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N E T W O R KT H E N E W S L E T T E R O F T H E I N T E R N A T I O N A L N E T W O R K F O R C A N C E R T R E A T M E N T A N D R E S E A R C H

Volume 3, Number 1, Autumn 2002 — Inside: Review-Pediatric Liver Cancer - 6

Forum - Brain Tumor and Retinoblastoma - 10 Report on Palliative Care - 13

Letters - 14 News - 16 Partner Profile: - 18 Profile in Cancer Medicine - 20

THE PRESIDENT’S MESSAGE

THE WORD ON CANCERby Ian Magrath

In the beginning was the Word.

—The Gospel of St John

Wittgenstein’s Tractatus Logico-Philosophicus, the only philosphicalwork he published during his lifetime,is written in a style reminiscent of asacred Hindu text. Each of its shortparagraphs—the equivalent of asloka in, for example, the BhagavadGita—expresses a thought or con-cept that can be fully understood onlyby the “initiated” or, as Wittgensteinhimself says, by those who have“thought the thought, or a similarthought, before.” This statement canbe applied to a great deal more thanthe Tractatus. It might well be takento heart, for example, by all teachersand students, for it implies that edu-cation is an active, not a passive pro-cess. Real understanding does notcome from an ability to regurgitatethe words of one’s teachers, or of es-sential texts — sacred or otherwise —for this entails the exclusive use ofmemory and does not necessarilyimply understanding. Even decidingwhat is useful to commit to memorycan be difficult in the absence of theadvice of a “guru”; learning the Brus-sels telephone directory by heart, for

Progress in pathology: Upper third (gross pathol-

ogy) shows enlarged ovaries due to infiltration by

tumor removed at a post-mortem examination.

Middle third (histopathology) shows a histological

section (slice) of a tumor stained with the standard

dyes, hematoxylin (blue) and eosin (pink) and

viewed under a microscope. Lower third (molecular

pathology) shows a DNA microarray in which each

spot represents the expression (at transcriptional

level) of a different gene in the tumor cells. Tens of

thousands of genes can be examined simulta-

neously. Red spots indicated genes expressed at a

higher than average level, green spots at a lower

than average level. The expression of specific sets of

genes (signatures) provides information about the

tissue of origin, the molecular abnormalities

present, or the likelihood that the tumor will re-

spond to a particular therapy.

example, would scarcely be ofvalue in understanding thetelephone system to which itrelates. And much useful in-formation learned by rote,such as the five principalcauses of a malar flush I wasmade to memorize as a medi-cal student, doesn’t teach anability to reason, only to asso-ciate one thing with another.This form of learning is bettercategorized as training ratherthan education, in which theability to carry out a specifictask is conferred on thetrainee, but in which an un-derstanding of the task or itspurpose is not necessary to itssuccessful completion. Theword education implies, in itsLatin origin, the act of leadingor drawing out. Not, in otherwords, a process of fillingempty space, but one of guid-ing the student in the use ofhis or her intellectual capac-ity.

The ability to make use ofknowledge depends verymuch on access to those whohave “thought the thoughtsbefore.” Good teachers do notmerely impart knowledge,

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but also, through their demonstrationof analysis and reasoning, show theway to understanding, a foundationupon which imagination can find so-lutions or create new knowledge.Isaac Newton, famously, pointed outthat: “If I have seen further than mostmen, it is by standing on the shoul-ders of giants.” In other words, by firstthinking their thoughts, he was ableto think his own.

The acquisition of understandingthen, is essential to the scientificmethod, enabling hypotheses to begenerated which can be tested forlegitimacy through observation andexperiment. Through our understand-

ing of natural laws we create a limitedability to predict the future, or at leastto know in advance what will happenin certain circumstances (e.g., that anapple, detached from its branch, willfall to the ground). In the context ofcancer, knowing which disease one isdealing with (the diagnosis) allowsprediction of the natural history, or re-sponse to treatments applied in thepast (the prognosis). The foundationof understanding which allows diag-noses and prognoses to be made isknown as pathology.

LOGOSThe Greek word logos was renderedby the translators of the King JamesBible as “word,” which, in the contextof the first sentence in St John’s Gos-pel (see epigraph), probably conveysvery little meaning to the modernreader. In ancient Greek, its meaningextended to include truth and reason(the English word logic, of course, isalso a cognate form) — and, as such,it was subsequently used metaphori-cally to refer to God incarnate (theequivalent of the Hindu Avatar). Thus,combined with the Greek word “pa-thos,” meaning “suffering,” we can seethat pathology refers not only to theunderstanding of the nature of dis-eases, but to the discipline wherebythese truths are rendered accessibleto the human mind — the Avatar, ifyou will, of disease!

Modern pathology is an amalgamof many disciplines (e.g., microbiol-ogy, biochemistry, immunology)which historically have been inter-mingled more or less with the prac-tice of clinical medicine. For centuries,the pre-eminent pathological tool, atleast in the context of patients, wasthe conduct of a post-mortem exami-nation — usually by the clinician whocared for the patient in life. One down

side of the clinician-pathologist waspointed out by Semmelweis, who rec-ognized that examining a patient af-ter conducting a post-mortem was aprincipal cause of puerperal fever inhis hospital. Unfortunately, his dem-onstration that this problem could beeffectively dealt with by the simpleexpedient of hand-washing prior toexamining a patient led to him beingdrummed out of Vienna! The tech-niques of pathology have changeddramatically only in recent years, asnew tools for the study of diseasehave emerged. The theory of imbal-ance in the four humors (yellow bile,phlegm, blood and black bile), heldsway as the principle theory of thecausation of human disease for some2000 years, and is generally ascribedto the Graeco-Roman physician Galen(130-201 AD), who built upon theideas of Hippocrates (460-370 BC).The emergence of pathology as a sci-entific discipline was finally madepossible by the publication, in 1543,of the first complete textbook of hu-man anatomy, De Humanis CorporisFabrica (On the Fabric of the HumanBody), by Andreas Vesalius (1514-1564). Subsequently, morbid (patho-logical) anatomy evolved through asuccession of concepts pertaining tothe “seat” or origin of human disease,each championed by a leading medi-cal scientist of the era. GiovanniMorgagni (1672-1771) claimed it wasthe organs, (Marie Bichat, (1771-1802)the tissues, and (Rudolf Virchow, 1821-1902) incriminated the recently dis-covered microscopic building blocksof the body—cells. But the study ofstructure can never be enough, andknowing what automatically leads toasking why (a critical question for on-tologists, and one to whichoncologists could, with benefit, givegreater weight!). It is Claude Bernard

Giovanni Battista Morgagni is consid-

ered the father of pathological anatomy.

His magnum opus, De sedibus et causis

morborum per anatomen indagatis (On

the Seats and Causes of Diseases, Investi-

gated by Anatomy), includes 70 letters

describing some 700 cases. (Photo cour-

tesy of the Claude Moore Health Sciences

Library, University of Virginia.)

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(1813-1878) who is usually claimed tobe the father of the discipline knownas patho-physiology, the study of dis-ordered function in the human body.He stressed the importance of labo-ratory experiments in understandingdisease, and pointed out in the mid-nineteenth century that: “We cannotimagine a physicist or a chemist with-out his laboratory. But as for the physi-cian, we are not yet in the habit of be-lieving that he needs a laboratory; wethink that hospitals and books shouldsuffice. This is a mistake; clinical infor-mation no more suffices for physiciansthan knowledge of minerals suffices forchemists and physicists.” Few woulddoubt the truth of this statement to-day, at least in the sense of the impor-tance of laboratory studies to under-standing disease. Yet physicians stilltend to have little more than a smat-tering of laboratory training and alimited understanding of the basicprinciples of research. To remedy thissituation would surely lead to morerapid progress in preventing or cur-ing disease.

In the late 20th century, a furtherparadigm shift occurred in the at-tempt to understand the nature andorigin of disease — the recognitionthat ultimately, it is derangements inthe structure and function of genesand proteins that cause human dis-ease. Some molecules, of course, in-vade the body in the shape of micro-organisms, but these must still act viatheir effects on the molecular path-ways of the cells. The historical marchof ideas from organs, through tissues,cells, and finally to macromolecule asthe “seat” of human disease did not,of course, lead to the replacement ofone idea with another. On the con-trary, all are necessary to understanddisease. Cancers arise in particular tis-sues in particular organs, and are

comprised of cells which, by virtue ofdisturbances in their normal molecu-lar pathways, are able to replicate incircumstances when they ought todie (via the process of programmedcell death, or apoptosis). Cancer cellsfrequently develop the ability tospread and survive in cellular and tis-sue environments that are normallyhostile. In effect, we might say thatcancer is the consequence of a longerlife, or even potential immortality be-ing conferred upon specific cells(Jorge Luis Borges has speculated onthe consequences of immortality be-ing conferred upon specific people inhis well-known story, El Inmortal). Butonce again, what is, promotes thequestion why. Looking at pathologi-cal tissue alone cannot give a com-plete picture of human disease, sinceit omits the influence of the world inwhich the patient lives. Most diseases(inborn errors of metabolism and in-herited malformations are possibleexceptions), including cancer, arisefrom interactions with the environ-ment and it is the discipline of epide-miology, the study of the way in whichdiseases emerge in populations, thatdeals with this area.

In the space of little more than 150years, basic tissue stains, which enablethe pathologist to distinguish thevarious elements of the tissue that heor she places under the microscope,have been supplemented by a largepanel of monoclonal antibodies,which, when coupled to appropriatemarkers, make visible the expressionof an equally large number of indi-vidual proteins within, or on the sur-face of tumor cells. With the adventof the “microarray” or microchip, weare now on the threshold of an era inwhich the entire “transcriptosome” or“proteosome” — i.e., the totality of thetranscription products of the ge-

nome, and all the proteins expressedin any given cell type (even in indi-vidual cells) will be measured in asingle test. Ultimately, it is the patternof protein expression (and, of course,changes in the pattern that are gov-erned by internal programs and ex-ternal events) that are responsible forall aspects of the life and death of acell — whether a cancer cell or a nor-mal cell. It would seem to be a self-evident truth that the further devel-opment of methods to study thesepatterns — either in cross section (aslice in time), or, ultimately, in real time,in response to changes in the cellularenvironment — will reveal the ulti-

Marie Francis Xavier Bichat has been

called the father of “tissue pathology,”

or histopathology. He studied over 600

cadavers and identified 21 tissues, but

he did not use a microscope, which he

thought unnecessary. (Photo courtesy of

the Claude Moore Health Sciences Li-

brary, University of Virginia.)

