolerability of the escalated dose ofchemotherapy. Other agents with novelmechanisms of action and with non-overlapping toxicity can potentially fur-ther improve the outcome when addedto the intensifiedstandard regimens.These potentiallyinclude cladribine,clofarabine, FLT3kinase inhibitors andgemtuzumab.

A recent study byCastaigne and col-leagues6 is amongseveral important randomised trialsevaluating the benefit of a low dose ofgemtuzumab added to the back-bone ofcytarabine and anthracycline-basedinduction chemotherapy. In this trial,280 patients with newly diagnosedAML aged between 50 and 70 yearswere randomly assigned to receivecytarabine 200 mg/m2 as a continuousinfusion for seven days and daunoru-bicin 60mg/m2 daily for three days with

or without a fractionated course of gem-tuzumab 3 mg/m2 on days 1, 4 and 7.6

There was a significant overall andevent-free survival advantage for thepatients treated with gemtuzumab.Attwo years, event-free survival was41.4% versus 15.6% in patients treatedor not treated with gemtuzumab,respectively, translating to an overallsurvival advantage for patients whoreceived gemtuzumab (median 25.4months vs 15.3 months). This benefitwas mainly seen in patients in the bet-ter-risk groups based on baseline cyto-genetic assessment.

In the SWOG 106 study, patientsbetween the ages of 18 and 60 yearswith AML were randomly assigned toreceive chemotherapy with or withoutgemtuzumab 6 mg/m2, and althoughthere was no overall survival benefit,patients with favourable-risk cyto-genetics who received gemtuzumabhad an improved overall survival.7 It isimportant to note that patients whoreceived gemtuzumab were treatedwith a lower dose of daunorubicin(45 mg/m2 for three days, now consid-

ered inferior) com-pared with 60mg/m2

for three days forpatients not receiv-ing gemtuzumab,with the intent ofproviding ‘equitoxic’regimens.

Burnett and col-leagues have reported

that the addition of a low dose of gem-tuzumab (3 mg/m2) to standard AMLchemotherapy regimens was associatedwith a significant improvement in overallsurvival in younger (mainly ≤60 years)patients with favourable-risk and inter-mediate-riskAML.8 Furthermore,Delau-nay and colleagues reported that theaddition of a low dose of gemtuzumab(6mg/m2) to chemotherapy significantlybenefits younger patients (between 18

and 60 years) who did not receive anallogeneic stem-cell transplant on firstremission (event-free survival advan-tage for patients who received gem-tuzumab P=0.045).9 A more recentstudy reported by Burnett and col-leagues came to the same conclusion asthe previous trial, again demonstratinga benefit for intermediate-risk andfavourable-risk cytogenetic groupsamong the older patients (between 51and 84 years) who received chemo-therapy plus gemtuzumab comparedto those receiving chemotherapy alone(three-year overall survival 25% vs 20%for those treated with versus withoutgemtuzumab, P=0.05).10

With the exception of the SWOG106 trial, where the addition of gem-tuzumab was associated with a signifi-cant increase in induction mortality(5.8% vs 0.8%, although these datahave not been well scrutinised), in allother reported studies, gemtuzumabwas not associated with a significantincrease in morbidity and mortality. Inparticular, and perhaps because of thelow doses of gemtuzumab employed inall trials, the incidence of sinusoidalobstructive syndrome of the liver waslow. Therefore, low doses of gem-tuzumab are able to increase the inten-sity of induction therapy withoutincreasing its toxicity and, in doing so,benefit the more-favourable-riskpopulation of patients with AML.This benefit in patients with morefavourable risk is as would be expected

Key pointThe addition of a low dose of gem-tuzumab ozogamicin to cytarabine andanthracycline-based inductionandcon-solidationchemotherapy improves sur-vival in patients with more-favourable-risk acutemyeloid leukaemia.

55

”“Low doses of gemtuzumab

are able to increase theintensity of inductiontherapy withoutincreasing its toxicity

according to the arguments for the sus-ceptibility of this population to doseintensification.

