PART 2 Coran Pediatric Surgery, 7th ed.pdf

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CHAPTER 28

Principles of Pediatric Oncology,Genetics of Cancer,

and RadiationTherapyMatthew J. Krasin and Andrew M. Davidoff

A number of milestones in the evolution of cancer therapy have come from the field of pediatric oncology. The first clearevidence that chemotherapy could provide effective treat-ment for childhood malignancy occurred in 1950 whenFarber reported temporary cancer remission in children withacute lymphoblastic leukemia (ALL) treated with the folicacid antagonist aminopterin.1 The first successful use of a multidisciplinary approach to cancer treatment occurredin the 1960s and 1970s through the collaborative efforts of pediatric surgeons, radiation therapists, and pediatric oncol-ogists aiming to improve the treatment of Wilms’ tumor inchildren.2 Such a multidisciplinary approach is now usedthroughout the field of oncology. The successful use of acombination of chemotherapeutic agents to cure Hodgkindisease and ALL during the 1960s led to the widespreaduse of combination chemotherapy to treat virtually all types

of cancers. Since the late 1980s, neuroblastoma has been theparadigm for the use of therapies of variable intensitydepending on risk stratification determined by clinical andbiological variables, including molecular markers. Other ad-vances in pediatric oncology have included the developmentof interdisciplinary, national cooperative clinical researchgroups to critically evaluate new therapies, the efficacy ofdose-intensive chemotherapy programs in improving theoutcome of advanced-stage solid tumors, and the supportive

care necessary to make the latter approach possible. Thedevelopment and application of these principles and ad-vances have led to substantially increased survival rates forchildren with cancer and profound improvements in theirquality of life.

Additional ly, advances in molecular genetic research inthe past 3 decades have led to an increased understandingof the genetic events in the pathogenesis and progressionof human malignancies, including those of childhood A number of pediatric malignancies have served as modelsfor molecular genetic research. Chromosomal structuralchanges, activating or inactivating mutations of relevantgenes or their regulatory elements, gene amplification, andgene imprinting may each play a role in different tumortypes. In some instances, these genetic events occur earlyin tumorigenesis and are specific for a particular tumor type,such as the chromosomal translocation t(11;22)(q24;q12) inEwing sarcoma; other aberrations occur in a variety of differ-ent tumor types and are almost always associated with addi-tional genetic changes, such as chromosome 1p deletion inneuroblastoma and Wilms’ tumor. Some alterations involveoncogenes—genes that, when activated, lead directly tocancer—whereas others involve tumor suppressor geneswhose inactivation allows tumor progression. The result ofalterations in these genetic elements, regardless of the mech-anism, is disruption of the normal balance between prolifer-ation and death of individual cells. These discoveries havehighlighted the utility of molecular analysis for a variety ofpurposes, including diagnosis, risk stratification, and treat-ment planning; the understanding of syndromes associatedwith cancer; genetic screening and genetic counseling; andprophylactic treatment, including surgical interventionSoon, treatment regimens are likely to be individualized onthe basis of the molecular biological profile of a patient’s tu-mor. In addition, molecular profiling will lead to the devel-opment of new drugs designed to induce differentiation oftumor cells, block dysregulated growth pathways, or reacti-vate silenced apoptotic pathways.

Epidemiology and Survival

StatisticsCancer in children is uncommon; it represents only about2% of all cancer cases. Nevertheless, after trauma, it is thesecond most common cause of death in children older than1 year. Each year, approximately 130 new cases of cancer areidentified per million children younger than 15 years (orabout 1 in 7000). This means that in the United States, about9,000 children younger than 15 years are diagnosed withcancer each year, in addition to 4,000 patients aged 15 to19 years.3 Leukemia is the most common form of cancer

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in children, and brain tumors are the most common solidtumor of childhood (Table 28-1). Lymphomas are thenext most common malignancy in children, followed by neuroblastoma, soft tissue sarcomas, Wilms’ tumor, germ celltumors, osteosarcoma, and retinoblastoma. A slightly differ-ent distribution is seen among 15- to 19-year-olds, in whomHodgkin disease and germ cell tumors are the most fre-quently diagnosed malignancies; non-Hodgkin lymphoma,nonrhabdomyosarcoma soft tissue sarcoma, osteosarcoma,Ewing sarcoma, thyroid cancer, and melanoma also occurwith an increased incidence.

In general, the incidence of childhood cancer is greatestduring the first year of life, peaks again in children aged 2to 3 years, and then slowly declines until age 9. The inci-dence then steadily increases again through adolescence.Each tumor type shows a different age distribution pattern,however. Variations by gender are also seen. For example,Hodgkin disease, ALL, brain tumors, neuroblastoma, hepa-toblastoma, Ewing sarcoma, and rhabdomyosarcoma aremore common in boys than in girls younger than 15 years,whereas only osteosarcoma and Ewing sarcoma are morecommon in boys than in girls older than 15 years. However,girls in the older age group have Hodgkin disease and thyroidcancer more frequently than boys do. Distribution also variesby race: White children generally have a 30% greater inci-dence of cancer than do black children. This difference isparticularly notable for ALL, Ewing sarcoma, and testiculargerm cell tumors. The probability of surviving childhoodcancer has improved greatly since Farber induced the first re-missions in patients with ALL. In the early 1960s, approxi-mately 30% of children with cancer survived their disease.By the mid-1980s, about 65% of children with cancer werecured, and by the mid-1990s, the cure rate had increased tonearly 75%.4 Currently, greater than 80% are cured. Thesegreat strides have resulted from three important factors:(1) the sensitivity of childhood cancer, at least initially, toavailable chemotherapeutic agents; (2) the treatment of childhood cancer in a multidisciplinary fashion; and (3)the treatment of most children in major pediatric treatmentcenters in the context of a clinical research protocol usingthe most current and promising therapy. Although progressin the treatment of some tumor types, such as ALL and Wilms’ tumor, has been outstanding, progress in the treat-ment of others, such as metastatic neuroblastoma and rhab-domyosarcoma, has been modest. Therefore there is stilla need for significant improvement in the treatment of childhood cancer.

Molecular Biology of Cancer

During normal cellular development and renewal, cells evolveto perform highly specialized functions to meet the phys-iologic needs of the organism. Development and renewalinvolve tightly regulated processes that include continued cellproliferation, differentiation to specialized cell types, andprogrammed cell death (apoptosis). An intricate system of

checks and balances ensures proper control over these phys-iologic processes. The genetic composition (genotype) of a celldetermines which pathway(s) will be followed in exerting thatcontrol. In addition, the environment plays a crucial role ininfluencing cell fate: Cells use complex signal transductionpathways to sense and respond to neighboring cells and theirextracellular milieu.

Cancer is a genetic disease whose progression is driven by aseries of accumulating genetic and epigenetic changes influ-enced by hereditary factors and the somatic environment.These changes result in individual cells acquiring a phenotypethat provides them with a survival advantage compared withsurrounding normal cells. Our understanding of the processesthat occur in malignant cell transformation is increasing; many discoveries in cancer cell biology have been made by usingchildhood tumors as models. This greater understanding of the molecular biology of cancer has also contributed signi-ficantly to our understanding of normal cell physiology.

NORMAL CELL PHYSIOLOGY

Cell Cycle

Genetic information is stored in cells and transmitted to sub-sequent generations of cells through nucleic acids organizedas genes on chromosomes. A gene is a functional unit of he-redity that exists on a specific site or locus on a chromosome,is capable of reproducing itself exactly at each cell division,and is capable of directing the synthesis of an enzyme or otherprotein. The genetic material is maintained as DNA formedinto a double helix of complementary strands. The cell mustensure that replicated DNA is accurately copied with each celldivision or cycle. DNA replication errors that go uncorrectedpotentially alter the function of normal cell regulatory pro-teins. The molecular machinery used to control the cell cycleis highly organized and tightly regulated.5 Signals that stimu-late or inhibit cellular growth converge on a set of evolution-arily conserved enzymes that drive cell-cycle progression. Various “checkpoints” exist to halt progression through thecell cycle during certain environmental situations or timesof genetic error resulting from inaccurate synthesis or damage.Two of themost well-studiedparticipants in thecell-cyclecheck-point system are TP53 and retinoblastoma (RB) proteins.6

In normal circumstances, cells divide and terminally differenti-ate, thereby leaving the cell cycle, or they enter a resting state.Inactivationof theeffectors of cell-cycle regulation or thebypass-ing of cell-cycle checkpoints can result in dysregulation of thecell cycle, a hallmark of malignancy.