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mate secrets of cancer, and thus per-mit rational and highly specific ap-proaches to treatment. Pathology,and its primary incarnation, the diag-nosis, will necessarily undergo revo-lutionary changes as the techniquesfor understanding what makes a can-cer cell malignant become morewidely available. This is, doubtless,simply a question of time.

GNOSISLong before the comprehension ofhuman disease in terms of the broadrange of pathophysiological pro-cesses that we discern today, the ob-servation of the symptoms and signswas established as a critical element— for long, the only objective ele-ment — of reaching a diagnosis. Thelogic of the Egyptian medical papy-

ruses, written some 3,500 years ago,in this regard, is impeccable. Specificsymptoms and signs were providedfor each diagnosis, and the diagnosisled, in turn, to a prognosis and recom-mendation for treatment. In ancientEgypt, medical knowledge was con-sidered sacred, and therefore, by defi-nition, already perfect. We might con-clude that Egyptian medical gnosis(knowing, from the Greek, gnostikos),without continued nourishment fromLogos, petrified and eventuallywasted away. Knowledge basedlargely on intuition, as diagnosis andprognosis were until the emergenceof the science of pathology, providesa precarious basis for treatment deci-sions, although this mattered littleprior to the development of effectivetherapy in the 20th century. Intuitiveknowledge is not, of course, verifiableand in the absence of rational ap-praisal the ideas that prevail are thoseof the most powerful advocate. Thus,the Cathars, a gnostic sect whichemerged in Occitania (later to be-come part of France) in the eighthcentury, and which espoused reli-gious ideas that differed from thoseof the church, came to be viewed asheretics. Aiming to achieve directknowledge of God through intuitive,personal means (i.e., to become“Perfecti”), their spiritual form of reli-gion left no room for Papal authority.In 1209, Pope Innocent III launched agenocidal campaign against them —the Albigensian crusade. Lasting un-til 1255, it was characterized by indis-criminate slaughter of the citizens oftowns known to harbor Cathars. Itsclimax was the siege of the Catharfortress, Montségur, in 1244, whichended in a fiery holocaust in whichover 200 Cathars were immolated. Ina later era, the observations of scien-tists, such as Galileo, were also consid-

ered to be in conflict with the dogmaof the church, but scientific reasonhas, for the most part, prevailed overintuitive explanation, at least with re-spect to the question what, if not thequestion why.

But scientific understanding, eventoday, has significant limitations. Ourability to predict the outcome oftreatment in individual patients, forexample, is limited to statistical prob-ability gauged from observation ofprevious patients, or from the resultsof clinical trials conducted in samplepopulations. Nonetheless, this pro-vides a rational basis for the selectionof treatment, assuming an accuratediagnosis and evaluation of prognos-tic factors in the disease in question.As time goes by, the much greater“depth” of the diagnosis, i.e., the in-creasing amount of information thatis encapsulated in it, will lead not onlyto more accurate predictions of prog-nosis in the context of various poten-tial therapies, but also to a movementaway from the present practice ofdefining therapy for specific patientpopulations and towards individual-ized treatment. This will be made pos-sible by the design of drugs targetedat the molecular abnormalities thatare the immediate cause of cancer —molecular abnormalities that arelargely specific to the tumor cells.Each type of cancer has multiple mo-lecular abnormalities, some present inall cells, and some not, such that eachindividual cancer has its own “finger-print” which might be used to specifya particular combination of drugs,each targeted at a different molecu-lar lesion.

PATHOLOGY TODAYThe value of the pathological exami-nation of cells or tissue obtained froma presumed malignant tumor cannot

Rudolf Virchow claimed that every cell

can come only from another cell (Omnis

cellula e cellula). He is often considered

the father of cellular pathology. (Photo

courtesy of Axel Bauer’s Virtual Office for

History, Theory and Ethics in Medicine.)

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be overemphasized. At the extremes,the patient may be shown to have abenign tumor, for whom simpletherapy may suffice, or a cancer forwhich there is no curable option. Inbetween, a diagnosis based on teststhat go beyond the basic, subjectivehistological examination (whichlargely involves pattern recognition),by including the detection of a set ofsignature proteins, will not only im-prove the accuracy of the diagnosis,but increase its depth. Since treat-ment costs (including the use of hos-pital facilities, staff time, the cost ofdrugs, surgery or radiotherapy, andthe cost of managing toxicity) aregenerally much greater than the costsof improving the quality of the diag-nosis, reluctance to use the tools ofmodern pathology may well leadboth to an inadequate diagnosis andto sub-optimal therapy, with conse-quent wastage of resources. Betterdiagnosis requires, first and foremost,a well-trained and well-informed pa-thologist, but even the best patholo-gist is limited by the quality of the di-agnostic materials, particularly if rely-ing upon histopathology. Importantin this respect are the representative-ness of the biopsy, and the handling,fixation, sectioning and staining ofthe tissue.

As more objective tests, such asimmunohistochemistry and otherkinds of gene expression assays, in-cluding polymerase chain reactions(PCR) or in situ hybridization tech-niques (to say nothing of microarrayexamination of large numbers ofgenes), become increasingly avail-able, the pathologist’s skills will con-tinue to move away from pure patternrecognition to a knowledge of therange of tests best able to supple-ment (and perhaps eventually re-place) basic histological examination.

Such objective tests also provide thepathologist with a means of improv-ing his or her ability to more accuratelyinterpret histomorphology (the pat-tern) since they provide confirmationof the diagnosis. Additional means ofimproving the skills of the isolated pa-thologist (all too often the case in de-veloping countries) include referencematerials (images and descriptions)made available through the Internet.With appropriate telepathologyequipment, “virtual” consultations orteaching sessions with specialist pa-thologists can be held.

Interactions between the pa-thologist and clinician will need toimprove as more information ofprognostic importance emergesfrom the examination of the tumortissue. Clinicians will also need to beaware of the increasing amount ofinformation that may be obtainablefrom serum — sensitive and quanti-tative tests for tumor DNA andmarker proteins in serum will be-come increasingly available, and willhelp not only in establishing the di-agnosis, but in following the re-sponse to treatment. Already, the de-tection of particular molecular ab-normalities, such as tumor-associ-ated chromosomal translocations,provides a more sensitive assess-ment of response to therapy, and isbecoming increasingly important inthe management of some diseases(e.g., chronic myeloid leukemia). Inthe context of chemotherapy, themolecular profiles of both tumor andpatient are important. Factors gov-erning the metabolism and distribu-tion of drugs (including entry andexit from cells), free radical scaven-gers, DNA repair and programmedcell death are critically important tothe efficacy and toxicity of therapyand may be modified by a host of

genetic factors, either inherited, oremerging in the context of ongoingmutations in the tumor cells. Asmore drugs targeted at the caus-ative molecular lesions of cancer aredeveloped, it will become essentialto know whether their moleculartargets are indeed present in the tu-mor cells, just as it is necessary toknow whether the target of mono-clonal antibody-directed therapy isexpressed. In other words, we shallsee an increasing overlap betweendiagnosis and prognosis.

While many of the more recent di-agnostic techniques are simply notavailable in most institutions in de-veloping countries, the investment inat least some new technologies, suchas PCR, may be appropriate. It wouldseem premature at this time, exceptfor major research institutions, to in-vest in microarray or similar technol-ogy for major transcriptosome orproteosome analysis. Still a researchtool, it is probable that the relevantfindings from detailed expressionprofiling, e.g, a signature set of genesthat reflect prognosis, will direct theuse of simpler techniques (PCR, im-munohistochemistry, small arrays) forthe detection of only those geneproducts identified as important bylarge microarrays. In any event, agreat deal of clinico-pathological cor-relation will be necessary in prospec-tive studies before the value of thesenewer and expensive technologiescan be fully assessed.

One of Galen’s great works dealtwith the value of dreams in makinga diagnosis (On Diagnosis fromDreams). Today we may dream of theday when diagnosis not only fully en-compasses prognosis, but also pro-vides a precise guide to therapy, notin a particular disease, but in a par-ticular patient. ■

M E S S A G E

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LIVER CANCER INCHILDREN - NOW USUALLYCURABLE

In Volume 2, Issue 2 of “NETWORK”, anarticle compared the outcome of twoinfants with hepatoblastoma recentlydiagnosed in the same city. These twochildren reflect the improvement inprognosis for infants with this raretumor (median age 18-24 months)over the past 20 years.(1) Until theearly 1980s, most patients withhepatoblastoma were considered in-curable because in only 20-30% werethe tumors considered to be “resect-able” at diagnosis, and only half ofthese children (10-20% of the total)survived. The remainder died of pro-gressive disease. Chemotherapy wasnot considered particularly useful andTransplant Centres were unwilling toaccept children with hepatoblastomafor orthotopic liver transplantation(OLT) because the risk of recurrencewas so high. Treatment of the “Hospi-

tal A” patient, who died of progressivetumor, represents this “old-fashioned”approach, whilst the patient man-aged by “Hospital B” benefited fromtwo major recent advances and sur-vived. First, in the early 1980s,Cisplatin and Doxorubicin (PLADO),were recognised to be the most ac-tive available agents forhepatoblastoma. Second, it seemedmore logical to give chemotherapyprior to as well as after surgery—asin the case of most solid paediatrictumors—rather than only afterwards.Pre-operative PLADO was recognisedto make tumors (a) smaller, (b) lessvascular and (c) more “discrete,”thereby making surgical removal con-siderably safer (Figure 1).