The trial by Castaigne and col-leagues,6 corroborated by data from sev-eral other randomised trials, clearlyestablishes gemtuzumab as an impor-tant drug for patients with better-riskAML. Why gemtuzumab is effective inthis specific subset of patients requiresfurther preclinical, translational andclinical studies. Its high efficacy intreating acute promyelocytic leukaemia(APL) is well established and may berelated to the higher expression of thetarget molecule, CD33, in APL cells.Pending these studies, however, thebenefits of gemtuzumab should not bewithheld from the appropriate patients(including thosewithAPL). Progress inAMLhas been slow.We clearly need toaccept positive data produced and con-firmed by several randomised trials.

References1. W Kern, EH Estey. (2006) High-dose cytosinearabinoside in the treatment of acute myeloidleukemia: Review of three randomized trials.Cancer 107:116–1242. R Willemze et al. (2011) High dose (HD-AraC)vs. standard dose cytosine arabinoside (SD-AraC)during induction and IL-2 vs. observation afterconsolidation/autologous stem cell transplantation inpatients with acute myelogenous leukemia (AML):Final report of the AML-12 trial of EORTC andGIMEMA Leukemia groups on the value of highdose AraC [abstract]. Blood 118:a2573. B Löwenberg et al. (2011) Cytarabine dose foracute myeloid leukemia. NEJM 364:1027–364. CD Bloomfield et al. (1998) Frequency ofprolonged remission duration after high-dosecytarabine intensification in acute myeloidleukemia varies by cytogenetic subtype. CancerRes 58:4173–795. HF Fernandez et al. (2009) Anthracycline doseintensification in acute myeloid leukemia. NEJM361:1249–596. S Castaigne et al. (2012) Effect of gemtuzumabozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): arandomised, open-label, phase 3 study. Lancethttp://dx.doi.org/10.1016/S0140–6736(12)60485–17. S Petersdorf et al. (2009) Preliminary results ofSouthwest Oncology Group Study S0106: an

international intergroup phase 3 randomized trialcomparing the addition of gemtuzumab ozogamicinto standard induction therapy versus standardinduction therapy followed by a secondrandomization to post-consolidation gemtuzumabozogamicin versus no additional therapy forpreviously untreated acute myeloid leukemia[abstract]. Blood 114:a7908. AK Burnett et al. (2011) Identification of patientswith acute myeloblastic leukaemia who benefit fromthe addition of gemtuzumab ozogamicin: Results ofthe MRC AML15 trial. JCO 29:369–3779. J Delaunay et al. (2011) Addition of gemtuzumabozogamycin to chemotherapy improves event-freesurvival but not overall survival of AML patients withintermediate cytogenetics not eligible for allogeneictransplantation. Results of the GOELAMS AML2006 IR study [abstract]. Blood 118:a7910. AK Burnett et al. (2011) The addition ofgemtuzumab ozogamicin to intensive chemotherapyin older patients with AML produces a significantimprovement in overall survival: Results of the UKNCRI AML16 randomized trial [abstract].Blood 118:a582

Author affiliationsFarhad Ravandi and Hagop Kantarjian,Department of Leukemia, University of TexasMD Anderson Cancer Center, Houston, Texas

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

the research agenda?� Are you getting the career

breaks you need?� Which is better? Medical

oncologist or organ specialist,robot or surgeon?

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

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

www.cancerworld.org

56

60

Preoperative chemoradio-therapy improves survivalin oesophageal cancer� New England Journal of Medicine

Preoperative chemoradiotherapy improvessurvival among patients with potentially

curable oesophageal or oesophagogastric-junction cancers, a phase III Dutch study hasfound.

Oesophageal cancer, which is the eighthmost common cancer worldwide, is responsi-ble for more than 400,000 deaths a year, withfive-year survival rates rarely exceeding 40%.

For several decades the role of neoadju-vant chemoradiotherapy has been debated.“In most randomized trials, no survival ben-efit could be shown, and the trials were crit-icized for inadequate trial design, samplesthat were too small, and poor outcomes inthe surgery-alone group,” write the authorsof the current study. While meta-analyses

P=0.003). At one year, overall survival was82% for the chemoradiotherapy plus sur-gery group, versus 70% in the surgery-alonegroup; at two years it was 67% versus 50%;at three years 58% versus 44%; and at fiveyears 47% versus 34%.

