ANNALS OF MEDICINE THE THIRTY YEARS’ WAR Have we been fighting can c e r the wrong way?

BY JEROME GROOPMAN

o judge from recent headli n e s , we if o rn i a , has constituted a committee un- named Mary Las k e r .Bo r n in Wis c on s i n Tar e on the verge of con q u e r ing can - der the auspices of the Ame ri c an and educated at Rad cl i f f e, Lasker had ce r . The fea t u r e story in last week’s issue Soc i e t y to consider how the govern m e n t ach i e ved great success in the fashion in- of Ba r ron’s,entitled “In vesting in Health: should res p o nd to the cha l lenges of can - du s t r y;her husband, Al b e rt , had made a Cu r ing Cancer,” ended by saying that cer in the new mille n n i u m . fo r tune in advert i s i n g .Af ter the Las k e r s “we are fina l ly winning the war,” and pre- Im p o r tant advances have been made ret i re d ,t h e y devoted themselves to Dem- dicted that for our chi l d r en cancer will be in onc o l o g y in recent yea r s , and the cur- oc r atic Par ty politics and health-car e is- just another chr onic illn e s s , for which rent atmosphe r e of hope is not without su e s .M a r y Lasker was the quintessential th e y will simply “pop a few pills ever y fo u n d a t i on . But it is not without prec e - Ame ri c an idealist; she believed that with da y.” The cover of the May 28th issue of de n t ,e i t h e r : ever since 1971,when Pres - enough mone y, in flu e n c e , en e r g y, an d Tim e rea d , “Th e r e Is New Ammu n i t i o n ident Nix on decla r ed war on can c e r ,on- co nvi c t i o n you could accomplish any- in the War Against Cancer. These Are cologists and cancer patients have been th i n g .Th e n , in 1950, Al b e r t Lasker de- the Bulle t s , ” and Dr. Mi ch a el Gordon , caught in a cycle of eu ph o r ia and despair veloped intestinal can c e r . an oncologist at the Univer s i t y of Ar i- as the prospect of ne w treatments has For the first half of the twe n t i e t h zona , told Tim e rep o r ters that in 20 yea r s gi v en way to their sober rea l i t i e s . Th e ce n t u r y, cancer was mainly the provi n c e or so he “might just be out of a job.” Th e war on cancer turned out to be pro- of su r g e on s . Sma l l tumors that had not annual meeting of the Ame ri c an Soc i e t y fo u n d ly misconc e i v ed—both in its rhe t - sp r ead were cut out, al o ng with large of Cl i n i c al Oncology,ea r lier this mont h , or ic and in its exec u t i on . amounts of no r mal tissue, in an attempt was buoyed by a spirit of op t i m i s m ,a n d to cat c h any stray malignant cells . Sti ll , in the days that follo wed there was a he most ambitious health initiative mi c r oscopic deposits of cancer often sh a r p rise in the share prices of bi o t e c h- Tever undertaken by a country on be- rem a i n e d , and patients were given ra- no l o g y and pha rm a c e u t i c al comp a n i e s ha l f of its citizens began not with sc i e n - di a t i o n trea t m e n t s , intended to destroy that are developing cancer drug s .M e a n - ti s t s , physi c i a n s , po l i t i c i a n s , or patients the residual cells . A few che m o t h e ra p y wh i l e ,Senator Dianne Fei n s t e i n ,o f Ca l - but with a middle-aged New York e r dr ugs were used as well, so me of th e m

In 1971, the United Stat es gov ernment res o l v ed to find a cure for the in a congressional act that was signed into law by Richa r d

5 2 THE NEW YO R K E R, JUNE 4, 2001 de ri v ed from mus t a r d gas, wh i c h had Fou n d a t i on , in Boston. In the late for- bi l i t y,running a full-page advert i s e m e n t been used in the First Wor ld War .Th e s e ti e s , Far ber had discover ed that che m o - in the Tim e s that decla re d , “Mr .Nix on: tr eatments were highly toxic but seemed th e r apeutic drugs that blocked folic acid, you can cure can c e r. ”I f Ame ri c an deter- to shrink the can c e r ,at least temporari l y, an essential vitamin, br ought about re- mi n a t i o n and ingenuity had put a man in patients with such as Hodg- mi s s i o ns in some chi l d r en with acute on the moon just months before, wh y ki n ’s lymph om a . But for the vast major- le u k e m i a . His success in fighting this sh o u l d n ’t the nation attempt to conq u e r it y of patients whose had metas- de vastating pediatric cancer made him a cancer by Am e ri ca’s tw o - h u n d re d t h ta s i ze d , or spread beyond the initial site, fr equent “ci t i z en witness,” in vited by bi rt h d a y? This political gambit quickl y th e r e was little that could be done . Con g r ess to testify on behalf of me d i ca l gained mome n t u m . By the end of th e Lasker had , wh i c h did not le g i s l a t i on . Far ber believed that, if th e fo ll o wing summer, both the Senate and com p l e t e l y rem o ve the tumor. In t e s t i - right drugs were devel o p e d , the gains the House of Re p re s e n t a t i v es had unan- nal cancer spreads within the abdome n , he had seen in chi l d r en with leukemia im o u s l y passed a res o l u t i o n to cure can - de s t r oying the liver and often cau s i n g could be rep r oduced and improved upon. cer by the Bicentennial. gr eat pain. Af ter two years of un s u c - Lasker was also impressed by “ C u re In the ensuing debates over how this cessful trea t m e n t , Lasker died, and his for Cancer: A Nat i o nal Goal” (1 9 6 8 ) , a was to be accomp l i s h e d , Far ber argued wi f e—using her netwo r k of po l i t i ca l , bo o k by a Denver physician named Sol - be f o r e the House health subcomm i t t e e me d i ca l , and business cont a c t s , the ad- omo n Garb, who asserted that can c e r that res e a r chers did not need to fully un- ver tising savvy that he had embodied, cu r es could emerge quickl y if sc i e n t i s t s derstand the workings of cancer in orde r and the con s i d e rable re s o u rces from stopped searching for new answers and to proc e e d : “The 325,000 patients with his estate—set out to tran s f o r m the na- de voted themselves instead to aggres - cancer who are going to die this yea r ti o n’s res p o nse to the disease that had si ve l y exploiting existing knowl e d g e . cannot wait; nor is it necessary, in orde r ki l led him. By the late sixties, how e ver , the gov- to make great prog r ess in the cure of The Laskers had been major cont ri b - er nmental largesse that had cha ra c t e r - can c e r , for us to have the full solution of utors to the Am e ri can Cancer So c i - iz ed Lynd o n John s o n’s Great Soc i e t y al l the problems of basic res e a r ch. ” He et y, but after her husband’s death Mary pro g r ams had run its course; Nix on was pointed out that vaccination, di g i t a l i s , Lasker came to believe that onl y the de t e r mined to fight inflat i on , and Con- and aspirin were unquestiona b l y bene- gover nment had the financial and or- gr ess was under pres s u r e to hold down fici a l , even if doctors didn’t know ex- ga n i za t i o nal res o u r ces to launch a full- do mestic spending. To overc o me this ac t l y how they functione d : “The history fledged crusade against can c e r . In orde r res i s t a n c e , Ma r y Lasker organized the of me d i cine is replete with examples of to gain greater cred i b i l i t y in Was h i n g - first major gras s - r oots can c e r - a d v o ca c y cu r es obtained yea r s , de ca d e s , and even ton , she cultivated rel a t i o nships with gro u p , the Citizens Committee for the ce n t u r ies before the mechanism of ac - hi g h - p ro fi le academic physi c i a n s , mo s t Co nquest of Ca n c e r . On December 9, ti o n was understood for these cures . ” no t a b l y Sid n e y Farb e r , the scientific di- 19 6 9 , it began a campaign to make erad - What was needed, he maintained,was a rector of the Children ’s ica t i o n of the disease a fed e r al res p on s i - ge n e ro u s l y funded cancer institute with