The rarity of primary liver cancerin children—only 1 in 30,000 are af-fected—means that national and in-ternational collaboration is essentialif treatment is to be improved via theconduct of clinical trials. Only threenational groups - the USA/Canada (In-

tergroup), Japan and Germany/Aus-tria (GPOG)—were sufficiently largeto set up independent studies. Manyof the remainder have joined trials co-ordinated by the International Soci-ety of Pediatric Oncology Liver Can-cer (SIOPEL) Group. For example, inSIOPEL 1, a single-arm study of chil-dren with hepatoblastoma in whichthe PLADO combination and delayedsurgery were used, a total of 91 Cen-tres in 30 countries—representing allfive inhabited continents—recruited154 patients with hepatoblastoma injust over four years (35-40 patients/year).(2) Differences between SIOPEL1 and the Intergroup studies were,first, that in the Intergroup trials, sur-gical resection was recommended atdiagnosis, with “second look” surgerybeing carried out in initially“unresectable” cases—patients whohad responded to chemotherapy.Second, the Intergroup study in-cluded a randomised trial comparingthe Cisplatin/5-FU/Vincristine and

Study Number of Complete 5-Yr Event 5-Yr OverallPatients Resection Rate Free Survival Survival

(%) (% + CI) (%+CI)

SIOPEL 1 154 106 66% 75%

(Pritchard et al, Ref 2) (77%) (59-74%) (68-82%)

GPOG (H-89) 72 66 72% 76%

(von Schweinitz et al, Ref 4) 92% (*) (*)

US Intergroup

(INT-0098) 182 n/a 57/69%)** 69/72%**

(*) (*)

Japanese (JPLT-1 134 72% 66% 73.4%

(Sasaki et al, Ref 5) (*) (*) (*)

GPOG = German Paediatric Oncology Group; CI = Confidence interval; * = Overall CI not provided; n/a = not available** = Results from Regimen A (Cisplatin, Vincristine and 5-FU) (first figure) and Regimen B (PLADO) (second figure) provided separately

Figure 1: MRI scan of hepatoblastoma in

a 2-year-old boy pre- and post- four

courses (12 weeks) of “PLADO” chemo-

therapy. The tumor has shrunk dramati-

cally and the abdomen and liver have a

much more normal contour.

TABLE 1:MULTI-CENTRE STUDIES IN HEPATOBLASTOMA — COMPARISON OF RESULTS

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Cisplatin/Doxorubicin combinations.These two regimes showed equiva-lence, with respect to response and 5-year survival although greater toxic-ity was observed with the two-drugregime.(3) The results of the Germanand Japanese studies, both of whichalso included “up front” (i.e., initial)surgery, show that there is no thera-peutic advantage to (a) the additionof Ifosfamide (GPOG)(4) or (b) the in-fusion of anthracycline directly intothe hepatic artery (Japanese study)(5)

[Table 1]. Despite the fact that theSIOPEL study was conducted in somany centres with diverse facilitiesand varying experience, the resultsare at least as good as those of theother study groups, with an overall 5-year event-free survival of 66% (con-fidence interval 59 - 74%) and a 5-yearoverall survival of 75% (CI 68 - 82%)[Figure 2]. Notably, 7 of the 10 curedpatients had received liver transplantbecause many OLT Centres had bynow become convinced that PLADOreally did eradicate “micro-metastatic”disease and even, in some cases, vis-ible metastases (ie Stage 4 patients).(6)

There were both surgical and che-motherapy considerations for theSIOPEL Group as they planned theirnext studies. The “delayed surgery”strategy was successful in that, unlike

the situation in the other three col-laborative groups, no patient neededa second surgical resection with its at-tendant complications; SIOPEL sur-geons unanimously agreed that de-layed surgery was also much less riskythan surgery “up front” because oftumor shrinkage. This was consistentwith the finding of a high percentageof necrosis (100% in some specimens)in the resected tumors. With respectto the chemotherapy regimen, thefact that 5-FU and Vincristine had notbeen notably “active” againsthepatoblastoma in studies per-formed in the 1960’s and 1970’s, and

the equivalence of twoIntergroup regimenssuggested thatCisplatin was the crucialelement of PLADO.Moreover, whereas theDoxorubicin dose anddose intensity could notbe readily increased, forfear of the higher inci-dence of cardiotoxicitynoted in the IntergroupPLADO regime (inwhich the dose of

Cisplatin was 80 mg/m2 over 4 days,compared with 60 mg/m2 over 2 daysin the equivalent SIOPEL regime),Cisplatin could be intensified becausethere had been little nephrotoxicityor ototoxity in SIOPEL 1.

Analysis of the SIOPEL 1 results in-dicated that two “risk groups” couldbe delineated(7) [Table 2]. On the onehand, there were patients with no evi-dent metastases and tumors limitedto 1, 2 or 3 sectors of the liver (desig-nated “standard risk” patients) and onthe other, those with either all foursectors involved or extra-hepatic tu-mor, usually lung metastases. Patientsin these two latter categories werecombined as a “high risk” group [seeTable 2]). In the SIOPEL 2 study, usingthese criteria, patients were stratifiedinto two risk groups. All patientsagain had delayed surgery, includingOLT if tumours responded to chemo-therapy but all 4 hepatic sectors re-mained involved. “Standard risk” chil-dren (70% of the total) received singleagent but more intensive Cisplatin at2-weekly, rather than 3-weekly inter-vals, with careful auditory and renalmonitoring. “High risk” patients (30%

___________________________________________________________________________Risk Group Features of Tumors(% of Total)

___________________________________________________________________________Standard risk tumors PRETEXT group 1, 2 or 3(70%)

No metastases and no vascularextrahepatic spread

___________________________________________________________________________High risk tumors PRETEXT group 4(30%) or

Spread outside the liver

(usually lung metastases)

_________________________________________________________________________________PRETEXT = Pre-Treatment Extent of Primary Tumor

Tumor involving one hepatic sector only = PRETEXT 1, two sectors = PRETEXT 2 etc

The 4 sectors are: right anterior, right posterior, left medial, left lateral (see Ref 2 for details)

R E V I E W

TABLE 2: SIOPEL RISK STRATIFICATION FOR HEPATOBLASTOMA

Figure 2

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of the patients) received Doxorubicin,Carboplatin and Cisplatin in an alter-nating myelotoxic/non-myelotoxicsequence, a regime sometimes re-ferred to as “Super PLADO”. A total of140 patients were recruited to this“pilot” trial over 3 years - a higher re-cruitment rate than for SIOPEL 1. Theresults are reassuring since “good risk”patients in SIOPEL 2 appeared to havea similar prognosis to those in SIOPEL1 [Table 3]. This finding greatly influ-enced the design of the third SIOPELtrial (SIOPEL 3), now in progress. InSIOPEL 3, “good risk” patients arerandomised to receive either PLADO,according to the SIOPEL 1 schedule,or single-agent Cisplatin, according tothe “good risk” SIOPEL 2 regime. Thenumber of “high risk” patients inSIOPEL 2 was insufficient to draw con-clusions about any advantage of theSuper PLADO regime over standardPLADO, so SIOPEL 3 continues to usethis treatment in the “high risk” group.SIOPEL 3 is recruiting well and newCentres are joining in. Secure fund-ing has been acquired from the ma-jor UK cancer charity, “Cancer Re-search UK”, with important contribu-tions from the Swiss Cancer Leagueand a group of families of UK childrenwho had developed hepatoblastoma.SIOPEL 3 is coordinated and adminis-tered by Data Managers in the Leices-ter Office of the United KingdomChildren’s Cancer Study Group

(UKCCSG) and statistical input is fromDr Rudolph Maibach in Bayern, Swit-zerland.

Resection of hepatic lesions in chil-dren is a major undertaking and re-quires optimising the patient pre-op-eratively to achieve the best possibleresults. Malnutrition or infection mustbe treated. This is especially impor-tant in geographical areas where spe-cific types of malnutrition or endemicinfection, e.g., malaria, occur. Both canaffect the patient’s tolerance of a ma-jor hepatic resection. The functionalstatus of the liver must be assessed,to determine the capacity of the re-maining liver mass to sustain the childpost-operatively. Liver enzymes, com-plete blood count, coagulation fac-tors and serum proteins are measuredpre-operatively. Adequate amountsof blood products must be available.The coagulation profile should be asclose to normal as possible. Somechildren may benefit from a pre-op-erative dose of vitamin K. Occasion-ally an enema is administered the daybefore the procedure, though formal“bowel prep” is usually unnecessary.Intravenous antibiotics are given pre-operatively to cover for organismsthat might cause cholangitis.

The PRETEXT scheme is helpful for“risk group” classification, but thor-ough knowledge of the functionalanatomy of the liver, as described byCouinaud and others, is essential for

safe and successful resection of livertumors because it allows the surgeonto perform a relatively bloodless dis-section by dividing the tissue alongthe natural lines of demarcation be-tween segments. Using this classifi-cation, which is based upon the loca-tion of the portal pedicles and thehepatic veins, the liver has 8 segments(I-VIII).

The procedure is performed undergeneral endotracheal anaesthesiawith positive pressure to prevent airembolisation from the hepatic veinsor inferior vena cava during the dis-section. Monitoring lines and cath-eters usually include two large boreperipheral lines for volume infusion,a central venous catheter and arterialline to monitor central venous pres-sure and systemic arterial pressurerespectively, an indwelling urinarycatheter to measure urinary output,a nasogastric tube for gastric decom-pression, and a probe for core tem-perature measurement (oesophagealor rectal). In the event that the venacava is occluded during the proce-dure, it is vital to have enough intra-venous access in the upper trunk incase rapid fluid infusion is required,and to administer any necessaryproducts to stop bleeding. Some-times, an intra-operative cholangio-gram or ultrasound can be very help-ful. Details of surgical technique arebeyond the scope of this article.