Signal Transduction

Signal transduction pathways regulate all aspects of cell func-tion, including metabolism, cell division, death, differentia-tion, and movement. Multiple extracellular and intracellular

TABLE 28-1

Frequency of Cancer Diagnoses in Childhood

Type of Cancer Percentage of Total

Leukemia 30

Brain tumors 25

Lymphoma 15

Neuroblastoma 8

Sarcoma 7

Wilms’ tumor 6Osteosarcoma 5

Retinoblastoma 3

Liver tumors 1

398 PART III MAJOR TUMORS OF CHILDHOOD

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signals for proliferation or quiescence must be integrated by the cell, and it is this integration of signals from multiple path-ways that determines the response of a cell to competing andcomplementary signals. Extracellular signals include growthfactors, cytokines, and hormones; the presence or absenceof adequate nutrients and oxygen; and contact with other cellsor an extracellular matrix. Signaling mediators often bindto membrane-bound receptors on the outside of the cell,but they may also diffuse into the cell and bind receptors in

the cytoplasm or on the nuclear membrane. Binding of aligand to a receptor stimulates the activities of small-moleculesecond messengers—proteins necessary to continue the trans-mission of the signal. Signaling pathways ultimately effect theactivation of nuclear transcription factors that are responsiblefor the expression or silencing of genes encoding proteinsinvolved in all aspects of cellular physiology.

Receptors with tyrosine kinase activity are among the mostimportant transmembrane receptors. Several important trans-membrane receptors with protein kinase activity have beenidentified and grouped in families on the basis of structuralsimilarities.7 These families include the epidermal growthfactor receptors (EGFRs), fibroblast growth factor receptors,insulin-like growth factor receptors (IGFRs), platelet-derivedgrowth factor receptors (PDGFRs), transforming growth factorreceptors, and neurotrophin receptors (TRKs). Abnormalitiesof members of each of these families are often found in pedi-atric malignancies and therefore are thought to play a role intheir pathogenesis. Characteristic abnormalities of these re-ceptors often form the basis of both diagnostic identificationof certain tumor types and, more recently, targeted therapy for tumors with these specific abnormalities.

Programmed Cell Death

Multicellular organisms have developed a highly organizedand carefully regulated mechanism of cell suicide to maintaincellular homeostasis. Normal development and morphogene-sis are often associated with the production of excess cells,which are removed by the genetically programmed processof cell death called apoptosis. Apoptosis limits cellular expan-sion and counters cell proliferation. Apoptosis is initiatedby the interaction of “death ligands,” such as tumor necrosisfactor-a (TNF-a), FAS, and TNF-related apoptosis-inducingligand (TRAIL), with their respective receptors. This interac-tion is followed by aggregation of the receptors and recruit-ment of adapter proteins to the plasma membrane, whichactivate caspases.8 Thus the fate of a cell is determined by the balance between death signals and survival signals.9

An alternative to cell death mediated by receptor–ligandbinding is cellular senescence, which is initiated when chro-mosomes reach a critical length. Eukaryotic chromosomeshave DNA strands of unequal length, and their ends, calledtelomeres, are characterized by species-specific nucleotiderepeat sequences. Telomeres stabilize the ends of chromo-somes, which are otherwise sites of significant instability.10

With time and with each successive cycle of replication, chro-mosomes are shortened by failure to complete replication of their telomeres. Thus telomere shortening acts as a biologicalclock, limiting the life span of a cell. Germ cells, however,avoid telomere shortening by using telomerase, an enzymecapable of adding telomeric sequences to the ends of chro-mosomes. This enzyme is normally inactivated early in thegrowth and development of an organism. Persistent activation

or the reactivation of telomerase in somatic cells appears tocontribute to the immortality of transformed cells.

Malignant Transformation

Alteration or inactivation of any of the components of normalcell regulatory pathways may lead to the dysregulated growththat characterizes neoplastic cells. Malignant transformationmay be characterized by cellular de-differentiation or failureto differentiate, cellular invasiveness and metastatic capacity

or decreased drug sensitivity. Tumorigenesis reflects theaccumulation of excess cells that results from increased cellproliferation and decreased apoptosis or senescence. Cancercells do not replicate more rapidly than normal cells, but theyshow diminished responsiveness to regulatory signals. Positivegrowth signals are generated by proto-oncogenes, so namedbecause their dysregulated expression or activity can promotemalignant transformation. These proto-oncogenes may en-code growth factors or their receptors, intracellular signalingmolecules, and nuclear transcription factors (Table 28-2)Conversely, tumor suppressor genes, as their name implies,control or restrict cell growth and proliferation. Their inacti-vation, through various mechanisms, permits the dysregu-lated growth of cancer cells. Also important are the genesthat regulate cell death. Their inactivation leads to resistanceto apoptosis and allows the accumulation of additional geneticaberrations.

Cancer cells carry DNA that has point mutations, viralinsertions, or chromosomal or gene amplifications, deletions,or rearrangements. Each of these aberrations can alter thecontext and process of normal cellular growth and differenti-ation. Although genomic instability is an inherent property ofthe evolutionary process and normal development, it isthrough genomic instability that the malignant transformationof a cell may arise. This inherent instability may be altered byinheritance or exposure to destabilizing factors in the envi-ronment. Point mutations may terminate protein translationalter protein function, or change the regulatory target se-quences that control gene expression. Chromosomal alter-ations create new genetic contexts within the genome andlead to the formation of novel proteins or to the dysregulationof genes displaced by aberrant events.

Geneticabnormalitiesassociatedwithcancermaybedetectedineverycellinthebodyoronlyinthetumorcells.Constitutionaor germline abnormalities either are inherited or occur de novoin the germ cells (sperm or oocyte). Interestingly, despite thepresence of a genetic abnormality that might affect growthregulatory pathwaysin allcells,people aregenerally predisposedto the development of only certain tumor types. This selectivityhighlights the observation that gene function contributes togrowth or development only within a particular milieu or phys-iologic context. Specific tumors occur earlier and are more oftenbilateral when they result from germline mutations than whenthey result from sporadic or somatic alterations. Such is oftenthe casein two pediatric malignancies,Wilms’ tumor andretino-blastoma. These observations led Knudson11 to propose a “two-hit” mechanism of carcinogenesis in which the first geneticdefect, already present in the germline, must be complementedby an additional spontaneous mutation before a tumor can ariseIn sporadic cancer, cellular transformation occurs only whentwo(ormore)spontaneousmutationstakeplaceinthesamecell.

Muchmore common, however,are somaticallyacquired chro-mosomal aberrations, which are confined to the malignant cells

399CHAPTER 28 PRINCIPLES OF PEDIATRIC ONCOLOGY, GENETICS OF CANCER, AND RADIATION THERAPY

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These aberrations affect growth factors and their receptors,signal transducers, and transcription factors. The general typesof chromosomal alterations associated with malignant trans-formation are shown in Figure 28-1. Although a low levelof chromosomal instability exists in a normal population of cells, neoplastic transformation occurs only if these altera-tions affect a growth-regulating pathway and confer a growthadvantage.

Abnormal DNA Content

Normal human cells contain two copies of each of 23 chromo-somes; a normal diploid cell therefore has 46 chromosomes. Although cellular DNA content, or ploidy, is accurately deter-mined by karyotypic analysis, it can be estimated by the muchsimpler method of flow cytometric analysis. Diploid cells havea DNA index of 1.0, whereas near-triploid (also termed hyper-diploid) cells have a DNA index ranging from 1.26 to 1.76. Themajority (55%) of primary neuroblastoma cells are triploid ornear triploid (e.g., having between 58 and 80 chromosomes),whereas the remainder are near diploid (35 to 57 chromo-somes) or near tetraploid (81 to 103 chromosomes).12 Neuro-blastomas consisting of near-diploid or near-tetraploid cellsusually have structural genetic abnormalities (e.g., chromo-some 1p deletion and amplification of the MYCN oncogene),whereas those consisting of near-triploid cells are character-ized by three almost complete haploid sets of chromosomeswith few structural abnormalities.13 Of importance, patientswith near-triploid tumors typically have favorable clinicaland biological prognostic factors and excellent survival

rates compared with those who have near-diploid or near-tetraploid tumors.14

Chromosomal Translocations

Many pediatric cancers, specifically hematologic malignanciesand soft tissue neoplasms, have recurrent, nonrandom abnor-malities in chromosomal structure, typically chromosomaltranslocations (Table 28-3). The most common result of anonrandom translocation is the fusion of two distinct genesfrom different chromosomes. The genes are typically fusedwithin the reading frame and express a functional, chimericprotein product that has transcription factor or protein kinaseactivity. These fusion proteins contribute to tumorigenesis by activating genes or proteins involved in cell proliferation. Forexample, in Ewing sarcoma the consequence of the t(11;22)(q24;q12) translocation is a fusion of EWS, a transcriptionfactor gene on chromosome 22, and FLI-1, a gene encodinga member of the ETS family of transcription factors on chro-mosome 11.15 The resultant chimeric protein, which containsthe DNA binding region of FLI-1 and the transcription activa-tion region of EW S, has greater transcriptional activity thandoes EWS alone.16 The EWS–FLI-1 fusion transcript is detect-able in approximately 90% of Ewing sarcomas. At leastfour other EWS fusions have been identified in Ewing sar-coma; fusion of EWS with ERG (another ETS family member)accounts for an additional 5% of cases.17 Alveolar rhabdo-myosarcomas have characteristic translocations between thelong arm of chromosome 2 (75% of cases) or the short armof chromosome 1 (10% of cases) and the long arm of chromo-some 13. These translocations result in the fusion of PAX3