The most common major haematologicaltoxic effects for the chemoradiotherapy plussurgery group were leukopenia (6%) and neu-tropenia (2%); the most common major non-haematological toxic effects were anorexia(5%) and fatigue (3%). For both treatmentgroups the in-hospital mortality rate was 4%,with similar post-operative complications.

“This large, randomized trial of neoadju-vant chemoradiotherapy in patients withesophageal or esophagogastric-junctioncancer showed significantly better overall anddisease-free survival among patients whoreceived a chemoradiotherapy regimen basedon carboplatin and paclitaxel, followed by sur-gery, as compared with those treated withsurgery alone,” write the authors. Chemo-radiotherapy, they add, was associated with a

have suggested survival benefits fromneoadjuvant chemoradiotherapy, this hasbeen at the cost of increased postoperativemorbidity and mortality.

In the current study, between March 2004and December 2008 Ate van der Gaast andcolleagues, from Erasmus University MedicalCentre, Rotterdam, randomly assigned 368patients with resectable tumours (75%had adenocarcinoma, 23% squamous-cellcarcinoma, and 2% large-cell undifferentiatedcarcinomas) to receive chemoradiotherapy fol-lowed by surgery (n=178) or surgery alone(n=188). The chemoradiotherapy regimen con-sisted of weekly administration of carboplatin(doses titrated to achieve an area under thecurve of 2 mg/ml per minute) and paclitaxel(50 mg/m² of body-surface area) for five weeksand concurrent radiotherapy (41.4 Gy in 23fractions, five days per week).

Results show that the median overallsurvival was 49.4 months in the chemo-radiotherapy plus surgery group versus 24months in the surgery-alone group (HR 0.66;

Selected reports edited by Janet Fricker

61

low frequency of high-grade toxic effects andcould be given as an outpatient treatment.

One question that remains, note theauthors, is whether oesophageal and oesoph-agogastric-junction tumours should betreated with preoperative chemoradiother-apy or perioperative chemotherapy.

Two trials – the MAGIC trial and theACCORD 07 trial – found that perioperativechemotherapy provided better outcomes, theauthors report. However, both included gastrictumours in addition to oesophagogastric-junction tumours.

The POET trial, which randomly assignedpatients with oesophagogastric-junctiontumours to preoperative chemotherapy orchemoradiotherapy might provide a bettercomparator, suggest the authors. Here theinvestigators showed a non-significantsurvival trend favouring preoperativechemoradiotherapy.

� P van Hagen, M Hulshof, J van Lanschot et

al. Preoperative chemoradiotherapy for esophageal

or junctional cancer. NEJM 31 May 2012,

366:2074–84

Multidisciplinarycare boosts breastcancer survival� British Medical Journal

The introduction of multidisciplinary teams(MDTs) for the treatment of breast cancer

contributed to significant improvements inpatient survival, a Scottish study has found.

Cancer treatment has increasingly beenprovided within centralised, specialist MDTs inEurope, the US and Australia, after observa-tional evidence identified better outcomesfor such organisation. It has been unclear ,however, whether MDTs improve cancer sur-vival and the clinical benefits justify the costs.

In the current retrospective study, EileenKesson and colleagues, from Gartnavel RoyalHospital, Glasgow, evaluated the effects of

multidisciplinary care interventions for breastcancer implemented at National Health Serv-ice hospitals in the Greater Glasgow HealthBoard area in 1995, several years ahead of therest of the UK.

The MDTs consisted of a specialist surgeon(performing in excess of 50 operations forinvasive breast cancer each year), pathologists,oncologists, radiologists and specialist nurses.All worked to evidence-based guidelines, heldweekly meetings to agree on treatments forindividual patients and audited clinical activ-ity. In other west of Scotland areas, no sub-stantial reorganisation of breast cancer caretook place until 2000, when national guidancewas introduced.