on . The war on can c e r has been gen e rating cycles of eu p h o r ia and disappointment among patients and doctors ever since. st r ong leadership and a cle a r ly arti c u l a t e d fr om the sort of di r ected funding that in this country and around the world . ” battle plan. was now being prop o s e d . Th r ee decades later, the high expec- Ri ch a r d A. Rettig points out, in his Far ber dismissed such crit i c s , sa yin g ta t i o ns of the early seventies seem al- b o ok “Cancer Cru s a d e” ( 1 9 7 7 ) , t h a t that they were not “cancer people,” an d most willf u l ly naïve. This year alone , Farb e r ’s view was not univer s a l ly ac- we r e theref o r e ignorant of the possi- mo r e than a milli o n new diagnoses of ce p t e d . Some scientists argued that a bilities at hand. Con g r essmen who ex- major cancers will be made and about cu r e for cancer could not come about by p ressed doubts about the wisdom of five hundred and fifty thousand Ame r - di re c t i ve . One such dissenter was a col- rap i d ly spending vast sums of mon e y in ic ans will die of can c e r ,an aver age of fif- league of Farb e r ’s at Harva rd , Dr.Fran - res p o nse to what was essentially anecdo- teen hundred a day. In the course of a cis Moore, the surgeon- i n - ch i e f at the tal testimony became targets of the Cit- li fe t i m e , one of ever y three Ame ri ca n Peter Bent Brigham Hospital. Mo o r e, iz ens Comm i t t e e . Th e y rec e i v ed hun- wo men will develop a potentially fatal a medical - h i s t o r y buff, inv o ked what dr eds of thousands of pleading letters, ma l i g n a n c y. For men, the odds are one might be cal led the law of un i n t e n d e d and committee members threatened to in two . Al l the same, the triu m ph a l i s t co nsequences in scientific discover y. If w o rk against their re ë l e c t i on if t h ey rhe t o r ic that animated the war on can - th e r e had been a diabetes institute in di d n ’t rec o nsider their position. cer still shapes public opinion: ma n y the late nineteenth century,for example, Lasker also persuaded Cong r ess to people believe that cancer is, in essence, it would not have funded Lan g e rh a n s ’ s co nvene a panel of ex p e rt s , with Sid n e y a single foe, that a single cure can de- re s e a rch on the pancre a s , w h i ch led Far ber as the co-cha i rm a n ,w h i c h laid out st r oy it,and that the gover nment is both to the discover y of in s u l i n , be c ause the the battle plan for the war against can - res p o nsible for and capable of sp e a r - link between diabetes and insulin was ce r . The President would henceforth ap- heading the ca m p a i g n . The military not rec o g n i z ed at that time. Sim i l a r ly, a point the director of the Nat i o nal Can- me t a p hors have retained their potency— gover nment institute on polio prob a b l y cer Institute, and the institute’s budget even though they have proved to be in- wo u l d n ’t have supported the work of would be submitted direc t l y to the Whi t e ap p ro p r iate and misleading. Dr. Jo hn Enders in the late nineteen- Ho u s e , by passing the regular channels fo rt i e s , when he was attempting to grow of the Nat i o nal Institutes of H e a l t h .I n n the early nineteen-seve n t i e s ,m a ny the mumps virus and found the method De c e m b e r , 19 7 1 , Con g r ess passed the Ires e a r chers believed that a cancer was that ultimately proved essential to pro- Nat i o nal Cancer Act , and Nix on signed ge n e ra l ly caused by a virus that trig g e re d ducing the polio vaccine. Advances had it into law less than two weeks afte r - im p o r tant changes in a cell’s metab- oc c u r r ed in medical res e a r ch ,M o o re ar- wa rd . At a cerem o ny that made front - ol i s m , and that these changes accounted g u e d ,b e cause support had gone to cre- page headlines in newspapers across the for a tumor’s uncont ro l led growth . Ab - at i v e res e a r chers in univer s i t i e s , “oft e n co u n t r y, Nix on decla re d , “This legisla- no r malities in the genes of the can - young people, of ten unheard- o f pe o - ti on — p e r haps more than any legislation cer cell were thought to be incidental, pl e . ” In fact, he could not reca l l a single I have signed as President of the United rather than fundamental, to the disease. example of a scientific brea k t h r ough Sta t e s — c an mean new hope and comf o r t The virus hypothesis was plausi- of cli n i c al importance which had come in the years ahead for milli o ns of pe o p l e ble because there were some hundred vi r uses that were known to cause can c e r in amph i b i a n s , b i rd s , and mammals. These were so-ca lled re t rov i ru s e s — RN A viruses that made their way into no r mal animal cells , copied their genes into a DNA form, and then subvert e d the ordi n a r y functions of the cells for their own rep ro d u c t i on . The origin of most human can c e r s , the experts con- te n d e d , would prove to be ret r ovi r uses as we ll , and hundreds of mi ll i o ns of do l - lars were poured into res e a r ch to prove this assumption. Sid n e y Farb e r ’s panel didn’t just set the govern m e n t ’s burea u c r atic approa c h to can c e r ; it also dictated the Nat i on a l Cancer Institute’s scientific agenda in re- se a r ch and cli n i c al testing. The N.C.I. aw a r ded cont r acts to refi ne systems for gr owing cancer cells in bulk, and for pro- ducing enzymes that cut and copied DN A and RNA so that the nucleus of “What I’d like to know is what the hell happened the cancer cell could be dissected and to all the virgins in this town.” the hidden human cancer viruses ex- po s e d . Hu n d r eds of thousands of bo - ta n i c al extracts and che m i c al poisons we r e syst e m a t i ca l ly screened against dif- fer ent cancer cells to find the next gener- at i o n of cu ra t i v e drug s . To test these new dru g s , the N.C.I. ut i l i z ed a vast cli n i ca l - tr ials netwo r k of “co ö p e ra t i v e grou p s , ” wh i c h were organized with the help of fifteen new cancer centers across the na- ti on . The N.C.I.also designated funding to train young physicians to become on- co l o g i s t s , the specialists who would pre- sc r ibe the new drug s . The N.C.I. cli n i ca l - t r ials netwo r k em p l o yed three phases of testing new dru g s . Phase I sought to determine the tox i c i t y of the treatment and the max- im um dose that patients could toler- at e . Phase II assessed whether the ther- apy was of an y benefit, and what doses of the drug and schedule of tre a t m e n t seemed to work; it also established ob- j e c t i ve standards to measure success rat e s . Phase III studies comp a r ed the • • s a fe ty and benefits of the tre a t m e n t under revi e w with standard thera p i e s .I f the results were concl u s i ve l y favorab l e , lymph o ma res e a r ch in this country. It The prognosis for leukemia patients then the therapy would be submitted to wi l l cost five milli o n dolla r s , and in the was grim , but my family was extrem e l y the F.D. A . for approva l . end it will show that the treatment we ho p e f u l ; my gran d m o t h e r ’s doctors told Within two yea r s , the war on can c e r st a r ted with is as good as but no better us that scientists were close to identi- was well under way, but the mirac u l o u s than any of the others.’ ”A nd this, in - fy ing human cancer virus e s , and that cu r es failed to appear. Ma n y of the new de e d , was the res u l t . The need to justify ne w treatments would soon be available. che m o t h e r apeutic drugs proved to be so the burea u c ra c y meant that scores of Building on the logic of cancer as an in- to xic that they were quickl y abandone d . cli n i c al trials of rel a t i ve l y ineffec t i v e but fectious disease,res e a r chers thought that, In the absence of ef fe c t i v e single agents, to xic drugs were conducted with little if the body could some h o w be made to doctors began using comb i n a t i o ns of be n e fi t to the patient or to . rec o g n i z e the cancer cell as aberra n t ,i t s less effec t i v e drug s , gi v en at the high- im m une system would attack the tumor; est dose a patient could tolerat e . At the he same year that Nix on signed the by injecting the cancer patient with ex- same time, the cli n i ca l - t r ials netwo r k TNat i o nal Cancer Act , my gran d - tr acts of mi c ro b e s ,t h e y hoped to jump- had to justify its existence. Dr. Vin c e n t mother Rose, an energetic sixty- s e ven - st a r t that immune res p on s e . De Vi t a , a prominent cancer specialist year-old Bronx home m a k e r , fel l ill. She Af ter two years of st a n d a r d che m o - and a former director of the N.C.I.,wh o ex p e r ienced frequent bouts of ex h a u s - th e ra p y ,when my gran d m o t h e r ’s cond i - is now the head of the Yale Cancer Cen- ti on , her lower back ache d , and myst e r i- ti o n began to deterio r ate once more, a te r , reca l ls his frus t ra t i o n with the N.C.I. ous bruises began to appear on her arms specialist rec o mmended moving her to when he was working there in the sev- and legs. A blood test showed that her the front lines of im m une therap y .She en t i e s , be f o r e he became the direc t o r . wh i t e - b l o o d - c e l l count was extrem e l y was enrol led in an experimental trial that His res e a r ch group developed a trea t - hi g h , and that many of the cells were used an immune booster cal led MER ment regimen for an aggres s i v e form of a b n o rm a lly large and immature . M y (m e t h a n o l - e x t r acted res i d u e ) , a prep a r a- cancer cal led large-cell lymph om a ,u s i n g gr andmother had chr onic myel o g e n o u s ti o n from tuberculosis-like bacilli . Th i s a comb i n a t i o n of che m o t h e r apy drug s . le u k e m i a , or CML,a cancer of the bone - ex t r act was injected under the skin of In 1975, about forty- o ne per cent of th e ma r r ow stem cells . Malignant white cells her back. Ea c h injection was meant to patients with this lymph o ma were cured gr ow uncont ro ll a b l y, filling the marrow cause seve re infla m m a t i on , t h e re b y using DeVi t a’s re g i m e n . The N.C.I. and flooding the bloodstrea m . The ache st i m ulating her immune system to attack pr oceeded to comp a r e the therapy with in my gran d m o t h e r ’s back came from the can c e r .I was a medical student at the four similar trea t m e n t s . “I screamed my this expanding mass of leukemia pres s - ti m e , and I remember examining her head off, sa yin g ,‘You are all craz y! None ing within her bone s . Her exhaustion af ter the trea t m e n t s . Her back was stud- of these regimens is good enough to was caused by sever e anemia, and the ded with raised welts, the size of si l ver me r it being tested against another,’ ”De - de p l e t i o n of platelets in her blood was do ll a r s , that ran paral lel to her spine. Vita reca ll e d . “ ‘You will wrap up all the pr eventing it from clotting norma l ly. When I touched them, th e y felt hot and

THE NEW YO R K E R, JUNE 4, 2001 5 5 aw a r ded without any real scrut i n y.I was besieged by scientists who felt mone y was being wasted.” Instead of letting the senior staff at the N.C.I. co ntinue to dictate res e a r ch objectives and then con t r act outside laborat o r ies to perfo r m muc h of the work ,U p t on gave prio ri t y to non- g over nment scientists who ap- plied for gran t s . These applicat i o ns were assessed by an independent comm i t t e e of sc i e n t i fi c peers. “I took a lot of he a t for it,” Up t o n said. “Bu re a u c r ats didn’t like their turf being inva d e d . ” Dur ing this perio d , Dr. Ha r old Var - mus and Dr. M i ch ael Bishop, at the Un i ve r s i t y of Ca l i f o rn i a , San Fran c i s c o , who were using fed e r al funds to study vi r uses as the cause of can c e r , found ev- idence to suggest the opposite: that the seeds of our destruc t i o n are pres e n t within our DNA. These seeds are onc o - ge n e s , genes that can cause cancer when th e y mut a t e . Although the significan c e of oncogenes was not immediately un- de r s t o o d , by the early nineteen-eighties the notion that most cancers were cau s e d • • by human ret r ovi r uses had been largely di s ca rd e d . The bulk of cancer res e a r ch had been built on a false prem i s e . she winced in pain. Nevert h e l e s s , Ro s e Ma r y Lasker and President Nix on to my Yet the idea that the immune syst e m res o l u t e l y kept ever y weekly appoint- gra n d m o t h e r ’s oncologist—had rai s e d could be stimulated to rec o g n i z e and at- ment and rec e i v ed ever y injection. “I’m the hopes of Ame ri c ans suffer ing from ta c k cancer cells—that the power to heal going to lick this,” she said to my mother the disease to extrao rd i n a r y heights. ou r s e l ves lies within our own bodies— af ter each trea t m e n t . “Th e y didn’t give The Bicentennial celebrat i o ns came and remained tantalizing, even after the fail- me a placebo. I’m luck y. I’m getting we n t , and more people were dying of ur e of tr eatments like ME R. Some con- the cure. ” cancer than ever before. je c t u re d that the crude immune boosters Af ter nearly a yea r , it was clear that like the ones my grandmother rec e i ve d the immune therapy wasn’t worki n g . n 1977, when Dr. Ar thur Upton, a had failed onl y because the triggers were We were not told at the time, but MER Irad i a t i o n expert, was appointed di- not powe r ful enough,and that what was wa s n ’t working for anyone else in the rector of the Nat i o nal Cancer Institute, needed was a pure and potent stimul u s . st u d y , ei t h e r . My gran d m o t h e r ’s leuke- he was immediately attacked for the In t e r fer on, a natural protein that func- mia soon accelerat e d , then exploded into N. C . I . ’s failures . “I spent muc h of my ti o ns as part of the body’s immune sys- “blast cris i s , ”w h i c h means that hordes of time disabusing the public of the notion te m , was believed to be such a trig g e r . pri m i t i v e cells invade vital organs like that the war on cancer was like the Man- T h ree major types of i n t e rfe ron the lungs, the liver , and the kidneys ,a n d hattan Project or the Apo l lo space pro- had been identified — a l ph a , be t a , an d the patient becomes susceptible to in- gra m , ” he told me rec e n t l y. “It wasn’t gamma—and laborat o r y experim e n t s fec t i on s . In 1976, Gr andma Rose con- me re l y engineeri n g. We didn’t know suggested that all of them might be effec - tr acted a bacterial pne u m o nia and died. enough about biology to understand the ti v e in fighting aggres s i v e,che m o t h e ra p y - In many res p e c t s , my gran d m o t h e r ’s pr oblem and point to solutions . ” Cl i n i - resistant ca n c e r s , s u ch as melanom a , ex p e r ience in Phase I and Phase II tria l s cians argued that not enough mone y had metastatic breast can c e r ,and kidney can - was typi ca l ; most cancer treatments are been earma r ked for trials of di f fe re n t ce r . Animal tests were encourag i n g ; in unpleasant at best, and there is no way th e ra p i e s , while scientists doing basic mi c e , in t e r fer on caused tumors to melt to judge the efficac y of a new approa c h res e a r ch pointed to milli o ns of do ll a r s aw a y without harming normal tissue. without testing it on human beings. that had been spent chasing none x i s t e n t Soo n oncologists and journalists were What was unusual was how little sci- vi ru s e s . Up t o n began to question how speaking of in t e r fer on as the long - a w a i t e d en t i fi c basis there was for these parti c u - the N.C.I.’s budget was being handle d . pa n a c e a , and on March 31, 19 8 0 , Tim e lar experim e n t s , and how muc h sensa- “Bu re a u c r ats were spending vast sums ran a cover story on the drug .The Ame r - ti o nalism surrounded them. Eve r yone of mon e y at the N.C.I.without rigo ro u s ic an Cancer Soc i e t y spent two milli o n inv o l ved in the war on can c e r — f r om peer revi e w,” he said. “C on t r acts were do l lars on interfer on that had been puri-