TABLE 28-2

Proto-oncogenes and Tumor Suppressor Genes in Pediatric Malignancies

Oncogene Family Proto-oncogene Chromosome Location Tumors

Growth factors and receptors ERBB2 17q21 Glioblastoma

TRK 9q22 Neuroblastoma

Protein kinase SRC 7p11 Rhabdomyosarcoma,

Osteosarcoma, Ewing sarcoma

Signal transducers H-RAS 11p15.1 Neuroblastoma

Transcription factors c-MYC 18q24 Burkitt lymphomaMYCN 2p24 Neuroblastoma

Syndrome Tumor Suppressor Gene Chromosome Location Tumors

Familial polyposis coli APC 5q21 Intestinal polyposis, colorectalcancer

Familial retinoblastoma RB 13q24 Retinoblastoma,osteosarcoma

WAGR* WT1 11p13 Wilms’ tumor

Denys-Drash{ WT1 11p13 Wilms’ tumor

Beckwith-Weidemann{ WT2 (?) 11p15 Wilms’ tumor,hepatoblastoma, adrenal

Li-Fraumeni TP53 17q13 Multiple (see text)

Neurofibromatosis type 1 NF1 17q11.2 Sarcomas, breast cancer

Neurofibromatosis type 2 NF2 22q12 Neurofibroma,neurofibrosarcoma, braintumor

von Hippel-Lindau VHL 3p25-26 Renal cell cancer,pheochromocytoma, retinalangioma, hemangioblastoma

*WAGR: Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation.{Denys-Drash: Wilms’ tumor, pseudohermaphroditism, mesangial sclerosis, renal failure.{Beckwith-Weidemann: multiple tumors, hemihypertrophy, macroglossia, hyperinsulinism.


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(at 2q35) or PAX7 (at 1p36) with FKHR, a gene encoding amember of the forkhead family of transcription factors.18

The EWS-FLI-1 and PAX7-FKHR fusions appear to confer abetter prognosis for patients with Ewing sarcoma and alveolarrhabdomyosarcoma, respectively.19,20Translocations that gener-ate chimeric proteins with increased transcriptional activity alsocharacterize desmoplasticsmall round celltumor,21myxoidliposarcoma,22 extraskeletal my xoid chrondrosarcoma,23malig-nant melanoma of soft parts,24 synovial sarcoma,25 congenitalfibrosarcoma,26 cellular mesoblastic nephroma,27 and dermato-fibrosarcoma protuberans.28

Proto-oncogene ActivationProto-oncogenes are commonly activated in transformed cellsby point mutations or gene amplification. The classical exam-ple of proto-oncogene activation by a point mutation involvesthe cellular proto-oncogene RAS. RAS-family proteins areassociated with the inner, cytoplasmic surface of the plasmamembrane and function as intermediates in signal transduc-tion pathways that regulate cell proliferation. Point mutationsin RAS result in constitutive activation of the RAS proteinand therefore the continuous activation of the RAS signaltransduction pathway. Activation of RAS appears to be

involved in the pathogenesis of a small percentage of pediatricmalignancies, including leukemia and a variety of solidtumors.

Gene amplification (i.e., selective replication of DNAsequences) enables a tumor cell to increase the expressionof crucial genes whose products are ordinarily tightly con-trolled. The amplified DNA sequences, or amplicons, may bemaintained episomally (i.e., extrachromosomally) as doubleminutes-paired chromatin bodies lacking a centromere or asintrachromosomal, homogeneously staining regions. In aboutone third of neuroblastomas, for example, the transcriptionfactor and proto-oncogene MYCN is amplified. The MYCNcopy number in neuroblastoma cells can be amplified 5-fold to500-fold and is usually consistent among primary andmetastatic sites and at different times during tumor evolutionand treatment.29 This consistency suggests that MYCN ampli-fication is an early event in the pathogenesis of neuroblastomaBecause gene amplification is usually associated with ad-vanced stages of disease, rapid tumor progression, and pooroutcome, it is a powerful prognostic indicator.30,31 The cellsurface receptor gene ERBB2 is another proto-oncogene thatis commonly overexpressed because of gene amplification,an event that occurs in breast cancer, osteosarcoma, and Wilms’ tumor.32

Inactivation of Tumor Suppressor Genes

Tumor suppressor genes, or antioncogenes, provide negativecontrol of cell proliferation. Loss of function of the proteinsencoded by these genes, through deletion or mutational inac-tivation of the gene, liberates the cell from growth constraints

FIGURE 28-1 Spectrum of gross chromosomal aberrations usingchromosomes 1 and 14 as examples. HSR, homogeneously stainingregions. (From Look AT, Kirsch IR: Molecular basis of childhood cancer.In Pizzo PA, Poplack DG [eds]: Principles and Practices of PediatricOncology. Philadelphia, Lippincott-Raven, 1997, p 38.)

TABLE 28-3

Common, Recurrent Translocations in Soft Tissue Tumors

Tumor Genetic Abnormality

FusionTranscript

Ewing sarcoma/primitiveneuroectodermal tumor

t(11;22)(q24;q12)t(21;22)(q22;q12)t(7;22)(p22;q12)t(17;22)(q12;q12)t(2;22)(q33;q12)

FLI1-EWS

ERG-EWS

ETV1-EWS

E1AF-EWS

FEV-EWS

Desmoplastic small roundcell tumor

t(11;22)(p13;q12)t(11;22)(q24;q12)

WT1-EWSFLI1-EWS

Synov ial sarcoma t(X; 18)(p11.23;q11)t(X;18)(p11.21;q11)

SSX1-SYT

SSX2-SYT

Alveolar rhabdomyosarcoma t(2;13)(q35;q14)t(1;13)(p36;q14)

PAX3-FKHR

PAX7-FKHR

Malignant melanoma of soft part (clear cell sarcoma)

t(12;22)(q13;q12) ATF1-EWS

Myxoid liposarcoma t(12;16)(q13;p11)t(12;22)(q13;q12)

CHOP-TLS(FUS)

CHOP-EWS

Extraskeletal myxoidchondrosarcoma

t(9;22)(q22;q12) CHN-EWS

Dermatofibrosarcoma

protuberans and giant cellfibroblastoma

t(17;22)(q22;q13) COL1A1-PDGFB

Congenital fibrosarcoma andmesoblastic nephroma

t(12;15)(p13;q25) ETV6-NTRK3

Lipoblastoma t(3;8)(q12;q11.2)t(7;8)(q31;q13)

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From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors inchildhood. Semin Pediatr Surg 2001;10:106-118.


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and contributes to malignant transformation. The cumulativeeffect of genetic lesions that activate proto-oncogenes or inac-tivate tumor suppressor genes is a breakdown in the balancebetween cell proliferation and cell loss because of differentia-tion or apoptosis. Such imbalance results in clonal overgrowthof a specific cell lineage. The first tumor suppressor gene tobe recognized was the retinoblastoma susceptibility gene RB.This gene encodes a nuclear phosphoprotein that acts as a“gatekeeper” of the cell cycle. RB normally permits cell-cycle-

progression through the G1 phase when it is phosphorylated,but it prevents cell division when it is unphosphorylated.Inactivating deletions or point mutations of RB cause the pro-tein to lose its regulatory capacity. The nuclear phosphopro-tein gene TP53 has also been recognized as an importanttumor suppressor gene, perhaps the most commonly alteredgene in all human cancers. Inactivating mutations of theTP53 gene also cause the TP53 protein to lose its ability to reg-ulate the cell cycle. The TP53 gene is frequently inactivated insolid tumors of childhood, including osteosarcoma, rhabdo-myosarcoma, brain tumors, anaplastic Wilms’ tumor, and asubset of chemotherapy-resistant neuroblastoma.33–35 In ad-dition, heritable cancer-associated changes in the TP53 tumorsuppressor gene occur in families with Li-Fraumeni syn-drome, an autosomal dominant predisposition for rhab-domyosarcoma, other soft tissue and bone sarcomas,premenopausal breast cancer, brain tumors, and adrenocorti-cal carcinomas.36 Other tumor suppressor genes include Wilms’ tumor 1 (WT1), neurofibromatosis 1 (NF1), and vonHippel-Lindau (VHL). Additional tumor suppressor genesare presumed to exist but have not been definitively identified.