Using data from the Scottish Cancer Reg-istry, together with death records, outcomeswere compared for 6050 patients who hadattended hospitals offering multidisciplinaryservices and 7672 who attended hospitals inneighbouring areas that did not introducemultidisciplinary care until later. The com-parisons were made before and after theorganisational change.

Results show that before the introductionof multidisciplinary care (between January1990 and September 1995), breast cancermortality was 11% higher in the interventionarea than the non-intervention area (HR 1.11).However, after multidisciplinary care wasintroduced to the intervention area (betweenOctober 1995 and December 2000), breastcancer mortality was 18% lower in the inter-vention area than in the non-interventionarea (HR 0.82).

Subgroup analyses by age group showedthe effect of the intervention on breast can-cer mortality was greatest in patients aged 80years and older (P=0.001), and significantalso in patients aged 65–79 years (P=0.01). Nosignificant effects were found for womenaged less than 50 years and 50–64 years.

“Our results support the universal provisionof cancer care by specialist, multidisciplinaryteams,” write the authors. “Further analysisof clinical audit data for multidisciplinary carecould identify which aspects of care are mostassociated with survival benefits.”

Commenting on the finding that benefits ofmultidisciplinary working were greatest inolder patients, the authors write, “Since theintervention guidelines were not age specific,they could have given surgeons and otherteam members more confidence to activelytreat older patients rather than managingthem conservatively.”

� E Kesson, G Allardice, W George et al.

Effects of multidisciplinary team working on

breast cancer survival: retrospective, comparative,

interventional cohort study of 13 722 women.

BMJ, published online, 26 April 2012;

doi:10.1136/bmj.e2718

Lifestyle interventionsare durable in cancersurvivors� Journal of Clinical Oncology

Atelephone-based lifestyle interventionprogramme targeting diet and exercise in

cancer survivors proved durable, continuing tobe effective one year after discontinuation, aUS study has found.

Cancer survivors are known to be atincreased risk for second malignancies, car-diovascular disease, diabetes, osteoporosisand functional decline. While diet and exerciseinterventions have been tested in cancer sur-vivors as a way to reduce late effects andcomorbidities, few studies have assessedadherence and long-term health outcomes.

In the Reach Out to Enhance Wellness(RENEW) trial, Wendy Denmark Wahnefriedand colleagues, from the University of Ala-bama, Birmingham, delivered a home-baseddiet and exercise intervention to 641 over-weight or obese (BMI >40 kg/m²) survivorsof breast, prostate and colorectal cancer.Participants also had to be sedentary (takingless than150 minutes of physical activity aweek), over 65 years and mentally andphysically able to participate. Interventionsconsisted of a personally tailored workbook,

telephone counselling, 15 minutes ofstrength training exercise every other dayand 30 minutes of endurance exercise eachday, daily consumption of seven servings offruit and vegetables for women, or nine formen, restriction of saturated fat to less than10% of energy intake and modest weightlosses of less than 0.5 kg/week. A previousreport by the authors showed that the inter-vention-group experienced significantly lessdecline in functional status, improvementsin dietary quality, increased physical activity,and modest weight loss, compared withcontrol participants.

The latest results show that for the imme-diate intervention arm there was little changein the results at the end of one year (when theintervention ceased) and the end of two years,with the exception of functional decline.

Diet quality was 66.4 at year 1 versus65.1 at year 2, using the Healthy EatingIndex 2005 criteria; weekly physical activitywas 101.1 minutes at year 1 versus 100.9 atyear 2; BMI was 28.2 at year 1 versus 28.2 atyear 2, while physical function (according toSF-36 scores) was 74.4 at year 1 versus 70.6at year 2.

“Data from long-term follow-up suggestthat the intervention was not only repro-ducible but also durable. In contrast to amajority of lifestyle interventions, significantimprovements in diet and exercise behaviorswere observed and maintained over the 2-yearstudy period; moreover, the modest weightloss that was promoted in this overweightsample of high-risk elders was sustained overthe same period,” write the authors.