At left: Patient with hepatoblastoma:

(a) at 18 months, at diagnosis. She had a

huge “PRETEXT 3” primary tumor and

multiple lung metastases; (b) after four

courses of PLADO via the Hickman cath-

eter, but before surgical resection of pri-

mary; and (c) at 12 years, 10 years off

treatment, with hearing aids as a result

of cisplatin ototoxicity.

9

Excessive bleeding is by far themost common surgical complicationencountered, but can usually beavoided by strict adherence to safesurgical technique. Other intra-op-erative complications include bileduct injury, air embolisation, injury toadjacent intra-abdominal organs, ortumor rupture with spill. Subhepaticclosed suction drains are usuallyplaced and retained for 24-48 hours.The child can usually be extubatedpost-operatively and would normallyspend about 24 hours in the intensivecare unit. Metabolic abnormalitiesknown to occur after major hepaticresections including hypoglycaemia,hypophosphataemia, hypoal-buminaemia, and prolonged pro-thrombin time should be anticipated(and monitored for) and promptlycorrected. Later complications of he-patic resection include atelectasis, fe-ver, intra-abdominal or wound infec-tion, pneumonia, bile leak, “biloma” orbiliary fistula, post-operative bleedingand liver failure. This is not “easy sur-gery” and referral to a tertiary or qua-ternary centre may be advisable.

In summary, hepatoblastoma—arare tumor recently considered “incur-

TABLE 3: COMPARISON OF RESULTS OF FIRST TWO SIOPEL TRIALS

Study Actual 3 year 3 yearResection EFS % OS %Rate (CI %) (CI %)

SIOPEL 177% 68% 78%

(61-77%) (70-85%)

SIOPEL 2 Standard risk 96% 91% 89%

Patients (84-98%) (82-96%)

High risk 54% 52% 47% Patients (39-65%) (34-60%)

EFS = Event-free survival OS = Overall survival CI = Confidence interval

able” in most cases—is now regardedas one of the success stories in paedi-atric oncology, with cure rates nowapproaching those for Wilms’ tumor.Pleasingly, treatment is usually notcomplex, lengthy or especially expen-sive. For instance, the estimated che-motherapy and antibiotic costs forthe 2 arms of the SIOPEL 3 trial areapproximately 550 pounds sterling(Cisplatin only arm) and 1080 poundssterling (PLADO arm), respectively (al-though these costs will vary from onecountry to another). Toxicity is mildor moderate with easily manageablecomplications, so that most patientsare “cured at little cost.” Requirementsfor centres treating these children in-clude: (a) resources for the placementof secure central venous lines, themeasurement of serumalphafetoprotein (AFP) levels andmonitoring for the toxicities ofCisplatin, Carboplatin and Doxorubi-cin, (b) availability of expert liver sur-gery, including access to a paediatricOLT Centre and (c) the convictionthat most children with hepatoblas-toma can be cured, so that protocolsare followed closely. These resourcesare now available in many “develop-

ing countries”—one reason for thepopularity of the SIOPEL studies inter-nationally. Some centres, however, areeither unaware of, or unconvinced bythe results of the SIOPEL trials. It istherefore our responsibility—nurses,doctors, pharmacists and other health“professionals”—wherever we work,to bring these results to the attentionof our immediate paediatric and pae-diatric surgical communities, either by“word of mouth” or via our nationalPaediatric Cancer Study Group.

There are approximately 187 sepa-rate nations in the world. It appearsthat 150 of these countries are nottaking part in clinical trials. Throughvarious agencies, including the INCTR,we hope to increase the number ofparticipating centres considerablyover the next decade. Otherwise, chil-dren with hepatoblastoma may re-ceive ineffective or unnecessarilytoxic treatments and some of themwill die needlessly. Promising collabo-rations are now being developingbetween the SIOPEL, US/Canadian,Japanese and GPOG Study Groups. Inparticular, new strategies for the im-proved management of “difficult” livertumours—high-risk hepatoblastomaand also hepatocellular carcinoma(8)

—are under discussion and pilot tri-als, including Phase I and II studies ofnewly available agents, have alreadystarted. Information on the SIOPELtrials can be obtained from MargaretChilds, SIOPEL Trials Coordinator, atthe United Kingdom Childrens Can-cer Study Group (UKCCSG) in Leices-ter, at e-mail: msc8@leicester.ac.uk orfrom one of the authors of this article,drjpritchard@hotmail.comSubmitted by: J Pritchard,Royal Hospital for Sick Children,EDINBURGH ; and K H Mutabagani,New Jeddah Clinic, SAUDI ARABIA

(see References next page)

R E V I E W

10

N E T W O R K

OPTIMIZING CARE FORPATIENTS WITH BRAINTUMORS

Cancer of the brain is a devastating ill-ness. Because of the damage causedby the tumor itself (and by subse-quent treatment, be it surgery, radia-tion or chemotherapy), most patientswith brain tumors develop neurologi-cal, emotional and intellectual difficul-ties that compromise their ability tolive independently, to study and towork.

In Brazil, 1400 new patients withbrain tumors are diagnosed everyyear, the majority between the agesof 4 and 9 years. Today, if treated ad-equately, more than 60% of such pa-tients may be cured. However, in ad-dition to disabilities resulting frombrain damage caused by the tumoritself, after treatment, patients maysuffer from intellectual impairment,usually manifested as low IQ andmemory loss, visual impairment orspeech alterations. These late effectsare seen especially in patients under

the age of 3 who have been treatedwith radiotherapy. These side effectscan also be associated with chemo-therapy. Such sequelae can lead tosocial, learning and psychological dis-abilities. The protocols used are de-signed to avoid or delay the use of ra-diotherapy but this cannot always beachieved; an alternative, if available, isto use conformal radiotherapy inwhich the radiation beam is closelyadapted to the shape of the tumorfrom whatever angle the radiation isdirected, thus reducing the irradiationof normal brain tissue.

In order to cure more children whilealso reducing the likelihood of long-term ill-effects, the Brain Tumor Asso-ciation for Children and Adolescents(TUCCA), a charitable organization,was founded in 1998. The associationis dedicated to improving treatment,quality of life, and the long-term out-look for young patients with brain andspinal cord tumors through research,multidisciplinary support, educationand advocacy for families and survi-vors.

REFERENCES1 Hepatoblastoma – a bit of a success story.

Eur J Cancer 1994: 30: 1050-1051. EA Shafford

and J Pritchard.

2 Preoperative chemotherapy with

Cisplatin and Doxorubicin for childhood

Hepatoblastoma – Results of the First Study

of the International Society of Paediatric

Oncology. J Clin Oncol 2000: 18: 3819-3828.

J Pritchard, J Brown, EA Shafford, et al.

3 Randomized Comparison of Cisplatin /

Vincristine / Fluorouracil and Cisplatin / Con-

tinuous Infusion Doxorubicin for Treatment

of Pediatric Hepatoblastoma: A Report From

the Childrens Cancer Group and the Pediat-

ric Oncology Group. J Clin Oncol 2000: 18:

2665-2675. JA Ortega, EC Douglass, JH

Feusner, et al.

4 Efficiency and Toxicity of Ifosfamide,

Cisplatin and Doxorubicin in the Treatment

of Childhood Hepatoblastoma. Eur J Cancer

1997 : 33 : 1243-1249. D von Schweinitz, DJ

Byrd, H Hecker, et al.

5 Outcome of Hepatoblastoma Treated

With the JPLT-1 (Japanese Study Group for

Pediatric Liver Tumour, Protocol-1): A Report

From the Japanese Study Group for Pediatric

Liver Tumour. J Ped Surg 2002 : 37 : 851-856. F

Sasaki, T Matsunaga, M Iwafuchi, et al.

6 Prognostic factors for hepatoblastoma in

SIOPEL-1. Eur J Cancer 2000: 36: 1418-1425.

J. Brown, G. Perilongo, E A Shafford, et al.

7 Hepatocellular carcinoma in children -

Results of the first prospective study of the

International Society of Paediatric Oncology.

J Clin Oncol 2002: 20 : 2798-2804. P.

Czauderna, G. MacKinlay, G. Perilongo, et al.

Dr Sidney Epelman (far left) visits with Brazilian children being treated for brain and spi-

nal cord tumors. He and his wife, Claudia, are founding members of the Brain Tumor As-

sociation for Children and Adolescents (TUCCA) in São Paulo.

11

RETINOBLASTOMAMEXICO-BOLOVIA

El Instituto Oncológico del orienteBoliviano, fundado en 1974, es elúnico instituto de su clase en Bolivia,convirtiéndose en el único hospitaldonde se atiende exclusivamentepacientes oncológicos. Cuenta con unservicio de pediatría fundado en 1980y reorganizado y actualmentedirigido por la Dra. Yolanda Ernst con

importante con la ayuda de lapsicóloga la Lic. Marta Flores, quientiene a su cargo entrevistas periódicascon los padres de familia para podermantener una relación médico-paciente óptima, y así ayudar a que elpaciente pueda completar de manerasatisfactoria todo el tratamiento.Ayuda también en la adaptación delniño en su familia y su núcleo socialluego de la enucleación cuando esnecesario.

El compartir esta experiencia conlos colegas mexicanos ha sidoinolvidable por varias razones. Essiempre refrescante poder visitar uncentro grande como es el INP, con lagran cantidad de pacientes quemaneja, y la forma colaborativa detrabajar de pediatras de variasespecialidades. El ver y aprendercomo se conforma un grupo y setrabaja para mejorar el manejo inte-gral del niño con retinoblastoma meabre las posibilidades de poderrealizar un trabajo similar en miciudad con el fin de poder convertirmi centro en uno de referencia parael resto del país donde los colegasque trabajan con oncologíapediátrica en las otras ciudadespuedan referir sus pacientes con estapatología para que reciban unmanejo integral multidisciplinario.