Epigenetic Alterations

As stated previously, the hallmark of cancer is dysregulatedgene expression. However, not only do genetic factors influ-ence gene expression but epigenetic factors do as well, withthese factors being at least as important as genetic changesin their contribution to the pathogenesis of cancer. Epige-netic alterations are defined as those heritable changes ingene expression that do not result from direct changes inDNA sequence. Mechanisms of epigenetic regulation mostcommonly include DNA methylation and modification of histones, although the contribution of microRNAs (miRNA),a class of noncoding RNAs, is becoming increasingly recognized.

DNA Methylation DNA methylation is a reversible processthatinvolvesmethylation of the fifth position of cytosine withinCpG dinucleotides present in DNA. These dinucleotidesare usually in the promoter regions of genes; methylation of these sites typically causes gene silencing, thereby preventingexpression of the encoded proteins. This process is partof the normal mechanism for imprinting, X-chromosomeinactivation, and generally keeping large areas of genomicDNA silent, but it may also contribute to the pathogenesis of cancer by silencing tumor suppressor genes. However, bothabnormal hypomethylation and hypermethylation states existin human tumors, resulting in both dysregulated expressionand silencing, respectively, of affected genes. These modi-fications of the nucleotide backbone of human DNA arebecoming increasingly recognized in human cancer, both fortheir frequency and importance. For example, promoter

methylation resulting in silencing of caspase 8, a protein in-volved in apoptosis, likely contributes to the pathogenesis of MYCN -amplified neuroblastoma37 as well as Ewingsarcoma.23

Histone Modification Histones are the proteins that givestructure to DNA and, together with the DNA, form the majorcomponents of chromatin. The functions of histones areto package DNA into a smaller volume to fit in the cell, tostrengthen the DNA to allow replication, and to serve as a

mechanism to control gene expression. Alterations in histonescan mediate changes in chromatin structure. The compactedform of DNA, termed heterochromatin, is largely inaccessibleto transcription factors and therefore genes in the affectedregions are silent. Other modifications of histones can causeDNA to take a more open or extended configuration (euchro-matin), allowing for gene transcription. The N-terminal tails of histones can be modified by a number of different processesincluding methylation and acetylation, mediated by histoneacetyl transferases (HAT) and deacetylases (HDAC), andhistone methyltransferases (HMT). Each of these processesalters histone function, which, in turn, alters the structureof chromatin and therefore the accessibility of DNA to tran-scription factors. Methylation of the DNA itself can also effectchanges in chromatin structure.

MicroRNA As stated above, miRNAs are a group of small,regulatory noncoding RNAs that appear to function in generegulation. These miRNAs are single-stranded RNA fragmentsof 21 to 23 nucleotides that are complementary to encodingmRNAs.25 Their function is to down-regulate expression of target mRNAs; it is estimated that miRN As regulate the expres-sion of about 30% of all human genes.38 These miRNAs reg-ulate gene expression primarily by incorporating intosilencing machinery called RNA-induced silencing complexes(RISC). MiRNAs are involved in a number of fundamentalbiological processes, including development, differentiation,cell-cycle regulation, and senescence. However, broad ana-lyses of miRNA expression levels have demonstrated thatmany miRNAs are dysregulated in a variety of different cancertypes, including neuroblastoma and other pediatric tumors,39

frequently losing their function as gene silencers/tumor sup-pressors. The activity of miRNAs, like gene expression, is alsounder epigenetic regulation.

METASTASIS

Metastasis is the spread of cancer cells from a primarytumor todistant sites and is the hallmark of malignancy. The deve-lopment of tumor metastases is the main cause of treatmentfailure and a significant contributing factor to morbidity and mortality resulting from cancer. Although the dissemina-tion of tumor cells through the circulation is probably afrequent occurrence, the establishment of metastatic diseaseis a very inefficient process. It requires several events, includ-ing the entry of the neoplastic cells into the blood or lymphaticsystem, the survival of those cells in the circulation, theiravoidance of immune surveillance, their invasion of foreign(heterotopic) tissues, and the establishment of a blood supply to permit expansion of the tumor at the distant site. Simple,dysregulated cell growth is not sufficient for tumor invasionand metastasis. Many tumors progress through distinct stages


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that can be identified by histopathologic examination, includ-ing hyperplasia, dysplasia, carcinoma in situ, invasive cancer,and disseminated cancer. Genetic analysis of these differentstages of tumor progression suggests that uncontrolled growthresults from progressive alteration in cellular oncogenes andinactivation of tumor suppressor genes, but these geneticchanges driving tumorigenicity are clearly distinct from thosethat determine the metastatic phenotype.

Histologically, invasive carcinoma is characterized by a lack

of basement membrane around an expanding mass of tumorcells. Matrix proteolysis appears to be a key part of the mech-anism of invasion by tumor cells, which must be able to movethrough connective tissue barriers, such as the basementmembrane, to spread from their site of origin. The proteasesinvolved in this process include the matrix metalloproteinasesand their tissue inhibitors. The local environment of the targetorgan may profoundly influence the growth potential of extravasated tumor cells.40 The various cell surface receptorsthat mediate interactions between tumor cells and betweentumor cells and the extracellular matrix include cadherins,integrins (transmembrane proteins formed by the noncovalentassociation of alpha and beta subunits), and CD44, a trans-membrane glycoprotein involved in cell adhesion to hyaluro-nan.41 Tumor cells must decrease their adhesiveness to escapefrom the primary tumor, but at later stages of metastasis, thesame tumor cells need to increase their adhesiveness duringarrest and intravasation to distant sites.

ANGIOGENESIS

Angiogenesis is the biological process of new blood vesselformation. This complex, invasive process involves multiplesteps, including proteolytic degradation of the extracellularmatrix surrounding existing blood vessels, chemotactic migra-tion and proliferation of endothelial cells, the organization of these endothelial cells into tubules, the establishment of alumen that serves as a conduit between the circulation andan expanding mass of tumor cells, and functional maturationof the newly formed blood vessel.42,43 Angiogenesis involvesthe coordinated activity of a wide variety of molecules, includ-ing growth factors, extracellular matrix proteins, adhesionreceptors, and proteolytic enzymes. Under physiologic condi-tions, the vascular endothelium is quiescent and has a very low rate of cell division, such that only 0.01% of endothelialcells are dividing.42–44 However, in response to hormonal cuesor hypoxic or ischemic conditions, the endothelial cells can beactivated to migrate, proliferate rapidly, and create tubuleswith lumens.

Angiogenesis occurs as part of such normal physiologic ac-tivities as wound healing, inflammation, the female reproduc-tive cycle, and embryonic development. In these processes,angiogenesis is tightly and predictably regulated. However,angiogenesis can also be involved in the progression of severalpathologic processes in which there is a loss of regulatory control, resulting in persistent growth of new blood vessels.Such unabated neovascularization occurs in rheumatoidarthritis, inflammatory bowel disease, hemangiomas of child-hood, ocular neovascularization, and the growth and spreadof tumors.45

Compelling data indicate that tumor-associated neovas-cularization is required for tumor growth, invasion, andmetastasis.46–49 A tumor in the prevascular phase (i.e., before

new blood vessels have developed) can grow to only a limitedsize, approximately 2 to 3 mm3. At this point, rapid cellproliferation is balanced by equally rapid cell death by apopto-sis, and a nonexpanding tumor mass results. The switch to anangiogenic phenotype with tumorneovascularization resultsina decrease in the rate of apoptosis, therebyshifting the balanceto cell proliferation and tumor growth.50,51 This decrease inapoptosis occurs, in part, because the increased perfusionresulting from neovascularization permits improved nutrient

and metabolite exchange. In addition, the proliferating endo-thelium may supply, in a paracrine manner, a variety of factorsthat promote tumor growth, such as IGF-I and IGF-II.52

In experimental models, increased tumor vascularizationcorrelates with increased tumor growth, whereas restrictionof neovascularization limits tumor growth. Clinically, theonset of neovascularization in many human tumors is tempo-rally associated with increased tumor growth,53 and highlevels of angiogenic factors are commonly detected in bloodand urine from patients with advanced malignancies.107

In addition, the number and density of new microvesselswithin primary tumors have been shown to correlate withthe likelihood of metastasis, as well as the overall prognosisfor patients with a wide variety of neoplasms, including pedi-atric tumors such as neuroblastoma and Wilms’ tumor.54,55

Molecular Diagnostics

The explosion of information about the human genome has lednot only to an improved understanding of the moleculargenetic basis of tumorigenesis but also to the development ofa new discipline: the translation of these molecular eventsinto diagnostic assays. The field of molecular diagnostics hasdeveloped from the need to identify abnormalities of gene orchromosome structure in patient tissues and as a means ofsupporting standard histopathologic and immunohisto-chemical diagnostic methods. In most instances, the resultof genetic testing confirms light microscopic- and immuno-histochemistry-based diagnosis. In some instances, however(e.g., primitive, malignant, small round cell tumor; poorlydifferentiated synovial sarcoma; lipoblastic tumor), molecularanalysis is required to make a definitive diagnosis.

