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T 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 2, Number 3, Winter 2001/02 — Inside: Regional News - 5 Special Report on Childhood Leukemia - 8 ALL Case History - 10 Tata Memorial Centre - 13 Profile in Cancer Medicine - 14

THE PRESIDENT’S MESSAGE

THE RISE OF SCIENCE AND , CONSCIENCE in the first by Ian Magrath modern con- trolled trial, demonstrated Sir James Frazer, in his pioneering work the ability of on magic, mythology and religion, has oranges and much to say on the thought processes to of early human communities. In The . Golden Bough, he refers to the “primi- tive” magical reasoning that led to a broad range of ritual practices that en- able humans to survive in the face of odds weighted heavily in favor of the natural forces that threatened them. Primitive or not, and fallacious or not, the fruits of this formative era of hu- man culture continue to have a re- insufficient basis for the management ited from the past. Any hint of a depar- markable influence on our lives. A sec- of human affairs, since it does not in- ture from tradition has been given ond type of reasoning, which we may volve emotion, conscience or morality. short shrift. Paracelsus, for example, refer to as scientific, has played an in- We may, then, surmise that human so- who rejected the notion that medical creasingly dominant role in human so- ciety results from a compromise be- knowledge must be garnered from ciety; there are few corners of the tween these two thought processes, ancient texts, was barred from the uni- world that have not been touched by just as it also depends upon a compro- versity and in 1528 lost his position as its practical application, even though mise between the needs of the com- Physician to the city of Basle. His holis- most of the world’s population has had munity and those of the individual. tic approach to medicine was roundly little scientific training. It would be Throughout human history, these rejected in Europe for at least 400 years. pointless to discuss the pros and cons closely related dualities have vied for In the 21st century, science is, at last, of each type of reasoning since both supremacy. taking an increasingly prominent role are part of the human condition, al- In medicine, the threads of scientific as the basis for medical practice, but though it is surely correct to state that reason have existed since the begin- the hard edges of science must be in the absence of scientific reasoning, ning of time, although buried for much blunted by compassion. For at its heart, humans would not have evolved be- of human history under the weight of it derives from individualism - that as- yond the stage of hunter-gatherers. Yet magical thinking, or by tomes of medi- pect of “Western civilization” which scientific reasoning alone provides an cal wisdom, sacred or otherwise, inher- surged to center stage in the Renais- NETWORK

sance era. But in this same era private sacred animal or plant was also a criti- anthropology, mythology and reli- conscience also emerged, leading to cal dietary element (e.g., corn, or the gion. The primacy of magical thinking passionate discussions of the conflict- bison) the link between the animals’ in meeting the needs of the commu- ing interests of individuals and society, well-being and the salvation of the nity with respect to survival, accounts and so to human liberty and human community was direct. for the slow emergence of science, rights. Such ideas were alien to the Sometimes the vitality of the which required a degree of individual primitive communities described by people and their world were closely al- genius on the one hand, and toler- Frazer, who considered the individual lied to their King, who usually also en- ance by dominant societal forces (in- as a representative rather than a mem- joyed divine status. His enfeeblement variably threatened by new ideas) on ber of society. and death must therefore be avoided the other. Moreover, in the absence of logical precepts, glaring contradic- tions bore little weight, and thus had It is the duty of the physician to promote and safeguard the no ability to undermine the magical health of the people. The physician’s knowledge and conscience basis of society. Predictably, the rise of science has been associated with le- are dedicated to the fulfillment of this duty. gions of detractors, or overt oppo- —Declaration of Helsinki, 2000 nents, and even today, there are many who argue against it (The Flight from Science and Reason, Ann NY Acad. Sci, KILLING AND EATING GODS at all costs - by killing him whilst still vol. 774). In his chapter “Eating the God,” Frazer in his prime, in order to ensure that his In the practice of medicine, the in- describes how among the still vigorous soul would be passed on ability (or unwillingness) to perceive Acagchemem native American Indians to a younger successor. Plants, animals, how knowledge based on clinical tri- of California, “The notion of the life of a or people were often used as surro- als involving many participants can species as distinct from that of an indi- gates, particularly as gods became be applied in the service of the indi- vidual, easy and obvious as it seems to more supernatural. Frazer records that vidual patient has constantly hin- us, appears to be one which (they) “Twice a year, in May and December, dered the assimilation of the scientific ....cannot grasp.” He describes how the an image of the great Mexican god method. This attitude, part of the life of a species of animal cannot be Huitzilopochtli or Vitzilipuztli was backlash against science, has similar conceived of as “anything other than made of dough, then broken in pieces, origins - discomfort with novelty, a an individual life, and therefore ex- and solemnly eaten by his worship- perceived challenge to the su- posed to the same dangers and calami- pers.....” The Aztecs believed that by premacy of professional leadership, ties which menace and finally destroy consecrating bread their priests could and, to a degree, an aversion to the the life of the individual.” The turn it into the very body of their god, need to acquire new knowledge. Ac- Acagchemem worshiped the wild buz- “so that all who thereupon partook of cording to Murray Enkin’s foreword in zard, and every year, at the feast of the consecrated bread entered into a Alejandro Jadad’s excellent book, Panes, sacrificed one of these birds in mystic communion with the deity by Randomized Clinical Trials, practicing order to preserve the species - for ac- receiving a portion of his divine sub- physicians confronted by the initial cording to their rationale, killing a stance into themselves.” In this, the stirring of clinical science “were un- young healthy animal liberated the life Aztecs were entirely at one with their willing to hold their decisions in abey- force, which would then be reborn in Spanish conquerors. ance till their therapies received nu- another, equally vigorous bird. Not to merical approbation, nor were they kill, at intervals, one of these sacred ani- SCIENCE VERSUS TRADITION AND prepared to discard therapies vali- mals at the peak of its health would re- MAGIC dated by both tradition and their own sult in the gradual loss of the vitality of Frazer’s enormous scholarship and ac- experience on account of somebody the entire species, and eventually its ex- cumulation of volumes of evidence else’s numbers.” tinction - with serious consequences from all over the world had wide- Enkin describes how, in 1836, an ar- for those who held it sacred. When the spread implications for psychology, ticle by the Frenchman PDA Louis in 2 M E S S A G E