Un aspecto muy importante en elcual se esta trabajando es el dedisminuir la incidencia de diagnósticotardío a través de información a lapoblación y personal médico paraque exista la sospecha temprana y laderivación de estos niños a nuestrocentro donde se podrá confirmar eldiagnóstico y en estos casos iniciaruna terapia oportuna mejorando elpronóstico y calidad de vida denuestros niños afectados por estapatología. ■

Since last year, the association hasalso begun to develop strategies di-rected towards reducing late diagno-sis and improving treatment results inpatients with retinoblastoma, a tumorof the eye. A national campaign todraw attention to the significance ofleucokoria (a white gleam in the pu-pil that is a frequent early sign of thedisease), amongst pediatricians, oph-thalmologists and the population ingeneral was developed in associationwith INCTR.

TUCCA has joined in a collaborativeeffort with a number of institutions inBrazil to fund support programs andimprovements in the quality of life forchildren and their families that wouldotherwise exceed the budgets of theinstitutions; TUCCA raises fundsthrough donations and events, includ-ing gala dinners and recitals. The as-sociation also distributes a free guidefor the parents of children with braintumors throughout Brazil, co-sponsorseducational seminars and conferences,and provides online informationthrough www.tucca.org.br. ■

submitted by Claudia Epelman andSidnei Epelman, TUCCA – Associaçãopara crianças e adolescentes com tu-mor cerebral. São Paulo - Brasil

13 camas que funciona desde 1998.Nuestra área de cobertura abarcatoda la región oriente, incluyendoparte del sur este del país; losdepartamentos de influencia sonSanta Cruz, Beni, Pando, Tarija, yCochabamba. Anualmente recibimosaproximadamente 90 nuevospacientes de los cuales 6 a 10 por añoson pacientes con Retinoblastoma, lamayoría en estadios muy avanzados.Luego de varios casos encontramosque una de las principales causas parael diagnóstico tardío de estospacientes es la falta de informacióntanto de la población como de losmédicos ya sean estos médicos gen-erales, pediatras e inclusive algunosoftalmólogos por no tener lasospecha del tumor en estadios mástempranos. A través de nuestrocontacto con el INCTR pudimos poneren marcha un proyecto para podermejorar el diagnóstico temprano, y elmanejo de los niños con retinoblas-toma.

En contacto con el Dr. Carlos Lealdel Instituto Nacional de Pediatría(INP) y con el apoyo del INCTR, realicéun viaje a la ciudad de México enagosto de 2002 para ampliar misconocimientos en cuanto al manejode pacientes con retinoblastomas. Enel Instituto Nacional de Pediatría, elServicio de Oncología cuenta con ungrupo de atención especializada parapacientes con retinoblastoma. Estegrupo esta conformado por elpediatra oncólogo clínico, Dr. CarlosLeal; el oftalmólogo pediatra, Dr.Juárez; una psicóloga, Lic. MarthaFlores y un radioterapeuta, Dr.Amador. Estos doctores mantienenuna estrecha comunicaciónconsiguiendo de esta manera que lospacientes diagnosticados con retino-blastoma sean vistos en su integridad.El manejo se facilita de manera

F O R U M

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N E T W O R K

RETINOBLASTOMA ISA MOTHER’S ANGUISH,AN ACTIVIST’S CAUSE

Hunter Tylo, a celebrated daytimetelevision actress in the United Statesand mother of four, was sitting inchurch when she saw the white glintin her infant daughter’s eye. Despiteher access to the best health careavailable in the world, Tylo suspectedthat her child’s pediatrician hadmissed something, that somethingwas terribly wrong.

She was right. Katya had retinoblas-toma, a childhood cancer that is nearlyalways fatal if not treated before it es-capes the eye. With early diagnosis, thedisease is highly treatable and, in mostcases, saves eyesight and lives.

Katya, now 5, lost an eye to retino-blastoma. Hunter Tylo and her hus-band, Michael, responded to this per-sonal tragedy by establishing an inter-national organization that educatesparents about the disease and the besttreatments available worldwide. Theyjoined forces with another Hollywoodcouple, Matt and Christina Ashford,whose daughter also had been diag-nosed with retinoblastoma. As found-ing board members of RetinoblastomaInternational (RBI), the Tylos and theAshfords are endeavoring to raise pub-lic awareness of the disease, while rais-ing funds to help treat children fromdeveloping countries.

“Retinoblastoma is a double-edged sword of pain,” says HunterTylo. “When something as devastatingas this disease happens to your child,it is worth every effort to save evenjust ONE child’s life and hopefully,their eyesight.”

Retinoblastoma International isbased at Children’s Hospital of LosAngeles, California, where Dr. A. LinnMurphree is professor of ophthalmol-

ogy and pediatrics; he serves as chair-man of the board of RBI. Dr Murphreerecently served as a Visiting Expert forINCTR, spending time at the InstitutoNacional de Pediatria in Mexico City.

Retinoblastoma International re-cently launched retinoblastoma.netto reach parents, families, medicalprofessionals and key decision-mak-ers worldwide. Over the next fewmonths, the site will offer materialsand plans to build a significant inter-national network in the fight againstretinoblastoma.

The Tylos also are using their ce-lebrity status in the United States toget the word out to the 350 millionviewers worldwide who watch theCBS soap opera, The Bold and theBeautiful. They are producing a series

of public service announce-ments about retinoblastomafeaturing Hunter Tylo and Mat-thew Ashford (Ashford stars onDays of our Lives). The PSAs, inEnglish and Spanish, will airworldwide.

There are no precise figuresfor the number of cases of ret-inoblastoma occuring eachyear worldwide, but given thatthe incidence is likely to behigher in many developingcountries, it is probably in theregion of 12,000 to 16,000, andperhaps more. At least 90% ofthese cases occur in develop-ing countries, where many chil-dren die from the disease dueto delay in diagnosis or to a lackof expert medical care. In con-trast, 97% of infants survivetheir retinoblastoma in moredeveloped countries, althoughmost have a moderate to se-vere visual impairment. KatyaTylo was just six weeks oldwhen her illness was diag-

nosed, and it was already too late tosave the eye. Parents are urged toseek immediate medical attention ifthey notice a white glow or glint inone or both eyes, or if their child hascrossed or misaligned eyes. Bothmay be early signs of retinoblas-toma.

In addition, the feasibility, cost ef-fectiveness and utility of examiningthe retina (back of the eye) after di-latation of the pupil to screenyoung infants in developing coun-tries for retinoblastoma should beexamined. INCTR’s RetinoblastomaStrategy group is presently explor-ing the reasons for late diagnosis,and is working to develop publiceducation programs to improveearly detection. ■

Actress Hunter Tylo is an advocate for early

detection of retinoblastoma, starring in a series

of public service announcements about the

disease.

13

NNCTR/INCTR (NEPAL)PALLIATIVE CAREINITIATIVE

At the last INCTR Annual Meeting inBrussels there were a number ofmeetings regarding palliative care.The general feeling was that INCTRwas in a unique position to encour-age and promote the development ofpalliative care.

A Palliative Care Subcommitteewas formed and several memberswere able to meet in London in Au-gust with Dr Robert Twycross, Emeri-tus Clinical Reader in Palliative Medi-cine at Oxford University. At thatmeeting we felt that because INCTRalready has a presence in Nepal, viathe Nepalese Network for CancerTreatment and Research, NNCTR/INCTR (Nepal), and in particular hasrecently successfully initiated a cervi-cal cancer-screening program, weshould explore the possibility of apalliative care initiative in Nepal.

By way of background, Nepal is anemerging country with a populationof 23 million. The terrain varies fromplains in the south to rugged moun-tains in the north. There are many eth-nic groups in the country; 82% of thepopulation are Hindu and 8% Bud-dhist. IARC estimates the mortalityrate from cancer in Nepal to be 11,500

persons per year. We know that per-sons with advanced malignancy havemany severe symptoms includingpain and that 70% of these patientsrequire opioids. Nepal, then, hasmany thousands of patients and theirfamilies who would benefit im-mensely from the development ofpalliative care.

As chairman of the Palliative CareSubcommittee, I was fortunate to beable to visit Nepal in November andmet with a number of people whowere passionately interested in thecare of patients dying with advancedcancer. These, amongst others, in-cluded Dr Surendra B. Bade Shrestha,Dr Monahar Lad Shrestha, Dr AratiShah, Dr Sudip Shrestha, Dr Y.P. Singh,Dr Pradeep Vaidya and Mr Roy Kline. Iwas able to visit the Trubuhvan Teach-ing Hospital, (TU) Hospice Nepal, theBhaktapur Cancer Care Centre andthe Scheer Memorial Hospital inBanepa all of which are in or near toKathmandu.

At the Hospice Nepal and theBhaktapur Cancer Care Centre, astrong start has been made in pallia-tive care. At Hospice Nepal, which hasbeen open for only about threemonths, there are 8 to 10 beds, withplans to increase this number. Full-time palliative care nurses work at thehospice and the two oncologists, who

do daily wardrounds, arebased at TUTeaching Hos-pital. The hos-

pice was built through local dona-tions.

Bhaktapur Cancer Care Centre is a25-bed oncology hospital run by twooncologists who carry out chemo-therapy and radiotherapy. They esti-mate that at any particular time, fivepatients are receiving ‘purely pallia-tive care.’ Even those receiving treat-ment in the hope of achieving tumorregression, or even cure, generallyhave very advanced cancer and arehighly symptomatic. Plans are inplace to rebuild the in-patient wardsand to develop a dedicated unit ofabout 10 beds for palliative care.

The Scheer Memorial Hospital inBanepa houses the Kathmandu Uni-versity Medical School, which has astrong emphasis on communitymedicine and outreach to small ruralcommunities. It is also the location ofthe NNCTR/INCTR (Nepal) office. Theadministrative and medical staff feelthat there is strong need for a pallia-tive care unit at their hospital.

At the TU teaching hospital, planshave been made for a Home HospiceProgram.