5 6 THE NEW YO R K E R, JUNE 4, 2001 fied in Finland from the blood of vo l u n - cal led T lymph o c yte s . Dr.Ste ven Rosen- af f o r ds at best a marginal improvem e n t , teer dono r s . Pha rm a c e u t i c al and bio- be r g ,at the N.C.I.,ex p e r imented with re- so it is possible to discern its benefits te ch n o l o g y companies spent hundred s mo ving lymph o c ytes from cancer patients, on ly in large studies conducted ove r of mi ll i o ns of do l lars to genetical ly en- st i m ulating them with interle u k i n - 2 , lo ng perio d s . gineer alpha , be t a , and gamma inter- and ret u r ning them to the patients. In a Most of the new cancer drugs were fer on, then produced the proteins in few instances, th e r e seemed to be sig- ex t re m e l y toxi c , and the real advances large quantities.With great fanfare, cli n - ni fi cant shrinkage of metastatic mela- we r e in finding drugs that would tem- ic al trials began. n oma and kidney ca n c e r. A g a i n , the per their side effec t s . Pla t i n o l , wh i c h new s media were filled with speculations can cure testicular can c e r , caused in- s a cancer res e a r cher in Boston, I that a cure had been found. The N.C.I. tense nausea and projectile vomiting that Apa r ticipated in Phase II studies of spent mill i ons of d o llars supporting could last for days; in some patients, th e al p ha and gamma interfer on. As soon as in t e r leukin-2 tri a l s ,w h i ch were admin- ret c hing was so sever e that it tore the the trials were announced, we were del- is t e r ed to cancer patients both at the es o ph a g u s . It led res e a r chers to devel o p uged with requests from cancer patients N. C . I . and in cancer centers across the potent anti-emetics. Other che m o t h e r - who were desperate to parti c i p a t e ; we na t i on . The new treatment was also ex- apy drug s , like Adri a m yc i n ,d e s t r oyed so could admit onl y a few, and then had to tre m e l y toxi c . A few patients experi- ma n y white blood cells that the patient explain to hundreds of others that the enced seve re ca rdiac and pulmon a ry was susceptible to fatal infec t i on s . Pro- rosters were fille d . com p l i ca t i o ns and died. teins like G-CSF were found that could A woman I will cal l Nor a Dus q u e t t e In 1987, a fifty- s e ven - y ear-old frie n d st i m ulate the bone marrow to prod u c e was accepted for treatment in 1983. and colleague I will cal l Sam uel Dris c o l l white cell s ,t h e reby grea t l y reducing the Nora , a middle-aged scho o l t e a ch e r , wa s rec e i v ed a diagnosis of ki d n e y can c e r . likelihood of s u ch com p l i cating in- in the late stages of malignant mela- He underwent extensive surgery to ex- fec t i on s . Ev en some of the toxi c i t y of nom a . The cancer not onl y had forme d cise the prim a r y cancer and the meta- in t e r leukin-2 was ameliorat e d .T h u s ,t h e large black deposits in the skin on her static deposits, wh i c h were in his abdo- ho r r ors of che m o t h e r apy were some - ar ms and back but had spread to her men and lungs, but within a year the times made less sever e, or , at least, le s s lymp h nodes, her lungs, and her liver . cancer had ret u rn e d . Sam participated in pro l on g e d . Chemo also became easier We treated her with high doses of in t e r - a Phase II study using interle u k i n - 2 . to administer, and oncologists could of- fer on by injection three times a week. Lymph o c ytes were rem o ved from his fer some rea s s u r ance to their patients No ra lived in New Hampshire, and b l o o d ,t reated in the laborat o r y with the that refi nements in supporti v e therap y was still teaching full time when she im mu n e - s t i m ulating prot e i n , and then would reduce the sufferi n g . first came to see me, and yet she was rei n f u s e d . As with virtu a l ly all other pa- By the nineteen-eighties, a huge su- mo r e than willing to driv e two and a tients in these cli n i c al tria l s , he suffere d pe r s t ru c t u r e had resulted from the gov- ha l f hours to Boston for her therap y . se ver e side effects and had to be hospi- ern m e n t ’s war on can c e r . Some eight Nor a experienced intense side effec t s : ta l i ze d . He had high fever s , a widesprea d bi ll i o n dollars had been spent. Ab o u t fever s , chi ll s , loss of ap p e t i t e , and ex- ras h , and difficu l t y brea t h i n g ; his body th i r ty gover nment-funded comp re h e n - tr eme fatigue. Af ter her injections , sh e be c ame painfully bloated. Sam did enjoy si v e cancer centers and major reg i on a l was rare l y able to sleep through the a six-month rem i s s i on , du r ing which c o ö p e ra t i ve treatment groups linked ni g h t . She also started losing weight he continued to teach and do res e a r ch. v i rt u a lly all unive r s i ty hospitals and rap i d ly. Soo n she was no longer able to Then the cancer rec u r r ed—this time in com mu n i t y-based specialists.The Ame r - te a c h or to maintain her household,an d his lungs—and he died of pu l m on a r y ic an Soc i e t y of Cl i n i c al Oncology had she had to rel y on family members to fa i l u r e within a mont h . gr own from sever al hundred members take car e of he r . Af ter four mont h s , it to nearly ten thousand. Cancer trea t - was clear that the treatment wasn’t hav- hy did doctors welcome thera- me n t had become one of the cash cows ing any impact. The cancer spread to W pies with known tox i c i ty and o f a cademic and com mu n i ty hospi- her brai n , and a few weeks later she died. un c e r tain gain, and why did patients t a l s ,w h i ch competed fierc e l y for patient For the vast majorit y of can c e r s , it like Sam Dris c o l l subject themselves to refe r ra l s . Treatment had also become tu r ned out, in t e r fer on just didn’t work. them? Because the conven t i o nal thera- the focus of a wide range of can c e r - Al p ha interfer on did prove successful in pies were no better. The best way to a d v o ca cy gro u p s , whose con s t i t u e n t s the treatment of so me rar e can c e r s — e s - tr eat tumors is by detecting them early fo rc e f u l ly lobbied Cong r ess for more pe c i a l ly hairy- c e l l leukemia—but Nor a’s enough to prevent their growth and funds to address their needs. ex p e r ience was typi ca l : like the major- sp re a d , but many oncologists don’t meet Th e r e were some success storie s ; by it y of cancer patients who participate their patients until long after that point. la b o ri o u s l y cobbling together comb i n a - in these kinds of st u d i e s , she suffere d As one doctor said bitterly to me,“Wha t ti o ns of che m o t h e r apy agents, res e a r ch- con s i d e r able toxi c i t y with no apparen t do you say to these people—‘ Too bad, ers had discover ed that the majorit y of be n e fit . you flunked preven t i o n’? ” Ironi ca l ly,th e patients with Hodgkin’s lymph o ma and By 1985, hopes had shifted to a pro- na t u r e of the N.C.I. studies meant that ne a r ly all patients with testicular can c e r tein ca lled interl e u k i n - 2 , w h i ch had in Phase III trials treatments with slight could be saved . Gr eat strides were also been discover ed at an N.C.I. la b o ra t o r y. be n e fi ts were used on more patients for made in treating sever al pediatric can - In t e r leukin-2 stimulates immune cells a longer time; in t e r fer on, for example, ce r s .U n f o rt u n a t e l y, al l of these types of