the American Journal of Medical Sci- terms of the patient population, to the mated that the results of clinical trials ences, hailed by the editor as “the first cohort that participated in the clinical take, on average, 17 years to become formal exposition of the results of the trial. part of accepted medical practice! only true method of investigation in Controlling the treatment adminis- regard to the therapeutic value of re- JAMES LIND AND SCURVY tered by health service providers in a medial agents,” caused a storm of criti- The first documented controlled clini- non-research setting remains difficult, cism. Comments such as “The physician cal trial of modern times is believed to but the could have de- called to treat a sick man is not an ac- be that of James Lind, a ship’s doctor creed that sailors should be protected tuary advising a company to accept or in the Royal Navy. Lind performed a against scurvy in the manner shown deny risks, but someone who must study whilst at sea, which involved 12 by Lind to be effective. Why did it take deal with a specific individual at a vul- sailors with scurvy (a disease caused so long? While many factors may have nerable moment” and “Averages could by deficiency of C) and the use played a role, the lack of understand- not help and might even confuse the of six different remedies applied for ing of the scientific method is likely to practicing physician as he struggles to two weeks. The many study arms re- be an important one. But further in- apply general rules to a specific case.” lated to the many traditional nostrums sight may be gained by an experiment, Louis’ study, by the way, was on the role that needed to be refuted. He demon- also described in Lind’s book, of an- of blood letting in the treatment of strated the therapeutic effect of two other “,” carried out in the pneumonia, a method widely ac- oranges and a given daily and previous century, this time on scurvy cepted at the time, but which he clearly reported his findings in A Treatise on developing in the course of lengthy demonstrated to be useless. To be fair, Scurvy published six years after the sojourns in inhospitable places with the lack of understanding of the nature trial (1747). Lind also provided consid- no access to fruits and vegetables. of disease must have had a lot to do erable evidence that fruits could As reported by Lind: “Whereas the with the inability of doctors to compre- both cure scurvy and prevent it. Yet it first adventurers to that part of the hend the value of clinical trials. Today, was not until 1795, approximately 50 world, who wintered in the same we must be equally concerned with years later, that the Royal Navy intro- places, were almost all destroyed by the difficulty patients have in under- duced citrus fruits or into the the scurvy (1619 and 1631) … a set of standing the need for clinical studies, diet of British sailors, earning for them sailors consisting of seven men, was particularly randomized trials. This the nickname of “limeys” but greatly in- left two winters successively, in the problem is frequently aided and abet- ted by the culturally-instilled presump- tion of the physician’s omniscience, al- In medical research on human subjects, considerations though doctors too, must bear some related to the well-being of the human subject should take responsibility in this regard, for their frequent unwillingness to admit their precedence over the interests of science and society. ignorance. —Declaration of Helsinki, 2000 Clinical scientists, of course, know that evidence from clinical trials rarely provides a precise ability to predict the creasing their efficiency as a fighting years 1633 and 1634, at Greenland and outcome of a treatment or preventive force. This delay might be thought to Spitzbergen, by way of experiment, method in a particular individual, but have been unconscionable and even but every man of them next spring rather provides a reasonably accurate short-sighted - primarily in terms of was found to have died of the scurvy.” assessment of the likelihood that ben- the human suffering and death it Methods recommended to these luck- efit or harm will accrue. It does have the caused, but also on account of its pro- less sailors “for preservation” included ability to predict, within statistically foundly negative effect on the Royal purging, anti-scorbutic potions and defined limits, the outcome in a rea- Navy, the British economy and the on- , although these “infallibly in- sonably sized cohort or group of pa- going colonization of the New World. creased the malady… and hastened tients, assuming that the cohort in Even today, however, the Institute of their unhappy end.” There could have question is similarly structured, in Medicine in Washington has esti- been little thought for the rights of the 3 NETWORK

sailors, nor, indeed, is there much evi- the practice of medicine - by identi- regulated (at least with respect to dence of concern for their suffering. fying the causal factors and mecha- quality) at the point of service. Perhaps even more disturbing is the nisms of disease, thus creating the In 1758, Richard Price, a preacher lack of any hint that the experiments opportunity to prevent them, by clas- and moral philosopher, published A might have been considered highly sifying diseases, thereby creating a Review of the Principle Questions in unethical. It seems as though the lot basis for diagnosis and treatment, Morals, in which he argued that mo- of these unfortunate men had been and by systematically identifying rality is an inherent characteristic of cast by their lowly status, rather than chemical, biological and physical actions, and that good and evil could by the decision to perform such an ill- methods of ameliorating or curing be distinguished entirely by reason, conceived experiment. Even the well- disease. without the help of any “moral sense” intentioned may have blind spots But science, born of individualism, or appeal to sentiment. Some 250 where cultural mores and received is not enough. While the primary pur- years later, we can safely conclude attitudes obscure principles that may, pose of medicine is to relieve human that either reason has not prevailed, in another culture, time or place, ap- suffering, there are many who make or that Price was wrong. The atrocities pear glaringly obvious. their livelihoods from its practice, that litter the history of mankind, in- with the consequent inevitability that stigated with the aid of scientific dis- DAN MICHEL OF NORTHGATE their individual interests may on oc- coveries, seemed perfectly reason- In 1340, an obscure Kentish monk, casion be put before those of the pa- able to their perpetrators, if not to Dan Michel, wrote a book entitled tient. Multiple safeguards are neces- others. One might conclude that a Ayenbite of Inwyt. Michel’s work was sary to ensure that the patients’ inter- reversion to the tenets of magical a rather poor English translation of ests (including their psychological thinking, and the preservation and an earlier French treatise, commis- well-being) are protected, particularly promotion of “our community,” how- sioned by Philip the Bold, on all since patients are usually unable to ever defined, had much to do with known vices and virtues. Presumably, assess the appropriateness and qual- swamping the prick of the ayenbite the title, which refers to the repeated ity of care. Similar considerations ap- of inwyt. Science does not beget con- gnawing (remorse) of inner knowl- ply in the sphere of . Ul- science, but it surely needs it. edge (wit), implies that conscience, timately, where risks are not per- The year 1758 also saw the publi- and the psychological pain engen- ceived by the public, the only reassur- cation of the tenth edition of Linnaeus’ dered by ignoring it, are the deter- ance that the science of medicine is work System Naturae, in which the minants of moral behavior. Science, subservient to the general good, and Swedish naturalist classified humans, of course, and knowledge obtained that it is practiced with responsibil- giving them the epithet Homo sapiens by the scientific method, can be put ity and compassion, is conscience - in (wise man). He was presumably refer- to pragmatic use for good or evil. In part, the conscience of corporations ring to the ability to reason - which un- this respect, scientific knowledge dif- and individuals involved in health fortunately is not at all the same thing fers from received knowledge based care, and in part, the conscience of as wisdom. Science and conscience are on faith rather than evidence. For regulatory bodies. Regulations per- combined in the context of clinical re- faith can be used only as inspiration taining to clinical research are, in part, search, such that here, we hope, wis- or justification rather than a spring- a codification of the consciences of dom generally prevails. An expression board for technical progress. Belief in thoughtful persons concerned about of the relevant aspect of conscience a deity, it would appear, is insufficient patients (and sometimes, lawsuits!), may be found in the Declaration of to allow the creation of machines ca- but their effectiveness is dependent Helsinki, a document that has become pable of flying across the Atlantic, upon the individual consciences of something of a sacred text for clinical reaching the moon, or raining high those involved at all levels of the de- investigators. So it should be, although explosives on a perceived enemy - livery of health care. Regulations may its contents must not become frozen although it may be used to foster all be adequate or not, enforced or not, and allowed to whither with age. In- of these activities. Thus it is that sci- and obeyed or not. Moreover, the pro- stead, it should be subject to periodic ence, and only science, can advance vision of medical care is minimally revitalization. Le roi est mort. Vive le roi! ■