Like all visitors to the Kingdom ofNepal, I was impressed by the kind-ness and hospitality of all whom I met.I was just as impressed however, bythe strong commitment to palliativecare that I encountered in all thepeople I spoke to, especially thosementioned earlier. INCTR and NNCTR/INCTR (Nepal) plan to push forwardwith the development of a programfor the care of dying cancer patients.With time and effort we feel that thiswill help many thousands of patients.It is also hoped that such a programmight serve as a model for otherINCTR collaborating sites. ■submitted by Dr Stuart Brown, KingFaisal Specialist Hospital and ResearchCenter, Riyadh, Saudi Arabia

R E P O R T

Doctors strive

to make cancer

patients

comfortable in

the final stages

of disease.

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N E T W O R K

PEDIATRIC ONCOLOGY INCOLOMBIA

Facing the challenge of developingpediatric oncology in developingcountries is not easy. Limited re-sources and socio-economic con-straints are the main obstacles.

Colombia’s new National HealthSystem has increased accessibility tocare but does not provide all the fa-cilities required for high-quality careof cancer patients. Although special-ists are fully committed to pediatriconcology, lack of drugs and generalmedical supplies, together with thelack of high technology laboratory fa-cilities such as molecular biology labs,all contribute to the high mortalityrates in our patients. It might help ifinternational organizations such asthe INCTR and WHO could influencegovernment policies.

The National Association of Pedi-atric Oncologists/Hematologists hasrecently been established. Our aim is

PEDIATRIC ONCOLOGY INPERU

The Instituto de EnfermedadesNeoplásicas (INEN) in Lima, Peru—theonly cancer hospital in the country—began its reorganization 50 years agowith the development of specialtiesin the different fields of oncology. Themedical oncologists treated pediatricpatients until 1980 when two newpediatric oncologists joined themedical staff, upon completing train-ing in the U.S. The pediatric wardstarted with a five-bed unit in 1960and progressively increased its capac-ity to 41 beds by 2001.

As everywhere in the world, acuteleukemia is the most frequent neo-plasm affecting children, followed bylymphomas (Hodgkin’s disease andnon-Hodgkin’s lymphoma) and ret-inoblastoma, which is the most com-mon solid tumor seen at our Institu-tion. Unfortunately, the majority ofcases come to our hospital with ad-vanced disease due to delayed orwrong diagnosis, or inadequate medi-cal care. There are very few cases ofneuroblastoma and Ewing’s sarcomacompared to the incidence in othercountries.

We are currently seeing around400 new cancer patients per year

PEDIATRIC ONCOLOGY INEL SALVADOR

El Salvador, the smallest country inCentral America, has 6 million inhab-itants, almost 34% of whom are un-der 15 years of age. There is one na-tional pediatric hospital, where ap-proximately 175 new cases of cancerwere diagnosed each year between1996 and 2001.

Before 1993, the overall survivalwas only 10%; since 1994, local andinternational efforts have brought to-gether a pediatric cancer programwhich has resulted in the survival in-creasing to 65% for patients withacute lymphoblastic leukemia.

This program is the result of a col-laboration between the BenjaminBloom National Pediatric Hospital, theFundacion Ayudame a Vivir and theInternational Outreach program ofthe St. Jude Children’s Research Hos-pital (SJCRH) in the USA. Its three mainaims are: to secure access to knowl-edge and basic technology related tothe field of pediatric cancer, to con-solidate a multidisciplinary team, andto promote the education of childrenwith cancer and their parents.

In this context the priority be-comes integrated medical care. Theprogram promotes the best medicalpractices of all the health care provid-ers, it also raises the quality of supportneeded for modern treatment anddevelops the parents’ skills in improv-ing the nutritional status and generalhygiene of the child with cancer.The greatest achievements of the ElSalvador program includes the im-provement in survival, establishing amultidisciplinary medical team andthe coordination of local resourcesand international support.

Pediatric cancer is not a health pri-ority for most countries with limited

resources. Due to the transfer ofknowledge and technology, interna-tional endeavors, like the INCTR,MISPHO and SJCRH initiatives, havesignificantly improved medical prac-tice and have in a short time increasedthe survival of children with cancer. ■

Miguel BonillaHead of Oncology ServiceBenjamin Bloom HospitalEl Salvador

from all over the country, which has apopulation of approximately 25 mil-lion inhabitants, of whom half areunder 15 years of age. Only three pe-diatric oncologists manage this pa-tient load and not many young phy-sicians are interested in pursuing pe-diatric oncology as a specialty. This isthe major reason for not having abone marrow or stem cell transplantunit.With the treatments used, we have anoverall disease-free survival of 70% atfive years, but more intensive treat-ments are being implemented to im-prove upon this. ■

Antonio Wachtel M.D.Head, Pediatric OncologyInstituto de EnfermedadesNeoplásicas

15

L E T T E R S

to conduct cooperative multicenterepidemiological studies in order toincrease survival rates in children withcancer, despite our economic con-straints.

The Hospital Universitario del Vallein Cali has become an associate mem-ber of the INCTR. We hope tostrengthen this association and workclosely in clinical research, also ben-efiting from INCTR’s strategic ap-proach to building capacity.

We look forward to continuing todevelop cancer control under theguidance of the INCTR. ■

Dr. Margarita Quintero de CharryDepartment of PediatricsHospital Universitario del ValleCali, Colombia

LE TRAITEMENT DESCANCERS CHEZ LESENFANTS AFRICAINSLe Groupe Franco-Africaind’Oncologie Pédiatrique a 2 ans.J. LEMERLE*, F. MSEFER ALAOUI**, P.DOUMBE***

Depuis le mois d’octobre 2000 etaprès une dizaine d’années de con-tacts et d’échanges variés, le GFAOPconnaît enfin une existence officielle.

Son objectif est de développer desstratégies de diagnostic et detraitement des cancers de l’enfantadaptés à l’Afrique ainsi que deformer des médecins, des infirmièreset, des techniciens pour et sur cemême continent.

Sa motivation est de contribuer àmettre fin à une situationscandaleuse. En effet, en 2003, sur lesdizaines de milliers d’enfants africainsqui seront atteints d’un cancer et plusparticulièrement d’une leucémie,bien peu guériront. Probablement

guère plus de 5 à 10% d’entre eux.Une injustice d’autant plus criante

que 75% des petits malades des paysindustrialisés peuvent eux êtresauvés…

Afin de trouver des solutions, leGFAOP peut heureusement s’appuyersur le travail de ses partenaires.

Huit “Unités Pilotes” ont étéimplantées à Alger et Oran, à Tunis, àRabat et à Casablanca, à Dakar, àYaoundé et enfin à Antananarivo àMadagascar.

Ces UP ont, dors et déjà, développédes traitements adaptés auxpossibilités locales pour lesnéphroblastomes et les lymphomesde Burkitt. Trois cent cinq cas ont étérassemblés en 21 mois dont 175 casde lymphome de Burkitt. Lerecrutement des cas augmente demois en mois, des milliers de ques-tionnaires sont en cours detraitement et un nouveau projet derecherche clinique et biologique estdéjà en préparation.

Le lymphome de Burkitt,lymphosarcome aux visages divers,semble être la tumeur la plusfréquente chez l’enfant danscertaines régions d’Afriquesubsaharienne. Le GFAOP essayedonc d’en préciser la distribution, lesparticularités cliniques, mais aussibiologiques et thérapeutiques.Atteintes maxillo-faciales ou non,anticorps EBV, sensibilité variable auxchimiothérapies.

Le GFAOP est également à la re-cherche de facteurs pronostiquespour mieux adapter les traitementsaux différents cas rencontrés. Quelssont les cas qui pourront bénéficierun jour de traitements plus légers,comme ceux basés sur la prise d’unseul médicament le Cyclophospha-mide (Endoxan)? Cette hypothèse detravail est d’ailleurs déjà à l’étude de

façon très active en Afrique australeet orientale.

En tout état de cause, l’état généraldes enfants lors de leur prise encharge médicale est encore tropsouvent catastrophique, ce qui traduitun énorme problème de retard au di-agnostic. En Afrique, il faudraitimpérativement arriver à utiliser lesmoyens de communicationmodernes pour diffuser les images deces enfants au ventre déformé et auvisage défiguré par des tumeurstoujours rapidement évolutives etfaciles à reconnaître.

La formation des infirmièresafricaines à la précision et auxprécautions requises pour l’utilisationprudente des chimiothérapies est undes principaux chantiers du GFAOP.L’organisation de stages intensifs de6 à 8 semaines dans des unitésd’oncologie pédiatrique françaises, etdes visites d’étude en Afrique faitespar des équipes d’infirmières pourévaluer les besoins locaux,notamment en formation, sont déjàen cours.

Les problèmes d’éthique en rap-port avec la recherche clinique sontabordés dans deux domainesprincipaux. L’un est celui des bonnespratiques cliniques : l’éthique de larecherche clinique commence par lelavage des mains et la précision desprescriptions écrites et des mesures.L’autre est celui de la communicationavec les malades et leurs familles,préalable indispensable à la signatured’un « consentement éclairé ».