THE NEW YO R K E R, JUNE 4, 2001 5 7 tumors are rel a t i ve l y unusual. Hu n d re d s th r ough preven t i o n and early detection. of thousands of cancer patients under- In fact, the principal benefits from SHOWCASE BY ALEX & LAILA went experimental trea t m e n t s ; in most the war on cancer have been in other cas e s , the pain and discomf o r t caused by rea l m s . The technologies developed to the side effects were unaccompanied by seek out cancer viruses in the seven t i e s MOBY--DICK genuine benefit, and in some cases the and eighties coalesced in the new field of tr eatments were fatal. , wh i c h opened up the ce l l and its genetic blueprint to examina- n 1984,Vincent DeVit a , who had be- ti o n for the first time.This revo l u t i on a r y Ic ome the director of the Na t i on a l DN A work also spawned a highly lucra- ar lo Ad i n o l fit rained first as a Cancer Institute four years earli e r , pr o- ti v e industry. Using the tools devel o p e d Cda n c e r , and then, be c ause mone y vided Cong r ess with a new goal in the th r ough the Nat i o nal Cancer Institute’s was an object,as a carp e n t e r . His solo war on can c e r : a fifty-per-cent red u c t i o n con t ra c t s ,b i o t e ch n o l o g y companies have sh o w “One-Man ‘Mo b y - D i ck ’ ” wi l l in can c e r - r elated morta l i t y by the yea r cr eated lifesaving treatments for heart be presented at the New Bedford 20 0 0 . Acc o r ding to an arti c le by John C. d i s e a s e, s e p s i s , c o l i t i s , and countless Whaling Museum, in Massachu s e t t s , Bailar III and Elaine Smi t h , wh i c h ap- other serious maladies.Eq u a l ly dram a t i c on July 19th, to celebrate the hundred - pe a r ed in The New England Journal of gains were made in AI D S res e a r ch: th e an d - fi ftieth anniver s a r y of the novel ’s Me d i c i n e , in 1986, this pred i c t i o n was molecular techniques and reagents used pu b l i ca t i on , and later this summer at not justified by cli n i c al data. Ba i l a r , wh o to search for human cancer viruses proved the Sha k e s p e a r e & Com p a n y studio had worked at the Nat i o nal Cancer In- essential in identifying H.I.V.and map- festival in the Berks h i re s . In it, Adi n o l fi stitute as a statistician studying trends ping its genes.In addition, the inven t o r y pl a ys Ishmael (a surpri s i n g l y spry,cha t t y in cancer incidence and outcome s , ha d of failed cancer drugs includes agents like Is h m ae l , with something of an English gr own wary of the pred i c t i o ns surrou n d - AZ T, wh i c h proved beneficial in trea t i n g ac c e n t , since Adi n o l fi ,who is Italian,gr ew ing the war on can c e r .Bailar and Smi t h ’s AI D S . These unintended cons e q u e n c e s up in South Lond on ) ; he plays Aha b , p a p e r, d i s p a s s i on a t e ly analyzing the of the war on cancer make it more diffi- pegging the stage in a fury; an d , in a claims of recent “ad v a n c e s ” in trea t i n g cult to gauge its success or failure. rem a r kable piece of sp e c i e s - s h i ft i n g , can c e r ,de m on s t r ated that there had been “The idea of a war sets up a false met- Adi n o l fi also plays the whale.To become a slow and steady in c re a s e in cancer deaths ric , ” sa ys Dr. David Golde, wh o , as the the mons t ro u s ,m ys t e r ious crea t u r e, he over sever al decad e s . It conc luded that physi c i a n - i n - ch i e f at Memorial Slo a n - tu r ns away from the audience, tu c ks his “we are losing the war against can c e r. ” Ke t t e r ing Cancer Center, oversees all head below his shoulders, twists his fee t The paper was extrem e l y cont r over - the institution’s cli n i c al prog ra m s . “If a ar ound each other,and rol ls and rip p l e s si a l . Some felt that the authors hadn’t co mplete victory is not achi e ved , then his dorsal mus cl e s . The carp e n t e r gi v en certain treatments adequate time it is deemed a failure. ” Do we examine Adi n o l f i—he makes a living building to be prop e r ly measured ; others felt that the impact on patients and their fami- sets—has con s t r ucted a series of pro p s , their statistics were not meaningf u l lies? Do we ask whether patients’ qu a l - the gradual un veiling of wh i c h amounts without more specifics . In res p on s e , in it y of li f e is improved—do they get more to an adven t u r e story all its own : a few 1997 Bailar and Heather Gornik pub- time without can c e r , even if the tumor st r uts of wood become the prow of a lished a more sophi s t i c ated analysis in ul t i m a t e l y ret u r ns and kills them? Do whaling boat;Pip , the boy driv en mad the same journa l , entitled “Cancer Un- we measure success and failure in terms by a fall overb o a rd , is a wooden arti s t ’s de fe a t e d . ” He r e the authors examined o f cost and benefit , calculating how model suspended on a strin g ; a length a ll Am e ri can cancer deaths betw e e n muc h mone y is spent in treatment and of silk fabric become s ,v a ri o u s l y, th e 1970 and 1994 according to age, se x , h ow mu ch econ omic pro d u c t i v i ty is rippling water,the whale’s flan k ,a n d , and type of di s e a s e . Th e y showed that gained for the nation? Or do we mea- when sq u e e zed between Adi n o l fi ’s th e r e had been a six-per-cent increase in su r e it by knowledge gained, pro g r ess ha n d s , a mound of pr ecious sperm- age-adjusted morta l i t y due to can c e r in scientific understanding, even if th a t ac e t i . Adi n o l fit ra n s f o r ms a tiny stage since Cong r ess first acted, at the behest kn o wledge is not rea d i l y translated into into both the sea-locked world of of Ma r y Las k e r .Th e r e had been a rec e n t im p r ovements for patients? Th e r e is no the Peq u o d ’s decks and the vast, di p , about a quarter of a per cent per co nsensus among cancer specialists on un f a t h o mable sea itself. In an yea r , wh i c h they attributed to red u c e d these questions . ex t ra o rd i n a r y scene based on the ci g a r ette smoking and improved scree n - chapter “The Grand Arma d a , ” he drag s ing (thanks to mammogram s , co l on o - n the past decad e , cancer res e a r ch has a tiny wooden vessel on a wire acros s sc o p i e s , and Pap smears). This said lit- Ipro g r essed in a number of di f fe re n t the stage, wh i c h thereby becomes the tle for the enormous efforts that had di re c t i on s . In the area of im m une ther- oc e a n ’s surfa c e ,ar ched with endless sky. been made over the previous decades ap y , th e r e have been some promising Then he picks up the model and hangs on the therapeutic front . Bailar believes results from so-cal led mono cl o nal anti- it from a hook overh e a d , and suddenly th a t , instead of focussing exclu s i ve l y bo d i e s , like Rituxan,wh i c h train the im - we are in the other element—the deep, on fighting this generat i o n of can c e r s , mune system to rec o g n i z e tumor cells . wh e r e onl y the whales are at home . our work should be directed tow a rd Th r ee years ago, a flur r y of exc i t e m e n t th w a r ting future generat i o ns of tu m o r s g reeted some early results in animal —R eb e c c a Mead