4 R E G I O N A L N E W S

NEPAL Pokhara – or through the medical and surgical oncology facilities at the In February, Dr Ian Magrath and Mel- Tribhuvan University Hospital, issa Adde visited Nepal, where they Kathmandu. met with Dr Sankaranayanan of the If active case finding at the above IARC and various collaborators to dis- five facilities and other selected cuss joint studies (involving the IARC, sources (e.g., major centers in India) INCTR and the Nepalese Cancer Re- were to be implemented, a popula- lief Society) in population-based can- tion-based cancer registration for the cer registration and in the prevention Chitwan district would be feasible. and early detection of cervical cancer. One staff member at the BPKMCH has With respect to a population- already received training in popula- based cancer registry, all agreed that tion-based cancer registration at the this could be implemented at the BP At the INCTR Office at Scheer Hospital in IARC. An additional cancer registrar’s Koirala Memorial Cancer Hospital Nepal, Dr Sankanarayanan (left) and col- position would greatly facilitate can- (BPKMCH), a comprehensive cancer leagues assemble a culposcope provided cer registration and communication center supported by the government, by IARC to help detect cervical cancer. among the other institutions. located in Bharathpur in the Chitwan Further discussion of existing and district in Eastern Nepal, 150 km from planned cancer control activities in Kathmandu. The BPKMCH has are presently being seen at the Nepal took place with representatives steadily increased the number of new BPKMCH itself, while the remainder of BPKMCH, BCCC, Tribhuvan Univer- cancer patients cared for annually are probably treated at one of three sity Hospital, Bir Hospital, the Nepal and is expected to see more than existing radiotherapy facilities in Cancer Relief Society and the Nepal 2,000 new cases this year. Dr Nepal – Bir Hospital, Kathmandu, Network for Cancer Treatment and Sankaranayanan felt that a large pro- Bhakthapur Cancer Care Centre Research (NNCTR, INCTR’s Nepalese portion of the cancer cases in the (BCCC), Bhakthapur, and the radio- collaborating unit), who were enthu- Chitwan district (population 475,000) therapy facility at the Medical College, siastic about such collaboration. The BCCC, BPKMCH, and the Scheer Me- morial Hospital (where the NNCTR office has been established) will par- ticipate in an IARC-supported early detection program for cervical cancer. A course will be organized to train nurses in the screening methods and to train doctors in colposcopy and LEEP. The IARC would provide the equipment required, including colposcopes, cryotherapy devices, LEEP apparatus, speculae, reagents, punch biopsy kits and other supplies. The screening method to be used is visual inspection of the cervix with acetic acid. This is considerably cheaper than the western standard of pap smears. Because no delay is in- volved in obtaining the results, as is Nepal Cancer Relief Society, outside the Early Detection Cancer Clinic in Lilithpur, Nepal. the case when pap smears are per-