In an accompanying editorial, JenniferLigibel from Dana-Farber Cancer Institute,and Pamela Goodwin from Mount Sinai Hos-pital, write, “The RENEW study adds to earlierreports by demonstrating the feasibility anddurability of weight loss interventions admin-istered at a distance to cancer survivors.”

There are, however, “important caveats”,they add, including the small proportion ofeligible individuals who opted to participatein the study (approximately 6%), the 25%attrition rate at two years, and the fact that

(n=127). The patients came from 16 hospitalsin Australia, New Zealand, the Netherlandsand Brazil.

Results show that, at a median follow-up of40 months, 20 relapses occurred among 109patients in the adjuvant radiotherapy groupversus 34 among 108 patients in the observa-tion group (HR 0.56; P=0.041). However no dif-ferences were found for relapse-free survival,where 70 events occurred in the adjuvant radio-therapy group versus 73 in the observationgroup (HR 0.91: P=0.56); or overall survivalwhere 59 deaths occurred in the adjuvant radio-therapy group versus 47 in the observationgroup (HR 1.37; P=0.12). The most commongrade 3 and 4 adverse events were seroma(occurring in nine patients in the radiotherapygroup versus 11 in the observation group), radi-ation dermatitis (occurring in 19 patients in theradiotherapy group) and wound infections(occurring in three patients in the radiotherapygroup versus seven in the observation group).

“This report confirms that adjuvant radio-therapy reduces the risk of further lymph-node field relapse after lymphadenectomy inpatients at high risk of relapse, although it hadno significant effect on overall survival,” writethe authors.

Early toxic effects related to radiother-apy, they add, were infrequent and minor. “Ifthe intention of treatment is to reduce the riskof regional recurrence, adjuvant radiotherapyis a treatment option that should be discussedwith patients at high risk of lymph-node fieldrelapse after lymphadenectomy.”

Future studies, write the authors, shouldcentre on exploring the role of radiotherapy inthe preoperative setting, where modern imag-ing modalities could be used to identify high-risk patients before surgery.

In an accompanying commentary, RogerMacklis, from Cleveland Clinic, Ohio, writesthat it will be important to explore the additionof targeted melanoma agents such as ipili-mumab and vemurafenib to local-field radio-therapy. One hypothesis, he adds, suggeststhat radiation effects result in heightenedpresentation or processing of immune sys-tem targets.

all study measures, including weight, wereself-reported.� W Demark-Wahnefried, M Morey, R Sloane

et al. Reach Out to EnhanceWellness home-based

diet-exercise intervention promotes reproducible

and sustainable long-term improvements in health

behaviors, body weight, and physical functioning

in older, overweight/obese cancer survivors.

JCO 1 July 2012, 30:2354–61

� J Ligibel and P Goodwin. NEW and

RENEW: Building the case for weight loss in

breast cancer [editorial]. ibid. pp 2294–96

Adjuvant radiotherapyhelps high-riskmelanoma patients� Lancet Oncology

Adjuvant radiotherapy improves lymph-node control in patients with metastatic

melanoma at high risk of lymph-node relapse,a study from the Australia and New ZealandMelanoma Trials Group and Trans-TasmanRadiation Oncology Group (TROG) has found.

The use of adjuvant radiotherapy afterlymphadenectomy to reduce the risk of furtherrelapse has been controversial in melanoma.Early reports produced conflicting results, withthe data clouded by variability in target fieldsizes, radiation doses and fractionationschemes. Although many major melanomatreatment centres now offer adjuvant radio-therapy to selected patients, others haveremained cautious due to the absence of clearsurvival benefits, and concerns about the pos-sibility of long-term radiotherapy-associatedmorbidity, such as lymphoedema.

In the current trial, between March 2002and September 2007, Bryan Burmeister andcolleagues, from Princess Alexandra Hospital,Woolloongabba, Brisbane, randomised 250melanoma patients who had undergone lym-phadenectomy, in a 1:1 ratio, to receive adju-vant radiotherapy of 48 Gy in 20 fractionsover four weeks (n=123) or observation

62

� B Burmeister, M Henderson, J Ainslie et al.