5 8 THE NEW YO R K E R, JUNE 4, 2001 TNY—06/04/01—PAGE 5 9—LIVE OPI ART—TOP:R 9996A; BOTTOM:R 96 6 6 B — 1 3 3 S C . — CRITICAL CUTS TO BE WATCHED THROUGHOUT ENTIRE PRESS RUN!!!—#2 PAGE studies of an g i o g e n e s i s , co nducted by Norm a l ly, oncogenes provide the blue- the private and the public sectors began the res e a r cher Judah Fol k m a n . Fol k - pr int for proteins that signal when a cell se a r ching for ways to target these mal- ma n ’s res e a r ch identified comp o u n d s should divide, ma t u r e, and die; th e y are fu n c t i o ning genes. Ch e m o t h e r apy and that might prevent a tumor from gener- of ten described as the accelerators of th e rad i a t i o n have trad i t i on a l ly been crud e ating its own blood supply,and so chok e ce l l’s growth . A mutated oncogene may tools against can c e r , i n d i s c ri m i n a t e ly its growth .U n f o rt u n a t e l y,the first cli n i - di r ect a cell to rep r oduce wildly,and this smashing not onl y the diseased cells but cal studies have not shown significan t me a n s , in turn, that more mut a t i o ns are the healthy tissue around them. A so- sh r inkage of tu m o r s . li k e l y to occur. phi s t i c ated understanding of the cell’s By far the greatest source of exc i t e - In 1986, Weinberg isolated another wo r kings grea t l y increases the likelihood ment in cancer res e a r ch, how e ver , ha s type of ge n e s , cal led tumor suppres s o r s . that the mutant genes can be shut down been targeted therap i e s , an approa c h to These act as brakes on growt h , b u t , without affecting the healthy cells . In tr eatment that is tailored to specific kinds when they mut a t e , the brakes can fail. 19 9 3 , the Swiss drug comp a n y Ciba- of can c e r s . Unlike most experim e n t a l Yet a third genetic cont ro l , the so-call e d Ge i g y synt h e s i z ed hundreds of th o u - tr eatments of the past three decad e s ,t a r - te l om e r ase gene, helps determine how sands of possible targeted thera p i e s , geted therapies are based on a growi n g lo ng a cell can perpetuate itself. Nor - wh i c h it then tested against dozens of understanding of the molecular ma- mal cells can divide onl y a set number of oncogene prot e i n s . One of the targeted chi n e r y of the diseased cell. The onc o - ti m e s , but an alterat i o n in the telome ra s e dr ugs was STI- 5 7 1 . gene is the corne r s t o ne of the new ap- gene can make a cell immorta l . A cell be- pro a ch — w h i c h is based on the work of co mes can c e r ous when sever al prec on d i - oug Jenson is a sixty- s e ven - ye a r - Ro b e r t Wei n b e r g , a scientist at M.I.T. ti o ns are met: mut a t i o ns in onc o g e n e s , Dold ret i r ed systems engineer who In the late seven t i e s , Weinberg began or simply an excess of onc o g e n e s ,e i t h e r li v es in the Pac i fi c Nort h w e s t . Four yea r s co nducting just the sort of res e a r ch that of wh i c h promotes growth ; changes in ag o,attending a Promise Keepers ral ly in Far ber had insisted was no longer neces- tu m o r - s u p p r essor genes,wh i c h then fail Was h i n g t on , D.C . , he was overc o me by sa r y: an explorat o r y inves t i g a t i o n of th e to res t r ain growth ; and changes in telo- ex h a u s t i on . A month later,af ter lunch at onc o g e n e ’s possible rel a t i o nship to the me r ase genes, wh i c h sustain the mut a t - his chu r ch, he noted that his urine was or igin of human can c e r . Within a few ing cell. In 1999,Weinberg demons t ra t e d “the color of cra n b e r r y juice.” This was yea r s , he had found a concl u s i v e link be- this when he produced a cancer cell from fo ll o wed by wheezing and shortness of tween the mut a t i o ns of an oncogene and a normal cell in the test tube by intro- bre a t h . He went to his local doctor,wh o the devel o p ment of a bladder tumor. ducing on c o g e n e s , t u m o r - s u p p re s s o r ga v e him a blood test. The doctor call e d Mu t a t i o ns in all our genes occur ever y ge n e s , and telome r ase into a healthy cell. ba c k that even i n g .“I hate to tell you this mi n u t e ,be c ause there is an intrinsic error It was the first time that human can c e r over the phon e, ” he said,“but your white rate when DNA is copied. If the error s had been arti fic i a l ly crea t e d . count is more than three hundred thou- ar e extrem e , the cell will self-destruc t , As the significance of We i n b e r g’s sa n d . ” Je n s o n’s diagnosis was chr oni c but otherwise the aberrant cell survi ve s . wo r k became cle a r , res e a r chers in both my elogenous leukemia, the same can c e r that killed my gran d m o t h e r .“Th e y told me I had three to five years at the most,” Je n s o n said. He was a robust man, five feet eleven and two hundred and twe n t y po u n d s , but his cond i t i o n deterio ra t e d rap i d ly. In i t i a l ly, he was treated with ch e m o t h e ra p y, and that brought his white count down to about fifty thou- sa n d . This was a temporizing measure. Lat e r , he began interfer on trea t m e n t s . In t e r fer on has a modest benefit for CML pa t i e n t s , and significant side effec t s .J e n - so n became severe l y anemic, and then su f fe r ed a seizure. “The stuff is killi n g you , ” his hematologist said. But there seemed to be no alterna t i ve . Th e n , in September of 19 9 8 , Doug Jenson was refe r r ed to Dr. Br ian Druk e r , a leukemia ex p e r t at Oreg on’s Health Sciences Uni- ver s i t y, who enrol led him in a Phase I study of an experimental drug ,STI - 5 7 1 . Fiv e years earli e r ,Druker had rec e i ve d a series of co mpounds from Ciba-Geigy “Le t ’s not waste missiles on cities not important enough to test on malignant cells , and he worke d to have a professional sports fran ch i s e. ” with the comp a n y to choose what ap- pe a r ed to be the best of the series of candidate drug s . Amo ng them was the co mpound STI- 5 7 1 , wh i c h appeared to be an ideal tool: it de ft l y dismantles th r ee oncogene pro t e i n s ,i n cluding one cal led Abl, wh i c h is the accelerator of chr onic myelogenous leukemia. Whe n it was tested in small animals, how e ver , it was found to cause liver damage in d o g s , and the ph a rm a c e u t i cal com - pa n y, with meagre experience in can - cer drug s , was leery about beginning human tria l s . But Druker pushed hard, “Su r ely you can tell me your secret identity.” be c ause of the striking effects in the test tube against CML. In June of 19 9 8 , • • th r ee institutions — O re g on, U. C . L . A . , and M. D. And e r s on , in Houston— began a Phase I safe ty study in pa- at a Was h i n g t o n press confe re n c e , th e I spoke with Dr.Glenn Bubley,a can - tients with CML.To date,th e y have not Sec re t a r y of Health and Human Ser - cer res e a r cher at Boston’s Beth Israel re a ched a maximally tolerated dose, vi c e s , Tommy Th om p s on , an n o u n c e d D e a c oness Medical Center, w h o, i n meaning a dose of ST I-571 that cau s e s the F.D. A . ’s approval of STI - 5 7 1 ,a ft e r 1 9 9 7 ,c onducted a cli n i c al trial of a drug s i g n i ficant tox i c i ty in patients. T h e onl y two and a half mo nths of revi e w. It cal led SU-101. “SU-101 was touted as al a r ming dog studies proved not to be was the fastest agency cle a r ance ever for the Sec o nd Coming a few years ago,” rel e vant for human beings. a cancer drug . Bu b l e y told me. It is a small molecule Je n s o n had lost seven t y pounds dur- De V ita believes that the recent ad- th a t , like STI- 5 7 1 , bl o c ks PDGF - r , an ing his illness and prior trea t m e n t , and he vances in cancer will allo w us to oncogene that is believed to be impor- gained it all back when he started taking make enormous strides in treatment al- tant in the prol i fe ra t i o n of a number of STI - 5 7 1 . Within a few weeks,his white most immediately. For him, STI - 5 7 1 — in t r actable can c e r s . When human tu- count fel l to fifteen thousand. Not long no w known as Gleevec—is the proo f of mors that had high levels of PDG F - r af ter that, his anemia was ameliorat e d , the prin c i p l e . “I think we have the tar- we r e implanted in mice, tr eatment with and his platelets ret u r ned to norma l . Few ge t s , ” he said.