5 NETWORK

formed. This will also eliminate the need to recall screened women and will reduce the chance that early le- sions will go untreated. Women with positive lesions can usually be treated at the same visit, e.g., with cryo- therapy. Radha P Nakarmi, Program Officer, and Amala Devi Manandhar, Assis- tance Officer, presently staff the NNCTR office at the Scheer Memorial Hospital. During this visit, it was agreed that the NNCTR would be- come a Branch of the INCTR, since it will function at the regional and na- tional levels. Magrath and Adde also visited the Medical School of Kathmandu Univer- sity, located at the Scheer Memorial Hospital. Dr Arjun Kaki, the Director Doctors at the Nepal Network for Cancer Treatment and Research (NNCTR) are eager to of the Medical School and Dr Sharma, join a collaborative effort to facilitate cancer control activities in Nepal. the Vice-Chancellor of Kathmandu University, expressed interest in hav- were also on the agenda. complete manuscript will subse- ing the INCTR design and conduct an Adde presented the analysis of the quently be submitted for publication. intensive course for medical students results obtained by the three partici- Discussion of a successor protocol in cancer control. Plans were made to pating centers in the project “Treat- to MCP841 focused on the treatment schedule a course for June 2003. ■ ment of Acute Lymphoblastic Leuke- regimen. Given the excellent results mia in Children and Young Adults now being obtained in Mumbai, it with Protocol MCP841.” Dr David was felt that the most appropriate NEW DELHI, INDIA Venzon and Dr David Lieuwheuer of design would be to use a basic the Biostatistics Branch of the NCI MCP841 protocol, but to include ad- During the same trip, Magrath and performed the statistical analysis, ditional induction/consolidation el- Adde visited New Delhi to discuss the which revealed clear differences in ements. Two possible new treatment establishment of an INCTR Office in In- the patient populations at the three schemas will be prepared by the dia at the Sir Ganga Ram Hospital in centers at presentation, particularly INCTR and circulated to the group for Delhi. They also discussed the results with respect to the distribution of consideration. of an analysis of data from more than white counts, age, presence of Dr Kishor Bhatia led a discussion 1,000 patients with acute lympho- organomegaly and T cell disease. The about a plan for a detailed molecu- blastic leukemia (ALL) treated at three analysis of patient characteristics in lar analysis of ALL in India, and com- centers with protocol MCP841 be- Mumbai also revealed that the pa- parison with results from Saudi tween 1990 – 1997. A successor pro- tient population at the Tata Memo- Arabia and Egypt. Dr Sultan Al- tocol to MCP841 is being developed rial Hospital has changed over time. Sedairy, Director of the Research with these same three centers. Mo- The group agreed that the data Centre of the King Faisal Specialist lecular studies in ALL in India in col- should be published, and that an ab- Hospital in Riyadh was also present laboration with the King Fahad stract would be prepared by the at this meeting. Dr Al-Sedairy agreed Children’s Medical Center Research INCTR for approval by the group and to support the study in various ways, Department in Riyadh, Saudi Arabia, submitted to a suitable meeting. A including training Indian technicians and investigators in Riyadh. ■

6 N E W S

INCTR EDUCATIONAL and was set in the context of cancer It was decided that an Advisory Board WORKSHOP ON CLINICAL control in China. The workshop ap- to INCTR should be formally consti- TRIALS IN CHINA peared to be well-appreciated by the tuted, and that the main panel of the participants. Advisory Board should be comprised In conjunction with the Chinese So- We anticipate developing several of individuals from developing coun- ciety of Clinical Oncology, and sup- educational tools from the workshop, tries. The new Panel will advise INCTR ported by Eli Lilly, INCTR held a three- again with the support of Eli Lilly, who on its programs and projects, and play day educational workshop on the sent 11 people to this workshop. An a major role in the selection of recipi- Value and Conduct of Clinical Trials in edited video of the meeting will be ents of INCTR’s Awards. The first meet- China. There were 37 participants and available, and the presentations will ing of the Advisory Panel will take 16 faculty members from INCTR, the be assembled on a compact disc that place during INCTR’s Annual Meeting National Cancer Institute, Bethesda, will be made available for educational this year. ■ the International Agency for Research and teaching purposes. INCTR is con- on Cancer, the World Health Organi- sidering making the CD material avail- zation, St Bartholomew’s Hospital, able on its website, and would appre- NEW STAFF London, the International Drug De- ciate feedback as to whether this velopment Institute, Brussels, the Chi- would be useful. Two trainees, Capucine Deriez and nese Academy of Medical Sciences, We hope to facilitate additional Mounia Meftah, from the Institut the Chinese Society of Clinical Oncol- workshops of this kind, focused pri- Supérieur Economique de Secrétariat ogy and the Chinese State Drug Ad- marily on training of clinical investi- in Brussels, have each spent ten weeks ministration. gators, in other world regions. Inter- in the INCTR Offices. Both have made Dr Lorenzo Tallarigo, President of ested parties should contact the valuable contributions to the INCTR Intercontinental Operations for Eli INCTR. ■ and also benefited from the experi- Lilly, participated in the opening cer- ence of INCTR administrative staff. emony. Six officials represented the Our two volunteers, Sandra Jackson Chinese Society of Clinical Oncology. INCTR MEETINGS and Hilary Wallace, continue to pro- The workshop covered all aspects vide outstanding support, and have of clinical trials, including design, ethi- The Annual General Assembly of now been joined by a third person, cal considerations, regulations, docu- INCTR was held on February 23 in Caroline Houard. Welcome on board, ments, management, quality control, conjunction, for part of the day, with Caroline! ■ analysis and presentation of results a meeting of the Governing Council.

INCTR has enlisted the support of Eli Lilly to help train clinical investigators in develop- ing countries through workshops such as this one in China. 7 NETWORK

CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children under 15 years of age and accounts for 25% of all childhood cancers in industrial nations. Inci- dence data from many developing countries indicates that ALL is also Figure 1 the most common childhood malig- nancy in most world regions, with The diagram shows the relative frequencies of various molecular lesions in childhood some notable exceptions such as ALL (both pre-B and pre-T) in the USA (data from Rubnizt and Look, Childhood Leuke- equatorial Africa where Burkitt’s mias, Ed. Ching-Hon Pui). Most lesions result in fusion proteins derived from genes in- Lymphoma occurs in greater fre- volved in cell growth, differentiation and survival, the letters stand for the involved quency. In the USA, there is an inci- genes. Some of them are mentioned in the text. dence of three to four new cases of ALL per 100,000 children per year. The ALL is a malignant disease that re- ally performed. In a child with ALL, the incidence of ALL in developing coun- sults when developing lymphocytes blood counts typically reveal a high tries tends to be lower than in the become too numerous and fail to white blood count (WBC) with abnor- USA or Europe, although there is mature. The excess of immature lym- mal circulating lymphoblasts and of- country-to-country variation and phocytes (lymphoblasts) can involve ten a reduced number of normal some cases may not ever be diag- different stages of maturation during white cells (granulocytes), predispos- nosed. There is a peak age incidence the lymphoid differentiation process, ing to infection, fewer red blood cells in children, ages two to five years in giving rise to subtypes of ALL. The (anemia) and a low platelet count most countries, but this age peak, due leukemic lymphoblasts are found (potentiating bleeding). In the pres- to a specific sub-type of ALL, varies predominantly in the bone marrow ence of suspicious findings in the pe- and is sometimes missing. The inci- and bloodstream but can also be ripheral blood an examination of the dence continues to decrease found in the organs of the lymphatic bone marrow is required to make the throughout adolescence. Males have system. The malignant cells may also diagnosis and to determine the type a higher incidence than females and, invade many other organs, including of leukemia that is present. in the USA, white children have a the spinal cord and the brain. Immunophenotyping is a valuable higher incidence than black children. The signs and symptoms of leu- and relatively inexpensive tool that is Children with Down’s syndrome or kemia reflect the degree of bone part of the standard diagnostic work- certain other inherited disorders are marrow infiltration and the extent of up of patients with leukemia and is more likely to develop ALL than are spread of the disease to other organs. used to determine the sub-group of normal children. The most common signs and symp- ALL as well as to differentiate ALL Normal lymphocytes fight infec- toms include fever, pallor, fatigue, from other types of leukemia. It is tion, in part, by making substances bleeding, bone pain, and swollen more precise than cytochemical tests e.g., antibodies that attack viruses lymph nodes. The duration of symp- used in the past, although these are and bacteria. There are three types of toms may be days to months. The still sometimes used to distinguish lymphocytes, B, T and Natural Killer early signs and symptoms of ALL may ALL from acute myeloid leukemia (NK) cells. Lymphocytes are made by be similar to other illnesses, such as (AML). The two major sub-groups of the bone marrow and undergo fur- infections or other causes of anemia. ALL are precursor B cell and precur- ther maturation and differentiation in Therefore, when a child presents with sor T cell. Cytogenetics has played an the organs of the lymphatic system - signs and symptoms that could be important role in the identification of the spleen, thymus, and lymph nodes. caused by ALL, a blood count is usu- smaller sub-groups of patients with 8 C H I L D H O O D L E U K E M I A

specific chromosomal abnormalities associated with a worse outcome, ripheral blood after 7 or 10 days of which have considerable prognostic however, when treated with modern treatment with corticosteroid alone, significance. However, cytogenetics treatment protocols, patients with T or other drugs used in induction. Pa- has largely been replaced by molecu- cell ALL generally have an outcome tients who have a rapid reduction in lar techniques (particularly PCR) and similar to those with precursor B cell the percentage of leukemic cells in flow cytometry (DNA index). ALL. Hyperdiploidy, which is the pres- the bone marrow or those who have ence of additional copies of whole a rapid clearance of circulating leuke- POTENTIAL PROGNOSTIC chromosomes, can be evaluated by mic blasts have a better prognosis FACTORS measuring the DNA content of cells, than those who clear leukemic cells Prognostic factors are those that reli- a measure known as the DNA index. more slowly. The adverse impact on ably predict outcome. These are cat- Hyperdiploidy or a DNA index of > prognosis related to slow early re- egorized as follows: clinical and labo- 1.16 is associated with a better prog- sponse may be overcome by modify- ratory features at diagnosis; molecu- nosis. Hypodiploidy (fewer than nor- ing therapy in such patients, e.g., by lar characteristics at diagnosis; and re- mal chromosomes) is associated with prolonging and intensifying induc- sponse to initial treatment. It is impor- a higher risk of treatment failure. Re- tion therapy. tant to point out that prognostic fac- curring chromosomal translocations tors are largely treatment-dependent. (see Figure 1) that have prognostic TREATMENT OF ALL Many clinical and laboratory fea- significance include the t(12;21) cryp- Approximately 70 to 80% of patients tures at diagnosis have been de- tic translocation (i.e., normally unde- with ALL diagnosed in industrialized scribed as having prognostic signifi- tectable by cytogenetics), resulting in countries can be cured. The primary cance, perhaps the most important the fusion of two genes, TEL and treatment is chemotherapy. Treat- being age at diagnosis, WBC at diag- AML1, to create a single protein (TEL- ment consists of remission induction, nosis, gender, and race. Infants under AML1). Such patients have a good the prevention of spread to the cen- one year of age are at a very high risk outcome. The t(9;22), which involves tral nervous system (CNS), consolida- of treatment failure. In western coun- the same genes as in chronic myeloid tion, late intensification and mainte- tries, older children and adolescents leukemia, and also results in a fusion nance cycles. A typical remission in- (10 years and older) have less favor- protein, BCR-ABL, has an unfavorable duction consists of a glucocorticoid, able outcomes, while children ages 1 prognosis. Several translocations in- vincristine, and l-asparaginase, with or to 9 years tend to have more favor- volve the MLL gene, situated on chro- without an anthracycline. Complete able outcomes. Patients with high mosome band 11q23, each being as- remission is achieved in 95-98% of WBCs tend to have a worse outcome. sociated with a different prognosis, patients in industrial nations. Many Girls with ALL have a better progno- depending upon other factors such variations exist with respect to con- sis than boys in some series. White as the age of the patient, the WBC, the tinuation therapy, but most protocols children have a better prognosis than immunophenotype, and the specific include agents such as cyclophos- black children. translocation. One of them, for ex- phamide, cytarabine, methotrexate Molecular and biological charac- ample, the t(4;11) is associated with and mercaptopurine in addition to teristics of leukemia cells at diagno- up to 80% of infant leukemias, which the periodic reintroduction of agents sis that are associated with outcome do poorly. used for remission induction. Late in- include immunophenotype, chromo- Early treatment response has tensification, or re-induction therapy, some number, and certain chromo- proved to be a particularly good mea- appears to make an important differ- somal translocations. Precursor B cell sure of outcome, being, in fact, a di- ence to outcome in all risk groups. ALL, one of the two main sub-groups rect measure of the effect of chemo- CNS preventive therapy may include of ALL, can be further divided into therapy. Early response has been intrathecal therapy with methotrex- early pre-B and pre-B cell ALL. Patients evaluated by examination of the bone ate and cytarabine and, in some cir- with an early pre-B phenotype (no ex- marrow during induction therapy cumstances, cranial radiation. The to- pression of surface or cytoplasmic im- (e.g., 7 or 14 days after the initiation tal duration of therapy is between munoglobulin) have the best progno- of treatment), or by the clearance of two to three years. sis. The T cell phenotype used to be circulating lymphoblasts from the pe- 9 NETWORK