The molecular genetic methods most commonly used toanalyze patient tumor material include direct metaphasecytogenetics or karyotyping, fluorescence in situ hybridization(FISH), and reverse transcriptase polymerase chain reaction(RT-PCR). Additional methods, such as comparative genomichybridization, loss of heterozygosity analysis, and comple-mentary DNA (cDNA) microarray analysis, may eventuallybecome part of the routine diagnostic repertoire but arecurrently used as research tools at referral centers and aca-demic institutions. Each standard method is summarized inTable 28-4. As with any method, molecular genetic assayshave advantages and disadvantages, and it is important tounderstand and recognize their limitations.

The value of molecular genetic analysis of patient tissueis not limited to aiding histopathologic diagnosis. Many ofthe most important markers provide prognostic informationas well. MYCN amplification in neuroblastomas,13 for exam-ple, is strongly associated with biologically aggressive behav-ior. Amplification of this gene can be detected by routine


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metaphase cytogenetics or by FISH, and current neuroblas-toma protocols include the presence or absence of MYCN amplification in their stratification schema. Some fusion genevariants are also thought to influence prognosis. In initialstudies, two examples noted to confer relatively favorableprognoses are the type 1 variant fusion of EWS-F LI1 in Ewingsarcoma or primitive neuroectodermal tumor20 and thePAX7-FKHR fusion in alveolar rhabdomyosarcoma.19

New technologies are emerging that permit accurate,high-throughput analysis or profiling of tumor tissue: Geneexpression can be analyzed by using RNA microarrays, andproteins by using proteomics. These approaches identify aunique fingerprint of a given tumor that can provide diagnos-tic or prognostic information. Proteomic analysis can alsoidentify unique proteins in patients’ serum or urine; such aprofile can be used for early tumor detection, to distinguishrisk categories, and to monitor for recurrence. Additionaltypes of “omics” that are currently being used to evaluatetumor or patient specimens include transcriptomics (RNAand gene expression), metabolomics (metabolites and meta-bolic networks), and pharmacogenomics (how genetics affectshost drug responses). Information from each of these areas of investigation provides an increasingly precise and uniqueperspective on the biology, clinical behavior, and responsive-ness to specific therapeutic interventions of individual patienttumors. It is through these analyses that personalized therapy is likely to be realized. In addition, it is anticipated that withthe identification of new, critical components of oncogenesisand tumor progression will come new “druggable” targetsfor cancer therapy. Drugs that act on these targets will not

only be effective anticancer agents but, because of theirspecificity, will also have a broader therapeutic window,thereby improving safety and minimizing toxicity.

Childhood Cancer and Heredity Advances in molecular genetic techniques have also improvedour understanding of cancer predisposition syndromes.Constitutional gene mutations that are hereditary (i.e., passedfrom parent to child) or nonhereditary (i.e., de novo muta-tions in the sperm or oocyte before fertilization) contribu teto an estimated 10% to 15% of pediatric cancers.56

Constitutional chromosomal abnormalities are the result of an abnormal number or structural rearrangement of thenormal 46 chromosomes and may be associated with a predis-position to cancer. Examples are the predisposition to leuke-mia seen with trisomy 21 (Down syndrome) and to germcell tumors with Klinefelter syndrome (47XXY). Structuralchromosomal abnormalities include interstitial deletionsresulting in the constitutional loss of one or more genes.

Wilms’ tumors may be sporadic, familial, or associated withspecific genetic disorders or recognizable syndromes. A betterunderstanding of the molecular basis of Wilms’ tumor hasbeen achieved largely through the study of the latter two typesof tumors. The WAGR syndrome (Wilms’ tumor, aniridia, gen-itourinary abnormalities, and mental retardation) provides aneasily recognizable phenotype for grouping children likely tohave a common genetic abnormality. Constitutional deletionsfrom chromosome 11p13 are consistent in children with

TABLE 28-4

Comparison of the Cytogenetic and Molecular Methods Routinely Used as Aids in Pathologic Diagnosis of Soft Tissue Tumors

Method Purpose Advantages Disadvantages

Cytogenetics Low resolution analysis of metaphasechromosomes of cells grown in culture

Does not require a priori knowledgeof genetic abnormalitiesAvailable in most diagnostic centers

Requires fresh, sterile tumor tissue forgrowth in cultureLow sensitivity; will only detect largestructural abnormalitiesNo histologic correlationSlow and technically demanding (takes

up to several weeks to perform)In situhybridization

Detection of translocations, amplifications,and gene deletions by hybridization of nucleic acid probes to specific DNA ormRNA sequences

Can be applied to chromosomalpreparations as well as cytologicspecimens, touch preparations, andparaffin sectionsMorphologic correlation is possibleMultiple probes can be assayed at thesame timeRapid (usually only requires 2 days)

Cannot detect small deletions or pointmutationsInterpretation can be difficult, especiallywith formalin-fixed, paraffin-embeddedmaterialOnly a limited number of specific nucleicacid probes are available commercially

PCR and RT-PCR

Extremely sensitive detection of DNAsequences and mRNA transcripts for thedemonstration of fusion genes, pointmutations, and polymorphisms

Highest sensitivity and specificity of all the molecular diagnostictechniquesDNA sequencing of PCR products canconfirm result and provide additionalinformationRequires minimal tissueVersatile; can be applied to freshtissue as well as formalin-fixed,paraffin-embedded tissueMorphologic correlation is possibleThe presence of normal tissue willusually not affect test resultsRapid (usually requires 3-5 days)

Formalin-fixation diminishes sensitivityCombinatorial variability within fusiongene partners requires appropriateredundant primer design to avoid false-negative test resultsExtreme sensitivity requires exactinglaboratory technique to avoid false-positive test results

From Davidoff AM, Hill DA: Molecular genetic aspects of solid tumors in childhood. Semin Pediatr Surg 10: 2001;106-118.PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction.


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exquisitely so, the successful use of chemotherapy is oftenthwarted by two factors: the development of resistance tothe agent and the agent’s toxicity to normal tissues. Neverthe-less, chemotherapy remains an integral part of therapy whenused as an adjunct to treat localized disease or as the maincomponent to treat disseminated or advanced disease.

A number of principles and terms are essential to the under-standing of chemotherapy as a therapeutic anticancer modality. Adjuvant chemotherapy refers to the use of chemotherapy for

systemic treatment followinglocal control generally by surgicalresection or radiation therapy of a clinically localized primary tumor. The goal in this setting is to eliminate disease that is notdetectable by standard investigative means at or beyond theprimary tumor’s site. Neoadjuvant chemotherapy refers tochemotherapy delivered before local therapeutic modalities,generally in an effort to improve their efficacy; to treat micro-metastatic disease as early as possible, when distant tumorsaresmallest; or to achieveboth of these aims. Induction chemo-therapy refers to the use of chemotherapeutic agents as the pri-mary treatment foradvanced disease. In general, chemotherapy given to children with solid tumors and metastatic disease atthe time of first examination has a less than 40% chance of effecting long-term, disease-free survival. Exceptions include Wilms’ tumor with favorable histologic features, germ celltumors, and paratesticular rhabdomyosarcoma, but mostchildren with metastatic disease are at high risk of diseaserecurrence or progression. Combination chemotherapy refersto the use of multiple agents, which generally have differentmechanisms of action and nonoverlapping toxicities, thatprovide effective, synergistic antitumor activity and minimalside effects.

The mechanisms of action and side effects of commonly used agents are listed in Table 28-5. Alkylating agents interferewith cell growth by covalently cross-linking DNA and arenot cell-cycle specific. Antitumor antibiotics intercalateinto the double helix of DNA and break the DNA strands. Antimetabolites are truly cell-cycle specific, because they in-terfere with the use of normal substrates for DNA and RNAsynthesis, such as purines and thymidine. The plant alkaloidscan inhibit microtubule function (vinca alkaloids, taxanes) orDNA topoisomerases (camptothecins inhibit topoisomerase I;epipodophyllotoxins inhibit topoisomerase II), and these ac-tions also lead to breaks in DNA strands. Topoisomerasesare a class of enzymes that alter the supercoiling of double-stranded DNA. They act by transiently cutting one (topoisom-erase I) or both (topoisomerase II) strands of the DNA to relaxthe DNA coil and extend the molecule. The regulation of DNAsupercoiling is essential to DNA transcription and replication,when the DNA helix must unwind to permit the properfunction of the enzymatic machinery involved in theseprocesses. Thus topoisomerases maintain the transcriptionand replication of DNA.