“It ’s not difficult to synt h e - SU-101 blocked their growth . Safe t y white cells that show the mutated Abl si z e che m i c als that block those targets. tests in animals, unlike those invo lv i n g oncogene rem a i n . “I go up to the health And when they come into cli n i c al tria l s STI - 5 7 1 ,w e r e promi s i n g ,with no major club ever y day, so metimes twice a day,” th e y work— s u rp ri s i n g l y well. ” In the li v er toxi c i t y or other red flag s , and re- he said. “I take spinning classes three Ba r ron’s art i cl e , he said, “Within 15-20 se a r chers anticipated dramatic succcess times a week.” The onl y side ef f ect has yea r s , I think cancer will become just an- in the cli n i c al tria l s . been “a little puffiness around the eyes , other chr oni c , su r vivable disease, muc h A patient I will cal l George Mit- wh i c h comes and goe s . ” Ho w long the like hype rt e n s i o n or diabetes.” He pre- sopoulos was a res t a u r ant owner who be n e fi ts will continue is unknown , bu t , dicts that the difficulties will lie not with had prostate can c e r . He was still work- like the vast majorit y of the more than the science but with the lack of res o u rc e s ing when he entered the tria l , de s p i t e five hundred patients with CML who for cli n i c al trials to test all the drugs that the fact that his cancer had spread to his ha v e been treated with STI-571 in the wi l l soon be discovere d . bon e s . The tumors could no longer be Phase II study,Je n s o n has enjoyed a pro- con t ro l led by hormo nal therap y , and so found and sustained rem i s s i on . “It is a ut is making Gleevec the poster he began treatment with great hopes jo u rn e y I don’t wish on anyone, ” he said. Bchild of imminent targeted cures that SU-101 would ameliorate his con- “Bu t , al l things cons i d e re d , I’ve been pre m a t u r e—a rep l a y of Sid n e y Farb e r ’s di t i on . He quickl y discove re d ,h ow ever , ver y,ver y fortu n a t e . ” res p o nse to his success with chi l d h o o d that the drug had sever e side effec t s . “I Druker is cautious about the drug ’s leukemia? After all, cu r ing cancer en- am exhausted,” he told Dr. Bu b l e y. “I dr amatic res u l t s ; ne g a t i v e side effec t s tails understanding a hundred-odd dis- feel like I can hardly move out of be d . ” could still manifest themselves in the fu- ea s e s , wh i c h behave in differ ent ways He also had immense difficu l t y sleep- tu r e, and the leukemia could also be- in differ ent individuals. In the lab, th e in g , be c ause he felt terrible even when co me resistant to the drug , pre c i p i t a t i n g che m i c als that are being screened are he was lying down . Other patients in rel a p s e . St i ll ,S TI-571 is the most exci t - in t e r acting onl y with the proteins of the trial begged to interrupt the ther- ing new cancer drug in yea r s . It turns out oncogenes or tumor-suppressor genes. apy because of the exhaustion it cau s e d , that the drug blocks oncogenes that may In the patient, how e ver , th e y are inter- but Mitsopoulos was determined to per- be crit i c al to other kinds of can c e r , su c h acting with a complex living organism; s evere . The course of t reatment had as , a type of br ain tumor, it is impossible to accurat e l y predict the no lasting impact, and he died shortl y and gastrointestinal stromal tumor,a rar e success of che m i c als that look promi s - aft e rw a rd . sa rc o ma of the intestine. On May 10th, ing in the lab. Mi t s o p o u l o s ’ s experience with SU-101

THE NEW YO R K E R, JUNE 4, 2001 6 1 plex the biology of cancer is, and how little can be predicted about the effi- cac y of an y particular trea t m e n t . Th e statistician John Bailar, for one , rem a i n s sk e p t i c al of the new therap i e s . “In the ni n e t e e n - fi fti e s , th e r e was huge exci t e - ment about labora t o ry pro g rams to sc r een for che m o t h e r apy drug s , ” he says. “We found a few drug s , but not many. Th e n , in the nineteen-seven t i e s , th e r e we r e cancer virus e s . In the eighties, it was immu n o t h e ra p y, with biologics like interfer on and interleukin-2 as the model magic bulle t s . Now it’s can c e r ge n e t i c s . The rhe t o r ic today sounds just the way it did forty years ago. I have no doubt that there has been a huge in- cr ease in knowledge about can c e r . Th e pr oblem is to translate it into public be n e fi ts we can measure. I want to see an impact on population morta l i t y rat e s . If the treatments are rea l ly that goo d , then we’ll see it.” “And do you, Ste p h a n i e , pr omise to love, ho n o r , and ‘ob e y’? ” A fter decades of listening to un- realistic pre d i c t i on s , cancer-patient • • ad v o c ates have a jaundiced view of re- se a r chers who inflate prel i m i n a r y anec- dotes of su c c e s s . Fran Vis c o , the pres i - pr oved to be typi ca l . What went wrong ? doubles the likelihood of s i g n i fica n t dent of the Na t i onal Ma n y cancer cells may have red u n d a n t sh r inkage of br east cancers with Her-2. Co a l i t i on , told me rec e n t l y that she was ma ch i n e r y, with sever al differ ent onc o - But as a solo treatment for br east can - di s m a yed , at a meeting of cancer cli n i - genes driving growth ; if you block one , cer its impact has been modest. Last ci a n s , at the way res e a r chers interac t e d the others may take up the slack. Th e yea r , Ge n e n t e c h alerted physicians to a with members of the pres s . “These cli n - pha rm a c e u t i c al comp a n y that had sup- po t e n t i a l ly lethal res p i ra t o r y prob l e m ic al scientists rec e i v e media training and po r ted the res e a r ch was not enthusias- a m ong women who had breast ca n - ar e scripted by their hospitals,” she said. tic about publishing negative data,Bu b - cer that had spread to their lungs or “Th e r e are so many agendas here :f a m e, le y said—even high-profi le journals pre- who had prior lung disease. It can also patient refe r ra l s ,f u n d - ra i s i n g , pha rm a - fer arti c les with positive results—but he cause signi fi cant heart damage in some ce u t i c al gra n t s ,a cademic advancement.” be l i e ves that it is equally important to wom e n — p a rt i c u l a rly those re c e i v i n g El len Stov a ll , the president of the Na- publish accounts of the failures , in orde r Adri a m yc i n , a mainstay che m o t h e ra p y ti o nal Coalition for Cancer Surv i v o r - to inject a note of realism into the scien- dr ug in the treatment of the disease. sh i p , ag re e d : “The headlines are drea d - ti fi c debate. (A n arti c le about the failure This is because in this form of bre a s t fu l . ” She refe r r ed to the sensationa l i s m of SU-101 in treating pr ostate can c e r can c e r , as in some other can c e r s , th e su r r ounding the disease as “the porno g - was published last mont h in C l i n i ca l pr oblem lies not with a mutated onc o - rap hy of can c e r, ” ad d i n g , “I am exci t e d Ca n c e r Research.) gene but with an excess of no r mal onc o - by the new science, but show me hard Other targeted trea t m e n t s , like Her- ge n e s , and targeting them can damage da t a . We need to raise the skepticism ce p t i n , an antibody developed by Genen- he a l t h y heart tissue as well. The New ba r ome t e r. ” te ch , ha v e perfo r med better—but not England Journal of Me d i c i n e rec e n t l y de- Ma n y former members of the can c e r ne a r ly as well as some clinicians initially sc r ibed the Herceptin study as “a land- establishment express similar misgivings. expected them to. H e rceptin targets ma r k tria l , ” even though it extended life Sam uel Brod e r , who succeeded DeVit a He r - 2 , a protein produced by an onc o - for an aver age of onl y five mon t h s ,a n d in 1988 as the director of the Nat i on a l gene that is found in between twe n t y and onl y in the subset of patients who qual- Cancer Institute, and who is curren t l y th i r ty per cent of bre a s t - c ancer cas e s . ifi ed for the trea t m e n t . The descrip t i o n the chi e f me d i c al officer at Celera Ge- The early news was exci t i n g , and maga- is less an example of hype r bole than a nom i c s , be l i e ves that we req u i r e new zines and morning talk shows rep o rt e d so b e r ing reminder of the fact that no bre a k t h r oughs in the lab—parti c u l a r ly that Herceptin would make che m o t h e r - pr ior therapies had been shown to sig- in understanding the process of ho w apy treatment for breast cancer a thing of ni fi can t l y extend the lives of wom e n cancer sprea d s — b e f o r e we can be confi - the past. When Herceptin is used in con- with metastatic breast can c e r . dent of gr eat gains in trea t m e n t . ju n c t i o n with che m o t h e ra p y , it nearly These limitations reveal how com- “I cal l it the iron-lung synd r ome, ”