ACUTE LYMPHOBLASTIC LEUKEMIA in different ethnic or socioeconomic echocardiogram performed at this IN DEVELOPING COUNTRIES groups. Preliminary research on the time showed normal heart function, Patients with ALL in developing coun- molecular characteristics of ALL in In- but revealed a mediastinal mass that tries often present with more ad- dia suggests that chromosomal trans- was confirmed by a CT scan (Fig 1). vanced disease (see Case History) in locations associated with a poorer The surgeon at the local hospital, who which leukemic cells have not only prognosis in western series are more was not a specialist in oncology, made infiltrated the bone marrow, but also frequent, and those associated with a presumptive diagnosis of thymoma. invade other organs – in some cases a good prognosis, less frequent. Re- The patient underwent a median ster- this may be because the ALL was not search into the optimal therapy for notomy and excision of the mass on suspected initially, but the disease children with ALL in developing coun- May 5. The diagnosis made by the may also be more aggressive in tries needs to take into consideration local pathologist was thymoma: lym- poorer socioeconomic groups (see differences in clinical and laboratory phocytic type. Within one week from below). Co-morbidities such as hepa- features at diagnosis and molecular surgery and prior to discharge from titis, and malnourishment are and biological characteristics of the the hospital the patient developed also much more common, which may leukemia as well as other relevant fac- bilateral cervical lymphadenopathy. affect the patients’ ability to tolerate tors, such as co-morbidities. He was referred to the Tata Memorial treatment. Access to care in cancer Hospital (TMH) for evaluation and centers or pediatric oncology units is INCTR ACTIVITIES IN ALL pathology review. much more limited in developing INCTR is working to support research The patient was admitted to the countries, and patients and their fami- on the treatment and characteriza- Thoracic Surgical Unit of the TMH on lies often have to travel long dis- tion of childhood/adolescent ALL in May 29. Physical examination re- tances to reach hospitals capable of India, including assisting with the de- vealed bilateral gross cervical lym- making the diagnosis and/or provid- velopment of a cooperative group phadenopathy. His blood counts were ing necessary treatment. Further, within India so that more patients within normal limits. He underwent a even when they reach these centers, with ALL have better access to care. fine needle aspiration biopsy of one a family’s inability to pay for treat- We also hope to extend and further of the lymph node masses and ment due to socioeconomic factors develop this work in other countries samples previously obtained from the or the lack of health insurance often such as Brazil, China and Egypt. ■ thymic mass were reviewed. The di- impacts upon the type of therapy —Melissa Adde agnoses reported by the pathologist that is ultimately provided to the at TMH were suggestive of lympho- child. Continuation of treatment and blastic lymphoma (LL) in the lymph follow-up is often difficult, again be- node, but this diagnosis was con- cause of socioeconomic factors, the THE CASE OF MISTAKEN firmed when the sample from the ex- need to travel long distances, and the IDENTITY cised thymic mass was reviewed. The lack of trained physicians who can by Shripad Banavali, MD, Tata tumor cells in the thymic mass were manage their care outside the major Memorial Hospital, Mumbai, India shown to be of T cell type and ex- cancer center or pediatric oncology pressed CD3. Unfortunately, the pa- unit. The patient, a 13-year-old male, pre- tient and his family returned to their Treatment protocols typically ad- sented on May 3, 2001 to a local hos- hometown before receiving the pa- ministered to patients in more afflu- pital in a small city near Mumbai. He thology reports. The patient was then ent countries may not necessarily be had a seven-month history of breath- lost to follow-up. optimal for the treatment of children lessness on exertion which had sig- A month later, on June 29, the pa- with ALL in developing countries, nificantly worsened in the days imme- tient presented to TMH and was since prognostic factors may differ, diately prior to admission to the local promptly referred to the Pediatric and, as studies in India suggest, the hospital. At the time of admission, he Oncology Unit. The patient had clini- proportion of the major sub-types of had no palpable lymphadenopathy cally deteriorated and had increased ALL differ in various world regions or or organomegaly, and routine labora- breathlessness. On physical examina- tory tests were normal. A 2-D tion, multiple, moderately sized (2 x 3 10 C A S E H I S T O R Y

Figure 1: This rare in children and adolescents and computerized often associated with an underlying tomographic scan of disease. A standard diagnostic pro- the upper thorax cedure would be CT-guided or fine shows a large needle biopsy, thus avoiding surgery. anterior mediastinal Because he had not considered mass (M) and other possible diagnoses, such as compression and lymphoma, the surgeon did not order deviation of the supplementary immunohistochemis- trachea to the left (T). try tests on the biopsy material. This The CT scan was resulted in an inaccurate diagnosis performed before and also caused the patient to un- surgery. dergo an unnecessary major surgical procedure (albeit, the correct proce- dure for thymoma) which entailed significant risk given the size of the cm each) lymph nodes were palpable achieved complete remission. He mass and the presence of tracheal in the neck, one in the right axilla, and went on to receive cranial and testicu- compression (cardiac arrest, or the there was bilateral testicular enlarge- lar radiation with 2340 cGy each, fol- need for prolonged ventilation after ment. The liver and spleen were nor- lowed by re-induction and consolida- surgery are potential complications). mal in size. Routine laboratory tests tion therapy. He is currently in his sec- It is often worth incurring the small revealed an elevated white blood ond maintenance cycle and will con- additional expense of potentially de- count of 153,000 per mm3 with 43% tinue maintenance therapy until he finitive diagnostic tests in order to circulating lymphoblasts and high has completed a total of six cycles. ensure that an accurate diagnosis is serum lactic acid dehydrogenase and This case is an example of the made rather than using valuable re- uric acid levels (7060 U/L and 8.2 natural history of the evolution of sources in giving incorrect treatment mg%, respectively). A chest x-ray re- lymphoblastic lymphoma into acute – which can be expensive and some- vealed mediastinal widening. Exten- T-cell leukemia (the distinction be- times carries significant risk. Although sive retroperitoneal lymphadenopa- tween these “diseases” is arbitrary, the surgeon correctly referred the thy and bilateral enlarged testes were being based on the degree of bone patient to TMH after the development confirmed by ultrasound examina- marrow involvement). This case also of lymphadenopathy, there was poor tion. A bone marrow aspirate showed demonstrates some of the reasons for communication with the patient and 81% leukemic blasts of L1 morphol- delays in the diagnosis and treatment his family, which led to them being ogy and T cell immunophenotype. of pediatric oncology cases in devel- unaware of the diagnosis and re- An examination of the cerebrospinal oping countries. The lack of knowl- sulted in the patient becoming lost to fluid was also positive for leukemic edge of pediatric oncology by the follow-up. The delay in obtaining an blasts. surgeon at the local hospital who ini- accurate diagnosis and in starting A diagnosis of acute lymphoblas- tially evaluated the patient was evi- appropriate therapy resulted in dis- tic leukemia (ALL) of T cell dent in the preliminary differential ease progression, including the devel- immunophenotype was made and diagnosis. In patients of this age who opment of CNS and testicular disease, the patient was immediately admit- present with mediastinal masses, the and a consequently worse prognosis, ted to the Pediatric Oncology Unit most common diagnoses include requiring more prolonged therapy. and prepared for chemotherapy. He Hodgkin’s disease, lymphoblastic lym- We strongly recommend that chil- was started on protocol MCP841, a phoma/leukemia and large B cell lym- dren with tumors are referred imme- standard protocol for the treatment phoma. In a younger patient, germ diately to a specialized center where of ALL in India. At the completion of cell tumor and neuroblastoma would appropriate expertise in diagnosis induction therapy, the patient need to be considered; thymoma is and therapy exists. ■