The common toxic effects of these agents are also listed inTable 28-5. Most toxicity associated with chemotherapy is re-versibleand resolveswith cessationof treatment. However, somechemotherapeutic agents may havelifelongeffects. Of particularconcern is that certain drugs can lead to a second malignancy.Most notable is the development of leukemia after the adminis-tration of the epipodophyllotoxins and cyclophosphamide.75

Finally, understanding the metabolism of chemotherapeuticagents is important. Certain agents require metabolism at aspecific site or organ for their activation or are eliminated from

the body by a specific organ (see Table 28-5). The processes of activation and elimination require normal organ function(e.g., the liver for cyclophosphamide); therefore children withliver or kidney failure may not be able to receive certain agents.

RISK STRATIFICATION

Major advances in the variety of chemotherapeutic agents anddosing strategies used to treat pediatric cancers in the past

30 years are reflected in improved patient survival rates.Regimen toxicity (including late effects, which are particularly important in the pediatric population) and therapeuticresistance are the two main hurdles preventing further ad-vancement. As more information about diagnostically andprognostically useful genetic markers becomes available,therapeutic strategies will change accordingly. With molecularprofiling, patients can be categorized to receive a particulartreatment on the basis of not only the tumor’s histopathologicand staging characteristics but also its genetic composition.Some patients whose tumors show a more aggressive biolog-ical profile may require dose intensification to increase theirchances of survival. Patients whose tumors do not have anaggressive biological profile may benefit from the lowertoxicity of less intensive therapy. Such an approach may allowthe maintenance of high survival rates while minimizing long-term complications of therapy in these patient populations.

The paradigm for the use of different therapeutic intensitieson the basis of risk stratification drives the management of pediatric neuroblastoma. There is increasing evidence thatthe molecular features of neuroblastoma are highly predictiveof itsclinical behavior. Most current studies of the treatment of neuroblastoma are based on risk groups that take into accountboth clinical and biological variables. The most importantclinical variables appear to be age and stage at diagnosis,and the most powerful biological factors appear to be MYCN status, ploidy (for patients younger than 1 year), and histo-pathologic classification. These variables currently definethe Children’s Oncology Group risk strata and therapeuticapproach, which are further refined by determining whetherthere is 1p/11q LOH. At one extreme, patients with low-riskdisease are treated with surgery alone; at the other extreme,patients at high risk for relapse are treated with intensivemultimodality therapy that includes multiagent dose-intensive chemotherapy, radiation therapy, and stem celltransplantation. Other factors, such as 17q gain, caspase8 inactivation, and TRKA/B expression, are currently beingevaluated and may help further refine risk assessment in thefuture. The management of other solid pediatric tumors is alsoshifting to risk-defined treatment. For example, the currentprotocol for the management of patients with Wilms’ tumorincludes risk stratification and therapy adjustment basedon molecular analysis of the primary tumor for 16q and 1pdeletions.

TARGETED THERAPY

Another major change in the approach to the treatment of can-cer has been the concept of targeted therapy. Until recently, thedevelopment of anticancer agents was based on the empiricalscreening of a large variety of cytotoxic compounds withoutparticular regard to disease specificity or mechanism of action.Now, one of the most exciting prospects for improving the


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TABLE 28-5

Common Chemotherapeutic Agents

Class of Drug Agent SynonymsBrand Name Mechanism of Action Common Toxic Effects

Site o Activ

Alkylatingagents

Carboplatin CBCDCA Paraplatin Platination,intrastrand andinterstrand DNA

cross-linking

A, H, M, (esp. thrombocytopenia), N/V

Cisplatin CDDC Platinol Platination,intrastrand andinterstrand DNAcross-linking

A, N/V, R (significant), ototoxicity,neuropathy

Cyclophosphamide CTX Cytoxan Alkylation,intrastrand andinterstrand DNAcross-linking

A, N/V, SIADH, M, R, cardiac, cystitis Liver

Ifosfamide IFOS Ifex Alkylation,intrastrand andinterstrand DNAcross-linking

A, CNS, N/V, M, R, cardiac, cystitis Liver

Dacarbazine DTIC Methylation H, N/V, M, hepatic vein thrombosis Liver

Temozolomide TMZ Temodar Methylation CNS, N/V, M Spon

Nitrogen Mustard Mechlorethamine Mustargen Alkylation,

intrastrand andinterstrand DNAcross-linking

A, M (significant), N/V, mucositis,

vesicant, phlebitis, diarrhea

Melphalan L-PAM Alkeran Alkylation,intrastrand andinterstrand DNA,cross-linking

M, N/V, mucositis, diarrhea

Busulfan Busulfex Alkylation,intrastrand andinterstrand DNAcross-linking

A, H, M, N/V, P, mucositis

Antimetabolites Cytarabine Ara-C Cytosar Inhibits DNApolymerase,incorporated intoDNA

M, N/V, diarrhea, CNS Targe

Fluorouracil 5-FU (Several) Inhibits thymidine

synthesis,incorporated intoDNA/RNA

CNS, N/V, M, cardiac, diarrhea,

mucositis, skin, ocular

Targe


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TABLE 28-5

Common Chemotherapeutic Agents—cont’d

Class of Drug Agent SynonymsBrand Name Mechanism of Action Common Toxic Effects

Site o Activ

Mercaptopurine 6-MP Purinethol I nhibits thymidinesynthesis,incorporated intoDNA/RNA

H, M, mucositis Targe

Methotrexate MTX Trexall Blocks folatemetabolism, inhibitspurine synthesis

CNS, H, M, R, mucositis, skin

Antibiotics Dactinomycin Actinomycin-D Cosmegen DNA intercalation,strand breaks

A, H, M, N/V, mucositis, vesicant

Bleomycin BLEO Blenoxane DNA intercalation,strand breaks

P, skin, mucositis

Anthracyclines

Daunomycin Daunorubicin Cerubidine DNA intercalation,strand breaks, freeradical formation

A, M, N/V, cardiac, diarrhea, vesicant,potentiate XRT reaction

Adriamycin Doxorubicin Adriamycin DNA intercalation,strand breaks, freeradical formation

A, M, N/V, cardiac, diarrhea, mucositis,vesicant, potentiate XRT reaction

Plant Alkaloids Epipodophyllotoxins

Etoposide VP-16 VePesid Topoisomerase IIinhibitor, DNA strandbreaks

A, M, N/V, mucositis, neuropathy,diarrhea

Teniposide VM-26 Vumon Topoisomerase IIinhibitor, DNA strandbreaks

A, M, N/V, mucositis, neuropathy,diarrhea

Vinca alkaloids

Vincristine VCR Oncovin Inhibits tubulinpolymerization,blocks mitosis

A, SIADH, neuropathy, vesicant


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Vinblastine VLB Velban Inhibits tubulinpolymerization,blocks mitosis

A, M, mucositis, vesicant

Taxanes

Paclitaxel Taxol Interferes withmicrotubuleformation

A, M, cardiac, mucositis, CNS,neuropathy

Docetaxel Taxotere Interferes withmicrotubuleformation

A, neutropenia, cardiac, mucositis, CNS,neuropathy

Camptothecins

Topotecan TPT Hycamtin Topoisomerase Iinhibitor, DNA strandbreaks

A, H, M, N/V, mucositis, diarrhea, skin

Irinotecan CPT-11 Camptosar Topoisomerase Iinhibitor, DNA strandbreaks

A, H, M, N/V, diarrhea H, GI

Miscellaneous L -Asparaginase Erwinia Elspar L-Asparaginedepletion, inhibitsprotein synthesis

CNS, H, coagulopathy, pancreatitis,anaphylaxis

Corticosteroids Nuclear receptor–mediated apoptosis

avascular necrosis, hyperglycemia,hypertension, myopathy, pancreatitis,peptic ulcers, psychosis, saltimbalance, weight gain

H

Toxic effects: A, alopecia; CNS, central nervous system toxicity; H, hepatotoxicity; M, myelosuppression; N/V, nausea and vomiting; P, pulmonary toxicity;R, renal toxicity; SIADH, syndrome of inappropriate antidiuretic hormone; XRT, x-ray therapy.Solid tumors: BMT, conditioning for bone marrow transplantation; BT, brain tumor; EWS, Ewing sarcoma; GCT, germ cell tumors; NBL, neuroblastoma; OS, osteossarcoma; W, Wilms’ tumor.