Le secrétariat et la banque dedonnées du GFAOP sont situés àl’Institut Gustave-Roussy (Villejuif –France). ■

* Président du GFAOP

** Vice-Présidente du GFAOP

*** Trésorier du GFAOP

16

N E T W O R K

HEALTH MATTERS - BBC WORLDSERVICEDr Magrath participated in a BBCWorld Service broadcast of the pro-gram “Health Matters”on October 25which covered cancer prevention, andparticularly cervical cancer screening,acute lymphoblastic leukemia andpalliative care. In the same program,Dr Suresh Advani, of the LeukemiaStudy Group of India (see below),pointed out that treatment resultshave improved from 25% to some60% long-term survival in the last 30years. These results have beenachieved with a treatment protocol,MCP841, designed for a collaborativeprogram among three major Indiancenters and NCI/INCTR. ■

MEETING OF THE BRAZILIAN SOCIETY OFPEDIATRIC ONCOLOGY AND INCTR’SBRAZILIAN BRANCHDr Magrath participated in a meetingof the Brazilian Society of PediatricOncology between 30 October to 1November, in particular in a session onthe early detection of retinoblastoma.He also met with Dr Sidnei Epelmanconcerning the opening of the newINCTR Branch in Brazil and with repre-sentatives of the Bank of Brazil, whichhas supported the development of pe-diatric oncology centers in Brazil. Thisprogram has been very successful andINCTR will undertake discussions withthe Bank to explore possibilities ofworking together in Brazil. ■

PROGRESS IN LEUKEMIA STUDY GROUPOF INDIA (LSGI)In late November, at the time of theSIOP Asia Meeting in Delhi, the LSGI,a subcommittee of INCTR’s LeukemiaStrategy Group, also met. In the courseof this meeting a new treatment pro-

tocol for acute lymphoblastic leuke-mia (ALL) was finalized, and planswere made for implementation inmid-2003. A meeting was also heldwith the Sir Ratan Tata Trust inMumbai regarding possible fundingof this project along with plans to ex-tend treatment with the existing pro-tocol (MCP841) to other centers in In-dia, which will work closely with thethree major centers presently usingthis protocol (Cancer Institute,Chennai, All India Institute of MedicalSciences, and Tata Memorial Hospital).The achievements of our Indian col-leagues was mentioned in a recentnews article in Lancet Oncology. ■

MEETING WITH UICC AND ESOREPRESENTATIVES IN ANTWERPA meeting took place in Antwerp, onthe occasion of a meeting onWomen’s Cancer in Europe, with sev-eral members of the UICC—includingDr Louis Denis, Treasurer, Dr RobertHudson, Chairman of the UICC Copesprogram, Dr Arun Kurkure of the LadyRatan Tata Medical and Research Cen-ter in India—and Dr Alberto Costa, Di-rector of the European School of On-cology, to discuss possible areas ofcollaboration between these organi-zations. It was agreed that therewould be much to be gained by work-ing together, and cervical cancer wassingled out as a worthy initial focusof concerted efforts. ■

MEETING ON DEVELOPMENT OF ANINCTR E-LEARNING PROGRAMA meeting took place with Dr Jean-Claude Kurdziel and Dr Ali Khan onOctober 25 to discuss the develop-ment of an e-learning program forINCTR. Dr Kurdziel has extensive ex-perience in the development of e-

learning modules, and is willing toprovide his services gratis to INCTR. Itwas recognized that INCTR must uti-lize modern educational tools in itsprograms, and further discussions onhow this project can be moved for-ward and funded are planned. ■

COLLABORATION WITH THEINTERNATIONAL AGENCY FOR RESEARCHON CANCER (IARC)INCTR is undertaking collaborationwith IARC in the context of cervicalcancer, and in the establishment of apopulation-based cancer registry inLahore. A meeting was held with DrMax Parkin and Dr Sankaranarayananof IARC on December 4 to discussthese projects. Training in both areaswill be carried out by IARC, and INCTRwill assist in coordination and datamanagement relating to theseprojects. Additional projects, includ-ing collection of information on re-sources for cancer treatment and re-search and pediatric cancer registra-tion were discussed. All expressed in-terest in expanding IARC/INCTR col-laboration in these areas. ■

MEETING OF MECCA IN RIYADHThe Middle East Children’s Cancer As-sociation (MECCA) met in Riyadh onthe occasion of the Cancer 2002meeting which took place betweenOctober 14 and 16, and which was or-ganized by the King Faisal SpecialistHospital and Research Center. In thecourse of the MECCA meeting, whichwas coordinated by Dr Abdallah Al-Nasser, several important areas of pe-diatric oncology were discussed. Sixof the participating countries haveagreed to explore the developmentof a joint protocol for the treatmentof acute lymphoblastic leukemia. It

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was decided that the treatment pro-tocols used by the India LeukemiaStudy Group would provide a modelfor this project, and that a meetingwould be held in Spring 2003, with afollow-up joint meeting with the ILSGat the Annual Meeting to discuss thespecific treatment protocol design. ■

IAN PETER RENNERT LECTURE INPEDIATRIC ONCOLOGYDr Magrath was invited to give thefirst Ian Peter Rennert Lecture atGeorgetown University, WashingtonDC, on November 6. His lecture wasentitled Lessons from Burkitt’s Lym-phoma. This provided an opportunityto discuss INCTR’s work with severalmembers of the Vincent LombardiCancer Center, including the Director,Dr Richard Pestell, and Dr Aziza Shad,a member of INCTR’s GoverningCouncil. Possibilities of working moreclosely with the Lombardi CancerCenter, and in particular, in the con-text of e-learning in pathology, werediscussed. Dr Magrath also took theopportunity to visit NCI and to meetwith Drs Harford and Welsch of theOffice of International Affairs. ■

LYMPHOMA STRATEGY GROUPMEETINGA sub-committee of the LymphomaStrategy Group met on December 6and 7 to discuss a collaborative treat-ment program for patients withBurkitt’s Lymphoma (BL) in Africa. In-vestigators representing five institu-tions in Africa (Kenya, Nigeria, Tanza-nia and Uganda) participated. Theproblems encountered by each of theinvestigators were discussed in detail.A uniform treatment regimen fornewly diagnosed BL patients wasagreed upon. It was anticipated that

a year will be required in order to putinto place the necessary infrastruc-ture to conduct a formal clinical study.In this time, data managers will beappointed and common data collec-tion forms will be created. A formalprotocol will be developed duringthis time. A follow-up meeting isplanned for May 2003. ■

DATA MANAGER TRAININGMs Bhasha Kolhatkar of the Tata Me-morial Hospital in Mumbai receivedtraining relating to ethics, good clini-cal practice and data managementpractices in INCTR’s Clinical Trials Of-fice (CTO) in December. The experi-ence proved extremely useful forboth Ms Kolhatkar and the staff of theCTO. The exchange of informationthat took place during the two-weektraining period will be invaluable inpreparing a formal training course fordata managers in India. ■

MEETINGS OF THE CORPORATE LIAISONCOMMITTEEINCTR’s corporate Liaison Committeemet on December 20 to discuss ap-proaches to the development ofsponsorships of INCTR’s programsand meetings by the corporate world.Recent interest expressed by thepresidents of two pharmaceuticalcompanies in projects in Africa and inpalliative care were mentioned. Sev-eral specific approaches were dis-cussed and have been acted upon.

AUTUMN VISITORSDr Norman Coleman, Associate Direc-tor of National Cancer Institute’s Ra-diation Research Program and Chiefof Radiation Oncology at NCI, visitedINCTR to discuss potential collabora-

tion, particularly in the area oftelemedicine. Dr Coleman said that hethought the “progress (made) in twoyears by INCTR is remarkable.”

Dr Pierre Scalliet, Professor of Ra-diation Therapy at the Catholic Uni-versity of Louvain at St Luc UniversityHospital in Brussels, visited INCTR todiscuss his interests in radiationtherapy training in developing coun-tries and the possibility of workingwith INCTR in this area of endeavor.

Dr Birendra Amatya, a pathologistfrom Nepal who has been undertak-ing advanced training in Leuven, willbe the only hematopathologist inNepal, and asked for assistance in es-tablishing a program in Kathmandu.The possibility of INCTR assisting inthe establishment of a collaborativeprogram to be established in Nepal,with Dr Naresh, a hematopathologistsin Mumbai, was discussed. ■

AWARD WINNERSThe Special Panel of the INCTR Advi-sory Board has selected the winnersof the 2003 INCTR Awards. We are verypleased to announce that Dr MaxParkin of the International Agency forCancer Research is the winner of thePaul P. Carbone Award in InternationalOncology. Dr Federico Sackman-Muriel, formerly of the Garrahan Hos-pital, Buenos Aires, is the winner of theNazli Gad-el-Mawla Award. The AwardLectures will be presented on 29 May,after the opening session of the An-nual Meeting in Brussels. ■

INCTR at the Institut PasteurRue Engeland 6421180 Brussels - Belgium+32 2 373 93 23bene@inctr.bewww.inctr.org

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HEMATOLOGY ANDPEDIATRIC HEMATO-ONCOLOGY SERVICES INCASABLANCA

THE COUNTRY, THE CITY AND THEPEOPLEThe Kingdom of Morocco, situated atthe northwest tip of Africa and bor-dered by the Atlantic ocean and theMediterranean sea, covers an area of710,850 km2. The population exceeds31 million, with children under the ageof 14 representing almost 40% of thepopulation. Morocco faces the prob-lems typical of developing countries:19% of the population living below thepoverty line and up to 50% being illit-erate.

Casablanca is the capital; with morethan 4 million inhabitants, it is the mostdensely populated city in North Africa.More than 60% of Morocco’s economicactivity is concentrated there.

HEMATOLOGY AND PEDIATRICONCOLOGYThe Department of Hematology andPediatric Hemato-Oncology was cre-ated in 1980 by Professor NBenchemsi and Professor SBenchekroun, at a time when therewas no specialized unit in Moroccodealing with hematological malig-nancy. Given the inadequate qualityof supportive care facilities, specifi-cally the lack of blood products andantibiotics, intensive chemotherapywas not used. Most patients had nohealth insurance and could not affordto pay for their treatment. Likewise,the hospital had very limited re-sources and could not provide suchexpensive treatment. It thus becameclear that quality of care would notimprove without additional help. Anassociation of volunteers and donorswas therefore established in 1983.

Named ‘Agir,’ it has proven to be veryefficient and has helped the hospitalteam in its endeavors to provide op-timal care.

Unfortunately, the Department inCasablanca is still the only public fa-cility in Morocco treating adult pa-tients with hematological malignan-cies. Two pediatric units have beenestablished, one at the Children’s Hos-pital in Casablanca, the other in Rabat.The Department comprises an outpa-tient clinic and a day-care unit, wheremore than 100 patients are seen eachday, together with two wards—onewith 24 beds for adults the other with13 beds for children. Mothers are en-couraged to stay with their children.