11 NETWORK

TATA MEMORIAL CENTRE, MUMBAI; INDIA by Suresh Advani; Chief, Dept of Medical Oncology

The credit for developing oncology in India is due to the House of Tata’s, one of the leading industrial families of In- dia. They established the Tata Memo- rial Hospital (TMH) in memory of Lady Meherbai Tata, the first lady of the House of Tata’s, who died of leukemia in 1932 after treatment abroad. The hospital, the first cancer facility in the country, was opened on Feb 28,1941. TMC is the largest comprehensive cancer centre in the subcontinent. Nearly 650 new As the activities of the hospital grew, cases of children with cancer and at least 18,000 adults with cancer are seen every year. it was handed over to the govern- More than 75% of the patients are treated for free or at a nominal charge. ment, and since 1962 has been oper- ated by the Department of Atomic FACILITIES ACADEMIC PROGRAM Energy. In addition to the hospital, The medical oncology department is There are about 400 students under- the government established in 1952 the largest in the country; here thou- going training every year in medical what is now the Cancer Research In- sands of patients are treated each and non-medical fields, and over 200 stitute (CRI). The hospital and the In- year. We see and treat the largest professionals obtain short-term train- stitute were merged in 1966 under number of leukemic (both myeloid ing. TMC is a recognized center for the flag of Tata Memorial Centre and lymphoid) patients in the coun- post-graduate training in the fields of (TMC). For more than half a century, try. The department also has a six- medical, surgical and radiation oncol- the TMC has been at the forefront in bedded bone marrow transplant unit ogy as well as a center for obtaining the fight against cancer in India. where approximately 30 transplants Ph.D.’s in various specialties. About 70 are performed every year. The medi- faculty members are recognized as THE PROBLEM cal oncology department has its own supervisors in the University for Ph.D. India faces 2.5 million cases of can- hematology laboratory (with auto- work. TMC also imparts master’s de- cer at any given time. The most com- mated cell counters, flow cytometers, grees in oncological nursing. monly encountered cases are those etc.), cytogenetic laboratory, and mo- related to tobacco use in men, i.e., lecular biology laboratory. RESEARCH cancer in the head and neck region, Most remarkable, however, may be The Cancer Research Institute activi- lung and esophagus. In women, the that TMH is the first hospital in the ties cover a wide spectrum and in- most common cancers are cervical, country to introduce joint clinics. clude areas such as lifestyles in rela- breast, oral cavity, esophagus and Here, the onco-surgeon, medical on- tion to cancer patterns, environmen- stomach. Since most of these cancers cologist, and radiotherapist meet tal carcinogens (both chemical and are related to lifestyle, many are ame- with the pathologist, radiologist and viral), cancer immunology and cell nable to both primary and secondary molecular biologist to discuss each and molecular biology. There are prevention. The high cancer toll in de- patient, after which detailed manage- groups working on the development veloping countries like India is attrib- ment is planned. In addition to lym- of new laboratory models for human uted to late detection (70% of all phoma and cervical cancer joint clin- cancers. Clinical research is con- cases). Also, there are very few com- ics, we have joint clinics for breast can- ducted, using a multi-disciplinary prehensive cancer centres with good cer, ovarian cancer, head and neck approach, in collaboration with clini- infrastructure. cancer, retinoblastoma and other pe- cians at the TMH, mainly in cancers diatric solid tumors. prevalent in India. The Institute has 12 P A R T N E R P R O F I L E