Adjuvant radiotherapy versus observation alone

for patients at risk of lymph-node field relapse

after therapeutic lymphadenectomy for

melanoma: a randomised trial. Lancet Oncol

June 2012, 13:589–597

� R Macklis. Finally, a substantial role for

radiotherapy in melanoma. ibid, pp 561–562

Low-dose radioiodineis effective againstthyroid cancer� New England Journal of Medicine

Two separate studies published in the sameissue found that low-dose radioiodine pro-

tocols used in patients with low-risk thyroidcancer had similar rates of successful tissueablation as conventional protocols. Takentogether, the results of the French and UKinvestigations suggest radiation doses couldnow be cut, write the authors of an accom-panying editorial.

Radioiodine is administered to patientswith thyroid cancer after total thyroidec-tomy for three reasons. First to eradicatenormal-thyroid remnants in order to achieveundetectable serum thyroglobulin levels, sec-ond to irradiate any neoplastic focus in orderto decrease the risk of recurrence; and thirdto perform total-body scanning for persist-ent carcinoma. Adverse effects of using highdoses of radioiodine include patients stayingin hospital isolation units for at least twodays, lacrimal and salivary-gland distur-bances and an increased risk of developingsecondary cancers.

In the first study, funded by the FrenchNational Cancer Institute and the French Min-istry of Health, Martin Schlumberger and col-leagues, from the Institut Gustave Roussy,Villejuif, randomly assigned 752 patients withlow-risk differentiated thyroid carcinoma toundergo one of four strategies, each combin-ing one of two methods of thyrotropin

stimulation – administration of recombinanthuman thyrotropin or thyroid-hormone with-drawal – and one of two 131I activities(1.1 GBq or 3.7 GBq). Patients were recruitedfrom 24 centres between 2007 and 2010, withthyroid ablation assessed eight months afterradioiodine administration by neck ultra-sonography and measurement of recombinanthuman thyrotropin-stimulated thyroglobulin.

Results show that, of the 684 patientswith data that could be evaluated, thyroidablation was complete in 631 (92%). The thy-roid ablation rates were found to be similarbetween the four groups – 90% for patientstreated with recombinant human thyrotropinwho received 1.4 GBq, 93% for patientstreated with thyrotropin who received3.7 GBq, 92% for patients treated with thyroidhormone withdrawal who received 1.4 GBqand 94% for those treated with hormonewithdrawal who received 3.7 GBq.

“Thus, the use of recombinant humanthyrotropin and a low dose of 131I for post-operative radioiodine ablation represents aneffective and attractive option for the man-agement of low-risk thyroid cancer thatreduces the amount of whole-body irradia-tion and maintains the quality of life,” writethe authors.

In the second study, done by CancerResearch UK, Ujjal Mallick and colleagues,from Freeman Hospital, Newcastle upon Tyne,compared low- and high-dose radioiodine(1.1 GBq and 3.7 GBq, respectively) in combi-nation with thyrotropin alpha or thyroid hor-mone withdrawal before ablation. The studywas undertaken in 438 patients with T1 to T3thyroid tumours with possible spread tonearby lymph nodes, but no metastasis.

On analysing the data for 421 patients,researchers found that low-dose radioiodinewas as effective as high-dose radioiodine(ablation success rates of 85.0% vs 88.9%).Comparing the groups treated with thy-rotropin alpha with those treated with thy-roid hormone withdrawal, ablation successrates were also similar (87.1% vs 86.7%).

Breaking the results down further, low-dose radioiodine plus thyrotropin alpha

showed a success rate of 84.3%), comparedwith 87.6% for high-dose radioiodine plusthyroid hormone withdrawal and 90.2% forhigh-dose radioiodine plus thyrotropin alpha.

But significantly more patients ran-domised to high-dose radioiodine had hos-pital stays of three days or longer (36.3% vs13.0%, P<0.001). The higher dose of 131Iwas associated with a higher rate of adverseevents (33% vs 21%, P=0.007). Adverseevent rates did not differ by method of thy-rotropin stimulation.