6 2 THE NEW YO R K E R, JUNE 4, 2001 he told me. “If you had demanded that va ri e t y of disciplines working together so u r ces to develop and market them. So the N.I.H. so l ve the problem of po l i o to understand the complex mecha n i s m s fa r , mo r e than fifty compounds and mo- not through independent, in ves t i g a t o r - of the cancer cell. Af ter all, genes are lecular targets have been developed in dri v en discover y res e a r ch but by means me re l y the blueprints for prot e i n s , and it this manner, and two have entered the of a central ly directed prog ra m , the odds is the proteins that do the cell’s work. An first phase of cli n i c al testing. ar e ver y strong that you would get the ab i l i t y to decipher protein shapes—how Klausner ref ers to these ref o r ms as ve ry best iron lungs in the worl d — th e y change in health and disease—w i l l “an experim e n t , to see if science can take po r table iron lungs, tra n s i s t o ri z ed iron be important in combatting can c e r , an d over the Nat i o nal Cancer Institute, in - lungs—but you wouldn’t get the vaccine this will req u i r e advances in che m i s t r y, in stead of politics and hype . ” He cont i n - that erad i c ated polio.” He thinks that, co mputer science, and in physi c s . ue d , “Human beings seem to have this gi v en the perfo r mance of the targeted en d less ability to think they are at the th e r apies available so far,it would be pre- n recent yea r s , the mission to reë d u - end of hi s t o r y. The onl y people who ma t u r e to invest more in the fed e r al bu- Icate Cong r ess and the public about no w are saying we know enough are rea u c ra c y that oversees cli n i c al tria l s . the realities of cancer and to reverse the people who don’t know enough.” Br oder argues that the crea t i o n of un r ealistic attitudes and expectations ne w therapies is no longer the sole or that we have inherited from Nix on’s war rancis Moore’s cong re s s i o nal testi- even the prim a r y provenance of the gov- has been taken up by an unlikely advo- Fmo ny about science’s law of un i n - ern m e n t . “In i t i a t i v e and crea t i v i t y have cat e —the current head of the Nat i on a l tended consequences has been amply mo ved to the private sector,” he said. Cancer Institute, Dr. Ri ch a r d Kla u s n e r . pr oved over the past thirty yea r s . Th e “Th e r e is just no way of getting arou n d “I’m pret t y well plugged in to what’s fa i l u r es of the govern m e n t ’s war on can - it , and anyone who tells you otherwise is going on in res e a r ch, ” he rem a rk e d . “I cer have been matched by the unfore- on a differ ent planet.What was done in hear on the news ‘Major brea k t h ro u g h seen successes it led to in fighting other the early seventies was necessary,even in in can c e r ! ’ And I think, Ge e , I haven ’t di s e a s e s ; in d e e d , its greatest successes ret ro s p e c t , but that doesn’t mean we he a r d anything major rec e n t l y. Then I came from shattering its central prem - should do it that way now.” Furt h e r - listen to the broa d c ast and rea l i z e that i s e—the belief in cancer viru s e s . A s mo r e, pha rm a c e u t i c al companies pre- I’ve never heard of this brea k t h ro u g h . Mo o r e pred i c t e d , the most promi s i n g fer to run their own cli n i c al tria l s : bo t h And then I never hear of it again.” results stemmed from basic biological Gl e e vec and Herceptin were submitted Klausner himself has been under con- in q u i r y. And yet both Cong r ess and the to the F.D. A . for approval without hav- si d e r able pres s u r e to predict the erad i c a- public continue to view open-ended sci- ing entered N.C.I.-spons o r ed studies. ti o n of can c e r , be c ause powe r ful mem- en t i fi c inves t i g a t i o ns as nebulous, se l f - This frees more mone y for the sort of bers of Con g r ess have promised that in d u l g e n t , and wasteful of ta x p a yer s ’ basic res e a r ch supported by the Nat i on a l su c h a pred i c t i o n could mean milli on s mon e y, and are reluctant to fund them. Institutes of Health—the grant syst e m of ad d i t i o nal gover nment dollars for the For this rea s on , oncologists talk in terms and res e a r ch laborat o r ies that Brod e r N. C . I . But he refuses—not onl y be- of imminent cures through directed re- ref ers to as the jewels in the crown of th e cause to do so is impossible but becau s e se a r ch—both in their proposals for new N. I . H . Any scientist or clinician in the it would propagate the scientific falla c y pr ojects and in their assessments of on- United States can propose a new idea that cancer is a single disease. going work. The media attention that and seek support for testing it. “Whe n The most prod u c t i v e way to move results further misleads the public. the N.I.H.st i c ks to that,”Br oder said,“it fo rw a r d in cancer res e a r ch, Klausner be- If Ame ri c ans are unwi l ling to rej e c t does an astonishing job,and it is the envy li e ves , is to cal l off the war.He pref ers to the national myth o l o g y of can c e r ,it may of the world . ” think of cancer as an intric ate puzzle— be because they fear that the onl y alter- Ha r old Var mus is a former director of one that we curre n t ly lack both the na t i v e is despair. That fear can be tem- the Nat i o nal Institutes of He a l t h , an d , kn o wledge and the tools to solve .C l u e s pe r ed by the rapid pace and diver s i t y of like Brod e r ,his experience as the head of could come from any fiel d , and the re- ne w discover ies in science and techn o l - a large gover nment institute has made f o rms that he has undertaken at the og y that are influencing ever y dimension him wary of bu re a u c r atic efforts to direc t N. C . I . refl ect the need for such discipli- of cancer res e a r ch. Of co u r s e , it is im- sc i e n t i fi c res e a r ch. Now,as the pres i d e n t na r y openness. He has tackled the vast possible to say which type of cu r re n t l y of Me m o r ial Slo a n - K e t t e ri n g , he find s cl i n i ca l - t rials bure a u c ra cy of the co- in t r actable cancer will be cured firs t . In hi m s e l f in a curious position. “My view op e ra t i v e groups so that they no long e r the next ten yea r s , the survival rate of h e re is not ve ry popular—especially fu n c t i o n as a closed shop cont ro l led by people with a certain type of me l a n om a am o ng cancer res e a r chers and can c e r - in b r ed committees but are, in s t e a d , re- or lung tumor or lymph o ma or brea s t focussed senators—but I believe can c e r sp on s i v e to any res e a r cher with goo d cancer may not cha n g e . But it also might do e s n ’t deserve unique distinction for id e a s . He also rec o g n i z es that the N.C.I. im p r ove by fifty per cent, or ninety per fu n d i n g, ” he said rec e n t l y. Giving one should complement the drug comp a - ce n t . Be c ause of the uncerta i n t y inher- ad v o ca c y group special treatment simply n i e s ’e f f o rts rather than duplicate them; ent in scientific discover y, th e r e is simply do e s n ’t help the balance of res e a r ch. Var - to this end, the N.C.I. pr ovides assis- no way of kn ow i n g .Para d ox i ca l ly, fo r mus also believes that the greatest ad- tance to univer s i t y-based laborat o ri e s cancer patients and their families this vances in new knowledge will come not that are pursuing molecular targets and in a b i l i t y to predict the future become s fr om cancer genetics alone but from a candidate drugs but lack sufficient re- their sustaining hope. ♦

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