Each year, the Department admitsmore than 1,000 new patients, ofwhom approximately 250 are chil-dren suffering from various kinds ofcancer. Lymphomas, leukemias, my-eloma and aplastic anemia, togetherwith ‘benign’ conditions such as irondeficiency anemia, thalassemia, sicklecell anemia, and hemophilia, are themost prevalent conditions seen inadults, whereas in children, lympho-mas, acute lymphoblastic leukemia(ALL), nephroblastoma, neuroblas-

toma and bonetumors are themost frequentlyseen malignan-cies.

IMPROVEMENTSIN SUPPORTIVECAREImprovementsin supportivecare have re-

sulted in a significant decrease in mor-tality from neutropenic sepsis. Initiallythis was 30%, but a retrospectiveanalysis of 40 febrile episodes in chil-dren with AML treated between 1996and 2001 showed the mortality rateto have fallen to 5% in an era whenmore intensive treatment was beingused. In the initial series of 66 patientstreated between May 1980 and Janu-ary 1983, when hydroxyurea was theonly drug being used, complete re-mission (CR) was achieved in only 5patients. In contrast, CR was achievedin 15 of 20 patients admitted during2002. Current treatment comprisesremission induction therapy withdaunorubicin and cytarabine (ara-C),followed by 2 cycles of high-dose ara-C, given with doxorubicin oridarubicin.

This progress has been made pos-sible by improvements in supportivecare, increased awareness of the im-portance of hygiene, education of pa-tients and improvements in nursingeducation. Another factor has beenthe quality of blood products: a Qual-ity Control Committee for BloodTransfusion Services sees to this.Screening for hepatitis B and C and for

The Children’s

Hospital in

Casablanca.

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HIV is now routinely carried out. As aresult, the incidence of hepatitis C hasfallen from 26% to 6% in patients re-ceiving multiple transfusions. Mo-rocco has a very low incidence of HIV,but an Infection Control Committee,which works closely with the medicalstaff, has been established.

LYMPHOMAIn view of the potentially good prog-nosis of patients with lymphoma, thisgroup of diseases was considered tobe a priority and resources were allo-cated to improve survival in these pa-tients. Ninety-five patients withBurkitt’s lymphoma (mean age 6.7years, male: female ratio 1:2.5) havebeen treated according to the FrenchLMB89 protocol. Most patients(73.5%) had an abdominal presenta-tion; the diagnosis was made on thebasis of fine needle aspiration in 60%of cases. The majority of cases (63%)had Stage III disease. Complete remis-sion was achieved in 68.5% of casesand the five-year survival was 59%.Ten of the 15 patients who died didso before or shortly after initiation oftreatment due to metabolic and nu-tritional complications.

The greatest problem is that pa-tients present with very advanced dis-ease because of delays in diagnosis andthe long distances involved in reachingthe hospital. For example, 441 adultswere treated for non-Hodgkin’s lym-phoma between January 1998 andDecember 2000. Only 39 of them livein Casablanca. Only 10% had health in-surance. The mean duration of symp-toms before diagnosis was eightmonths; 70% had Stage III or IV diseaseat the time of presentation.

With regard to Hodgkin’s disease,181 children have been treated up to2001. Chemotherapy regimens com-

prised ‘MOPP’, ‘COPP’ or ‘ABV.’ In 1986, aphase II study was conducted to evalu-ate the use of vinorelbine. Again, mostpatients presented with advancedstage disease. An unexpected findingwas the incidence of Hodgkin’s diseasein very young children; 15 being 4years or younger at the time of presen-tation.

ACCOMPLISHMENTS ANDCOLLABORATIVE PROGRAMSThe Department is a major referral cen-ter for the treatment of children withcancer and for adult patients with he-matological disorders. We have partici-pated in the creation of the MoroccanSociety of Pediatric Oncology (SMOP)and have worked in collaboration withthe Center for Pediatric Oncology inRabat (Professor Msefer-Alaoui) in theorganization of the third SIOP meet-ing of Africa. We have organized 13workshops in hematology and pediat-ric oncology.

Currently there is no stem cell trans-plantation program in Morocco. Withthe help of our fundraising group weare working to set up a small unit forthis purpose. We are also lucky to havebeen involved with Professor JeanLemerle ( Villejuif, France) in theGroupe Franco-Africain d’OncologiePédiatrique. The group is focusing onBurkitt’s lymphoma and Wilms tumor.

We also have developed an ambi-tious program with the InternationalOutreach Program of St JudeChildren’s Research Hospital (USA), di-rected by Dr Judith Wilimas and DrRaul Ribeiro. This program has focusedon nursing, together with improve-

ment in pathology services and infec-tion control, as well as data manage-ment, ethical issues, immuno-phenotyping for leukemia and thedevelopment of therapeutic protocolsadapted to local circumstances.

WHAT NEXT?There are several aspects of treatmentwhich need improvement, includingcytogenetics and services for the treat-ment of thalassemia, sickle cell anemiaand hemophilia. Since there is no reli-able data on the epidemiology of can-cer in Morocco, a cancer registry is ur-gently needed. There is also a need forthe creation of other units throughoutthe country to take care of children suf-fering from cancer; we will be helpingwith the establishment of this pro-gram. Finally, since there is no accom-modation for the parents of childrenin the hospital, the fundraising groupis working to remedy this.

The medical team is very dedicatedand enthusiastic and is extremely in-terested in developing collaborativeprojects with experienced teams in he-matology and pediatric oncology. ■

Submitted by: Mhamed Harif (MD),Asmaa Quessar (MD), Said Benchekroun(MD) Service d’Hématologie etOncologie Pédiatrique Hôpital 20 août1953, Casablanca, Moroccoe-mail : agir@wanadoopro.ma

The medical care provided at Children’s

Hospital in Casablanca, which focuses on

both the physical and emotional needs of

young patients, gets a “thumbs up.”

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P R O F I L E S I N C A N C E R M E D I C I N E

DINSHAW LEADS CANCERREVOLUTION AT TATA

Radiation therapy is used in the treat-ment of two-thirds of all cancer pa-tients in India today. It is often thetreatment of choice as primarytherapy, and is frequently used incombination with surgery or chemo-therapy and for palliation in advancedcases. At the Tata Memorial Centre,Mumbai, India, where Dr. KetayunDinshaw is director, 400 patients re-ceive radiation treatment every day.

As a radiation oncologist-turned-hospital administrator at one ofIndia’s foremost cancer hospitals, Dr.Dinshaw has played a significant rolein the evolution of modern health carein that country, and radiation therapyhas led the way. Her hospital’s depart-ment of radiation oncology can de-liver both external beam therapy andbrachytherapy (temporary implanta-tion of radioactive pellets or wires intothe tumor). New, high precision treat-ment design and delivery methodssuch as three-dimensional conformalradiotherapy, in which the radiationbeam is automatically adjusted to theshape of the tumor during treatmentfrom several angles, and intensitymodulated radiotherapy, in which thestrength of the beam is similarly ad-justed, are available. Both of thesetreatments minimize the amount ofnormal tissue in the irradiated field.The cancer treatment methods avail-able at Tata Memorial Hospital rivalany in the world.

Over the past 25 years, Dinshawhas revolutionized cancer medicine inIndia, refining multi-modal treat-ments as the exception rather thanthe rule. Most recently, she has turnedher attention to expanding thehospital’s capabilities for clinical re-search. Clinical trials—a relatively new

concept in India—are underway intreating various cancers includingbreast, cervical, head and neck, lym-phomas and leukemias.

“We are very keen to be involvedin new collaborations with INCTR,”Dinshaw says. “Cervix is the most com-mon cancer in my country, and in cer-tain metropolitan areas breast canceris overtaking it. It will be extremelyuseful to be part of organized trialsthat might evolve from INCTR’s strat-egy groups in these areas.”

Dinshaw joined the staff of the TataMemorial Hospital, Mumbai, in 1974,and seven years later was named headof the department of radiation oncol-ogy. In 1995, she was appointed direc-tor of the Tata Memorial Hospital, andtwo years later was selected to over-see the Tata Memorial Centre (TataMemorial Hospital and Cancer Re-search Institute) as well.

Throughout her tenure, she hasbeen a driving force in establishingthe highest standards, organizing andrefurbishing all departments, provid-ing modern instrumentation for diag-nosis and treatment of cancer, andestablishing modern managementsystems and computerization in thehospital.

One of her earliest initiatives wasfostering an integrated team ap-

proach to cancer treatment, encour-aging radiologists and surgeons toreview new patients in the Lym-phoma Joint Clinic. Together, the doc-tors established clinical protocols, andnow channel cancer patients into ap-propriate treatment programs ac-cording to set guidelines—in the con-text of ongoing clinical trials. A vi-brant scientific review committee andhospital ethics committee monitorand guide all research programs in theTata Memorial Hospital.

A new facility housing the Ad-vanced Centre for Treatment Researchand Education in Cancer (ACTREC)opened just last year. The Cancer Re-search Institute at ACTREC will focus onmolecular genetics, molecular epide-miology, immunology, virology andnewer areas of genomics and drug de-velopment. The Clinical Research Cen-tre aims to introduce translational re-search from the bench to the bedsideand will focus on specific clinical trials.Validation by sophisticated laboratorymethodologies, predictive and prog-nostic assays, and tumor markers willbridge intense interaction betweenscientists and clinicians. Indigenousdevelopment of teletherapy units andmodels will also be addressed atACTREC, which is expected to be a hubof excellence in the region.

“Between the hospital and the re-search centre, we are strongly posi-tioned to provide leadership in allareas of medical services, educationand research,” she says. “While wehave concentrated on providing thebest patient service, we are also in-terested in all aspects of basic andclinical research, and in providingpost-graduate training. We placeemphasis on teaching and using ourwealth of excellent clinical materialfor research.” ■