“Our study answers two central ques-tions involving radioiodine ablation of thyroidremnants after surgery for differentiatedthyroid cancer: namely, that the efficacy oflow-dose radioiodine is similar to that ofhigh-dose radioiodine, and that the efficacyof low-dose radioiodine ablation is not com-promised by the use of thyrotropin alfainstead of thyroid hormone withdrawal,”write the authors.

In an accompanying editorial Erik K Alexan-der and P Reed Larsen, from Harvard MedicalSchool, Boston, write, “These results shouldchange standard practice, although they alsoraise the question of whether any radioiodinetherapy is required for low-risk patients, since21 to 59% of the patients in these two studieshad already met the goal of a low thyroglobu-lin level after thyroidectomy alone.”

The future hope, they add, is that iden-tification of a pattern of gene expressionor patient characteristics associated witha higher risk of recurrence might allowmore-aggressive treatments to be focusedappropriately.

� M Schlumberger, B Catargi, I Borget et al.

Strategies of radioiodine ablation in patients with

low-risk thyroid cancer. NEJM 3 May 2012,

366:1663–73

� U Mallick, C Harmer C Yap et al. Ablation

with low-dose radioiodine and thyrotropin alfa in

thyroid cancer. ibid pp 1674–85

� E Alexander, P Reed Larsen. Radioiodine for

thyroid cancer – is less more? ibid, pp 1732–33

63

Ruth Conroy is a specialist registrar in clinical oncology at the Christie

Hospital in Manchester, UK. She came first out of a class of 62 young

oncologists from 28 countries in the learning assessment test at the

end of this year’s ESO Masterclass in Clinical Oncology.

� Why I chose to work in oncology…I didn’t havemuch exposure to oncologyas amedical student or a junior doctor soI think it held an air of mystery thatmademewant to find outmore. I reallyenjoyed my first oncology job and I’vebeen hooked ever since.

� What I love most about my job…I love the variety and the patient con-tact. It means no two work days areever the same.

� The hardest thing about my job…Patients’ expectations are growing andwith new drugs being developed all thetime it is getting increasingly difficult totalk about what comes next when treat-ment options are exhausted.

� What I’ve learnt about myself…I’m not very good at switching off fromwork butwith such a demanding job it isvery important to do so and I’ve realisedhow important it is tomaintain activitiesoutside work.

� I’ll never forget…The sight and smell ofmy first fungatingtumour!Whilst Iwas planning the radio-therapy with my consultant I did not

havemuch faith thatwewere going to beable to do much to help, but on seeingthe patient again in a few months itreally brought home to me what a mas-sive impact we have on people’s lives.

� A high point in my career…Obviously coming first in the Master-class examwas ahighpoint!Alsomy firstoral presentation at a conference, as itmade me realise how much I’d pro-gressed in my career and that all thehard work pays off in the end.

� I wish I were better at…Many things! Music would be up nearthe top of the list, I’ve always admiredthose who can just pick up a guitar andplay a tune. Hopefully one day I’ll findthe time for lessons.

� The most significant innovationin my specialty in recent years…It is difficult to pick just one but I thinkthroughout my career I have seen vastchanges in imaging techniques. As amedical student even CT was a some-what precious commodity and it wasn’tuntil I started work that I came acrossPET- CT, which is now part of the rou-tinework-up formany cancer sites.As a

clinical oncologist it is exciting to hear ofnew techniques that might help withtarget delineation for radiotherapy plan-ning to reduce toxicity.

� What I value most in a colleague…Honesty and reliability. I’ve found mostproblemscanbe sorted as long as peopleare honest about the situation. I don’texpect my colleagues to have all theanswers,but Iwant toknowthat Ican relyon themtodo their fair shareof thework.

� My advice to someone enteringmy specialty today would be…Enjoy it. Starting a new job can alwaysseem overwhelming but you are notexpected to know everything on yourfirst day so enjoy spending time withyour patients at difficult times in theirlives, and also being able to be at the cut-ting edge of medicine.

� What I wish I had learnt atmedical school…That it isOK tonot know the answer andthat sometimes there is no right answer!Patients and their illnesses havenot readthe textbooks somaynot follow the rules,so it is important to involve the individualwhen planning their treatment.

64