achieved national distinction as the Maharashtra. and haematopoetic system. A large first to develop transgenic mice, carry Whenever help is required to start cohort study to detect early cancers out research in human gene therapy a cancer hospital or a cancer wing in in women is supported by the Na- and develop an indigenous diagnos- a general hospital, TMC plays its ap- tional Institutes of Health (NIH), USA. tic kit to detect HIV infection. Along propriate role in providing the know- TMC is an active member of the INCTR, with basic and laboratory research, how. TMH has always felt that it through which it helps develop pro- clinical research is also carried out in should act as a catalyst rather than tocols for the treatment of childhood the fields of radiation, surgical and as a magnet. The hospital has there- cancers like retinoblastoma, osteo- medical oncology either through in- fore always placed emphasis on genic sarcoma and acute lymphoblas- stitutional trials or in collaboration training doctors from other regions, tic leukemia. with national and international so that they can return to their own groups. areas with new skill and knowledge. LOOKING INTO THE FUTURE To meet the challenges of the next COMMUNITY OUTREACH INTERNATIONAL COLLABORATION century, various facilities in the hospi- Education and prevention are vital TMC has received international ac- tal were recently upgraded and state- weapons against cancer. Thus TMH claim as a center of excellence in can- of-the-art equipment was commis- has paid particular attention to pre- cer research and treatment. There sioned. This includes MRI, new X-ray ventive oncology, with very satisfying have been several important interna- machines, a mammography unit, gains. More than 7,000 patients have tional collaborations. Studies are be- color doppler, a Clinac 2100 C/D lin- been evaluated and thousands more ing conducted in collaboration with ear accelerator with stereotactic ra- reached through presentations in the National Cancer Institute (NCI), diosurgery and radiography facilities. schools, public places, radio, etc. The USA and INCTR for treatment of Through a Computerized Manage- Bill and Melinda Gates Foundation, childhood acute lymphoblastic leu- ment Information System and com- through the International Agency for kemia (ALL) and non-Hodgkin’s lym- plete networking, on-line transactions Research on Cancer (IARC) of WHO, phoma. Collaboration was estab- are being made for patient adminis- is helping to fund a collaborative lished with the International Agency tration, materials management and project on cervical cancer prevention for Research in Cancer (IARC), France other similar activities. With the instal- with the rural cancer project of TMH regarding epidemiological studies lation of a hydroclave waste manage- at Barshi, a village in the state of for neoplasms of the lung, lymphatic ment facility in 1999, TMC was well ahead of the rest of the country in ful- filling its obligation to protect the en- ACUTE LYMPHOBLASTIC LEUKEMIA CLINIC vironment. The Clinical Research Secretariat A good axiom in research is to make a difference in a field where it matters. along with the state-of-the-art Digital One such case at TMH has been in Acute Lymphoblastic Leukemia (ALL). This Library has been established to pro- constitutes 35% of all pediatric cancers seen at TMH. It is also here that the vide the necessary infrastructure and cure rate has increased significantly from less than 10% in the 1970s to 60% crucial technical support to cultivate today. The protocol used was specially designed in collaboration with Dr Ian a research environment. The hospital Magrath of the National Cancer Institute, USA, and is particularly relevant for with its Scientific Review Committee, conditions in developing countries. The experience over the years has helped Ethics Committee and Data Monitor- us to anticipate possible complications. The visible impact is that in the last ing and Safety Committee is commit- decade, even continuing to use the same protocol, the disease-free and event- ted to maintain the highest scientific free survival rates have improved by 20 percent. This protocol has become and ethical standards in medical re- the gold standard in India and in fact, in this part of the subcontinent. Nearly search and treatment. 500 patients have been cured and are followed up systematically to see if As we enter the 21st century and there are any long-term effects of treatment, and efforts are being made to our 60-year anniversary, the fight prevent them from occurring. against cancer will go on. ■

13 NETWORK

PROFILES IN CANCER MEDICINE

DOING MORE WITH LESS people and serve them much bet- ter,” he says. The streamlined admin- Dr. M. Krishnan Nair takes a very istration of morphine he engineered pragmatic view of cancer treatment is a perfect example. A more ratio- in India: catch it early when you can, nal scheme has been devised for the and reach out to as many people as use of morphine in patients with ter- possible, and for those patients who minal cancer, which has resulted in have terminal cancer, provide them considerable saving of the drug. This a pain-free and dignified end. means that those patients who “We do not need to spent a lot might not have had access to mor- of money to die,” he says. “Every In- phine are now receiving it. And still, dian knows he will die one day. He no cancer patients die in pain. looks forward to death, and to re- Nair is equally committed to ad- birth. Indians don’t welcome the vancing cancer research in his coun- western philosophy of fighting try. As chairman of the Board of death. What they do welcome is a Studies in Health Sciences at Kerala painless death.” University, he is responsible for train- Nair, director of the Regional Dr. M. Krishnan Nair is one of the most re- ing a new generation of doctors. He Cancer Center (RCC) in Trivandrum, spected doctors in India. He was awarded also has led more than two decades India, also believes Indians don’t the prestigious Padmasree Award in 2000. of research, formulating and con- need to spend a lot of money - ducting more than 75 research money they don’t have - to treat start a community cancer center. projects investigating, for instance, cancer. That’s why early detection is Through public education and train- the effects of natural background so important. That, and a standard- ing of volunteers and doctors, they radiation, the relationship between ized approach to treatment that is were able to reach more cancer pa- cervical cancer and HPV infection, cost-effective. tients earlier. Nair was also respon- and low-cost strategies for early de- “Early detection strategies sible for launching the first pediatric tection of cervical and oral cancers. should focus on cost-effectiveness,” cancer canter, and for developing the In collaboration with major pharma- he insists, pointing to the Swedish largest network of pain and palliative ceutical companies such as Pfizer model where regular screening pro- care centers in the entire country. and Johnson & Johnson, RCC doc- grams and treatment facilities are Nair’s philosophy about drug tors are currently running 12 clinical readily available in a community therapies reflects his constant en- trials in breast cancer, lymphoma, setting. The young doctor who used deavor to stretch precious resources. and other types of cancer. to go into the villages to pick up He believes that there is too broad an “It is now known that over one- cancer patients for treatment; the application of the latest (and more ex- third of cancers are preventable, one activist who started training health pensive) drugs, and wants to stan- third are potentially curable pro- workers, dentists and volunteers to dardize diagnostic tests and cost-ef- vided they are diagnosed early in detect tell-tale lesions in the mouth; fective treatment. He also wants to their course and for the majority of the idealist who convinced the Chief channel resources to those areas, such incurable patients the quality of life Minister of State to fund a modern as pediatric cancers, where there is can be improved by palliative care. cancer center in India, still dreams the greatest opportunity for cure. However, control of cancer will not of doing more with less. The RCC, un- “The main objective should be to come about without an established der Nair’s direction since the doors identify treatment that can be univer- mechanism.” first opened in 1981, was the first to sally employed. We could reach more --Marcia C. Landskroener

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