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therapeutic index of anticancer agents, as well as overcomingthe problem of therapy resistance, involves targeted therapy. As the molecular bases for the phenotypes of specific malig-nancies are being elucidated, potential new targets for therapy are becoming more clearly defined. The characterization of pathways that define malignant transformation and progres-sion has focused new agent development on key pathways in-volved in the crucial processes of cell-cycle regulation,receptor signaling, differentiation, apoptosis, invasion, migra-

tion, and angiogenesis, which may be perturbed in malignanttissues. Information about the molecular profile of a given tu-mor type can be assembled from a variety of emergingmethods, including immunohistochemistry, FISH, RT-PCR,cDNA microarray analysis, and proteomics. This informationcan then be used to develop new drugs designed to counterthe molecular abnormalities of the neoplastic cells. For exam-ple, blocking oncogene function or restoring suppressorgene activity may provide tumor-specific therapy. In addition,molecular profiling may lead to the development of drugsdesigned to induce differentiation of tumor cells, block dysre-gulated growth pathways, or reactivate silenced apoptoticpathways.

Some agents target alterations in the regulation of cell pro-liferation. Trastuzumab (Herceptin) is a monoclonal antibody that binds to the cell surface growth factor receptor ERBB2with high affinity and acts as an antiproliferative agent whenused to treat ERBB2-overexpressing cancer cells.76 Pediatrichigh-grade gliomas that overexpress EGFR may be amenableto a similar therapeutic agent, gefitinib (Iressa), a small-molecule inhibitor of EGFR (ERBB1).77 In addition, small-molecule tyrosine kinase inhibitors, such as imatinib(Gleevec), designed to block aberrantly expressed growth-promoting tyrosine kinases—ABL in chronic myelogenousleukemia78 and c-KIT in gastrointestinal stromal tumors79—are being evaluated in clinical trials. Imatinib may also be use-ful in treating pediatric tumors in which PDGF signaling playsa role in tumor cell survival and growth. Also of potentialtherapeutic utility are small-molecule inhibitors that recognizeantigenic determinants on unique fusion peptides or one of the fusion peptide partners in tumors that have chromosomaltranslocations (e.g., sarcomas). Tumors that depend on auto-crine pathways for growth (e.g., overproduction of IGF-IIin rhabdomyosarcoma or PDGF in dermatofibrosarcomaprotuberans) may be sensitive to receptor blocking mediators(e.g., antibodies to the IGF-II or PDGFR).

Other agents target alteration of the cell death and diffe-rentiation pathways. Caspase 8 is a cysteine protease thatregulates programmed cell death, but in tumors such as neu-roblastoma, DNA methylation and gene deletion combine tomediate the complete inactivation of caspase 8, almost alwaysin association with MYCN amplification.80 Caspase 8-deficienttumor cells are resistant to apoptosis mediated by death recep-tors and doxorubicin; this resistance suggests that caspase8 may be acting as a tumor suppressor. However, brief expo-sure of caspase 8–deficient cells to demethylating agents, suchas decitabine, or to low levels of interferon gamma can lead tothe reexpression of caspase 8 and the resensitization of thecells to chemotherapeutic drug-induced apoptosis. Histonedeacetylase also seems to have a role in gene silencing asso-ciated with resistance to apoptosis81; therefore histone deace-tylase inhibitors, such as suberoylanilide hydroxamic acid(SAHA), are also being tested for the treatment of certain

pediatric malignancies. Finally, cells with alterations in pro-grammed cell death as a result of the persistence or reactiva-tion of telomerase activity, which somatic cells normally loseafter birth, can be targeted by various telomerase inhibitors.

Several methods of targeting tumor cell differentiation arebeing used for the treatment of neuroblastoma. Treatmentwith 13-cis-retinoic acid, a vitamin A derivative that signalsthrough receptors that mediate transcription of different setsof genes of cell differentiation, including HOX genes, is now

standard of care for maintenance therapy in patients withhigh-risk neuroblastoma.82,83 Also, different neurotrophin re-ceptor pathways appear to mediate the signal for both cellulardifferentiation and malignant transformation of sympatheticneuroblasts to neuroblastoma cells. Neurotrophins areexpressed in a wide variety of neuronal tissues and othertissues that require innervation. They stimulate the survival,maturation, and differentiation of neurons and exhibit adevelopmentally regulated pattern of expression.84,85 Neuro-trophins and their TRK tyrosine kinase receptors are particu-larly important in the development of the sympathetic nervoussystem and have been implicated in the pathogenesis of neu-roblastoma. Three receptor–ligand pairs have been identified:TRKA, TRKB, and TRKC, which are the primary receptors fornerve growth factor, brain-derived neurotrophic factor(BDNF), and neurotrophin 3 (NT-3), respectively.84 TRKAappears to mediate the differentiation of developing neuronsor neuroblastoma in the presence of nerve growth factor li-gand and to mediate apoptosis in the absence of nerve growthfactor.85 Conversely, the TRKB-BDNF pathway appears topromote neuroblastoma cell survival through autocrine orparacrine signaling, especially in MYCN -amplified tumors.86

TRKC is expressed in approximately 25% of neuroblastomasand is strongly associated with TRKA expression.87 Studies areongoing to test agonists of TRKA in an attempt to inducecellular differentiation. Conversely, blocking the TRKB-BDNFsignaling pathway with TRK-specific tyrosine kinase inhibi-tors such as CEP-751 may induce apoptosis by blockingcrucial survival pathways.66,86 This targeted approach hasthe attractive potential for increased specificity and lowertoxicity than conventional cytotoxic chemotherapy.

Inhibition of Angiogenesis

Because tumor growth and spread appear to be dependent onangiogenesis, inhibition of angiogenesis is a logical anticancerstrategy. This approach is particularly appealing for severalreasons. First, despite the extreme molecular and phenotypicheterogeneity of human cancer, it is likely that most, if not all,tumor types, including hematologic malignancies, requireneovascularization to achieve their full malignant phenotype.Therefore antiangiogenic therapy may have broad applicabil-ity for the treatment of cancer. Second, the endothelial cells ina tumor’s new blood vessels, although rapidly proliferating,are inherently normal and mutate slowly. They are thereforeunlikely to evolve a phenotype that is insensitive to an angio-genesis inhibitor, unlike the rapidly proliferating tumorcells, which undergo spontaneous mutation at a high rateand can readily generate drug-resistant clones. Finally, be-cause the new blood vessels induced by a tumor are suffi-ciently distinct f rom established vessels to permit highly specific targeting,88,89 angiogenesis inhibitors should have a


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high therapeutic index and minimal toxicity. The combinationof conventional chemotherapeutic agents with angiogenesisinhibitors appears to be particularly effective.

The first clinical demonstration that an angiogenesis inhib-itor could cause regression of a tumor came with the use of in-terferon alpha in a patient treated for life-threateningpulmonary hemangioma.90 An increasing number of naturaland synthetic inhibitors of angiogenesis, which inhibit differ-ent effectors of angiogenesis, have since been identified, and

many of these agents have been tested in clinical trials. Exam-plesinclude drugsthat directly inhibitendothelial cells, such asthalidomide and combretastatin; drugs that block activators of angiogenesis, such as bevacizumab (Avastin), a recombinanthumanized anti-VEGF antibody, or “VEGF trap”; drugs thatin-hibit endothelium-specific survival signaling, such as Vitaxin,an anti-integrin antibody; and drugs with nonspecific mecha-nisms of action, such as celecoxib and interleukin-12 (IL-12).

Immunotherapy

The immune system has evolved as a powerful means to detectand eliminate molecules or pathogens that are recognized as“foreign.” However, because tumors arise from host cells, they are generally relatively weakly immunogenic. In addition, ma-lignant cells have evolved several mechanisms that allow themto elude the immune system. These mechanisms include theability to down-regulate the cell surface major histocompati-bility complex molecules required for activation of many of the immune effector cells, to produce immunosuppressive fac-tors, and to variably express different proteins that might oth-erwise serve as targets for the immune system in a processknown as antigenic drift. Nevertheless, because of the largenumber of mutations and chromosomal aberrations occurringin cancer cells, which results in the expression of abnormal,new, or otherwise silenced proteins, it is likely that most, if not all, cancers contain unique tumor-associated antigens thatcan be recognized by the immune system. Examples includethe fusion proteins commonly found in pediatric sarcomasand the embryonic neuroectodermal antigens that continueto be produced by neuroblastomas.

Recruiting the immune system to help eradicate tumor cellsis an attractive approach for several reasons. First, circulatingcells of the immune system have ready access to even occultsites of tumor cells. Second, the immune system has powerfuleffector cells capable of effectively and efficiently destroyingand eradicating targets, including neoplastic cells. Initialefforts to recruit the immune system to recognize and destroy tumor cells by using cytotoxic effector mechanisms that areT-cell dependent or independent focused on recombinantcytokines. Cytokines act by directly stimulating the immunesystem66 or by rendering the target tumor cells moreimmunogenic.

Neuroblastoma has been a popular target for immunother-apy in the pediatric population. Although a particular neuro-blastoma antigen has not been defined, murine monoclonalantibodies have been raised against the ganglioside GD2, apredominant antigen on the surface of neuroblastoma cells.These antibodies elicited therapeutic responses,37,91 but withsubstantial toxicity, particularly neuropathic pain.92 Becausethe induction of antibody-dependent cell-mediated cytotoxic-ity with anti-GD2 antibodies is enhanced by cytokines, such

as granulocyte-macrophage colony-stimulating factor92 andinterleukin-2 (IL-2),93 current antineuroblastoma antibodytrials are evaluating the use of a humanized, chimeric anti-GD2 antibody (ch14.18) with these cytokines and a fusionprotein (hu14.18:IL2) that consists of the humanized 14.18antibody linked genetically to human recombinant IL-2 A recently completed randomized phase III trial usingch14.18 alternating with cycles of granulocyte-macrophagecolony-stimulating factor (GM-CSF) or interleukin-2 added

to maintenance therapy of cis-retinoic acid demonstrated asignificant improvement in 2-year event-free survival for thosewho received immunotherapy in addition to retinoic acid.94

General Principles of RadiationTherapy

Radiation therapy is one of the three primary modalities usedto manage pediatric cancers in the modern era. Radiationtherapy is delivered to an estimated 2000 or more childrenper year for the primary treatment of tumor types as diverseas leukemia, brain tumors, sarcomas, Hodgkin disease, neuro-blastoma, and Wilms’ tumor.95 Delivery of radiation therapyin the pediatric setting differs from that in the adult settingbecause of the balance between curative therapy and an anti-cipated long life span during which long-term morbidity mayresult from the therapy.

CLINICAL CONSIDERATIONS

Radiation therapy for the management of pediatric cancer ismost frequently combined with surgery and chemotherapyas part of a multidisciplinary treatment plan. The sensitivenature of pediatric tumors requires the use of a combinedtherapy approach to maximize tumor control while minimiz-ing the long-term side effects of treatment. Radiation may bedelivered preoperatively, postoperatively (relative to a defini-tive surgical resection), or definitively without surgicalmanagement. Systemic therapy may also be integrated intothis management approach.

Definitive Irradiation

Definitive radiation therapy is an alternative local approach tosurgical resection of primary solid tumors. It is often the onlylocal therapeutic approach f or children and adolescents withleukemia or lymphoma.96,97 Definitive radiation therapy forrhabdomyosarcoma has been used as an alternative to surgicalresection, which has potentially greater morbidity; it hasachieved high rates of local tumor control while allowing pres-ervation of function.38 The Ewing sarcoma family of tumorsmay also be considered candidates for definitive radiationtherapy as an alternative to surgery. With careful patient selec-tion, excellent local tumor control rates can be maintainedwhile reducing or avoiding the morbidity associated withdifficult surgical resections.98,99

Preoperative Irradiation

Targeting of a localized tumor is straightforward in the preop-erative setting; the tumor has clearly defined margins undis-turbed by a surgical procedure. The volume of normalhealthy tissues receiving high doses of radiation may be


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reduced, because the areas at risk for disease involvement canbe better defined. Preoperative radiation therapy has beenused rarely in the management of Wilms’ tumor to decreasethe chance of tumor rupture100 and in the management of nonrhabdomyosarcoma soft tissue sarcoma and Ewing sar-coma to facilitate surgical resection.101,102 One of the limita-tions may be the slightly higher incidence of postoperativewound complications noted in the sarcoma population.102

Postoperative IrradiationPostoperative radiation therapy combined with surgicalresection is the most common application of adjuvant radia-tion treatment in the United States. Despite some degree of difficulty in targeting, a postoperative approach allows areview of tumor histology from the complete tumor specimen,including identification of the tumor margins and the re-sponse to any previous therapy. Wound healing complicationsappear to be reduced with this approach, and the radiationdose can be more accurately tailored to the pathologic findingsafter primary resection.

Interactions of Chemotherapy and Radiation

Most children’s cancersare managed withsystemic chemother-apy. In children receiving radiation therapy as well as systemicchemotherapy, issues of enhanced local efficacy and enhancedlocal or regional toxicity need to be considered. Solid tumorsthat are frequently treated with combined chemotherapy andradiation therapy include Wilms’ tumor, neuroblastoma, andsarcomas. These tumors are subdivided into those in whichchemotherapy is given concomitantly with radiation ther-apy 103,104 and those in which it is given sequentially, beforeor after radiation therapy.83,100,105 When delivering radiationtherapy concurrently with or temporally close to a course of chemotherapy, several issues must be considered.

Chemotherapeutic Enhancement of LocalIrradiation

Several systemic chemotherapeutic agents used againstpediatric tumors may enhance the efficacy of radiation therapy when delivered concomitantly. Cisplatin, 5-fluorouracil,mitomycin C, and gemcitabine, for example, are well-knownradiation sensitizers.106–108 Concomitant delivery of any of these drugs with radiation therapy may require that they beadministered at a dose and schedule different from thosetypically used when the drugs are delivered alone. Despitethe potential of increased toxicity, significant improvementsin local tumorcontrol have been shown in randomized studiesof concomitant drug and radiation therapy.106,107

Irradiation Combined with Agents Having

Limited or No Sensitizing EffectIn the management of pediatric malignancies, radiation isoften combined with systemic therapy not to increase its localefficacy but to allow continued delivery of systemic therapy tocontrol micrometastatic or metastatic disease. Agents com-bined with radiation therapy in this setting are common inthe management of pediatric sarcomas and include ifosfamideand etoposide, which are delivered concurrently withradiation therapy for Ewing sarcoma, and vincristine andcyclophosphamide, which are delivered concurrently withradiation therapy for rhabdomyosarcoma.103,104 Althoughlocal toxicity may be increased by such an approach, this risk

is often outweighed by the benefit of continuously deliveredsystemic therapy, particularly in tumors associated with ahigh incidence of micrometastatic disease.

Agents That Increase Radiation Toxicity

Several agents significantly increase the local toxicity of radiation. For this reason, these agents are not given concom-itantly with irradiation and are often withheld for a period af-ter the completion of radiation therapy. The two most notableagents are doxorubicin and actinomycin, both of which caninduce significant skin and mucosal toxicity when deliveredconcurrently with radiation therapy.38,109 The camptothecins(including irinotecan and topotecan) also potentiate mucosaltoxicity when delivered concurrently with radiation ther-apy.110,111 Although this increase in toxicity suggests a possi-ble increase in local efficacy, this benefit has not been notedwith current treatment approaches and chemotherapeuticdosing guidelines. For this reason, these agents are avoidedduring the delivery of radiation therapy and are withheldfor 2 to 6 weeks after the completion of treatment.

The current era of systemic therapy continues to broadenwith the availability of many new agents that target molecularpathways. It is important to consider the possibility of newtoxicities when combining novel agents with a known therapy such as radiation.

FRACTIONATION OF RADIATION THERAPY

Conventional, external beam irradiation is delivered in afractionated form. Fractionation implies daily doses of radia-tion delivered 5 days per week and amounting to the pre-scribed dose for a particular tumor type. Radiationdelivered once daily at a fraction size between 1.5 and 2.0Gy on 5 days per week is considered “conventionally” frac-tionated. This daily dose is well tolerated by normal tissues

adjacent to the tumor and appears to effect local tumor con-trol in many tumor systems. Though adult malignancies may be treated with increased doses per fraction to overcome theradioresistance of many carcinomas (termed hypofractiona-tion), nearly all the literature describing radiation therapy,its efficacy, and its toxicity in children is based on conven-tional fractionation.

RADIATION THERAPY TREATMENT

TECHNIQUES

Traditional Radiation Therapy

The planning and delivery of traditional, or conventional,radiation therapy are based on nonvolumetric imaging studies(i.e., conventional radiographs). Patients are positioned in amanner that allows the orientation of radiation beams fromthe conventional directions: anterior, posterior, and lateral.Limitations of this approach are related to the ability of conventional radiographs to accurately convey the locationof tumor-bearing tissue. Although treatment beams are ori-ented around the tumor, adjacent normal tissues also receivehigh doses of radiation. Depending on the accuracy of thedelineation of adjacent normal tissues on radiographs, thedose to those tissues may not be known. Radiation is deliveredby a photon beam generated by a linear accelerator.


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Focal Radiation Therapy

Focal radiation therapy comprises a group of techniques thatdeliver radiation to a defined volume, usually delineated by computed tomography (CT) or magnetic resonance imaging(MRI). Relatively low doses may be incidentally deliveredto surrounding normal tissues. Radiation therapy may be de-scribed as image guided when four criteria are met: (1) three-dimensional imaging data (CT or MRI) are acquired with the

patient in the treatment position; (2) imaging data are used todelineate and reconstruct the tumor volume and normaltissues in three dimensions; (3) radiation beams can be freely oriented in three dimensions in the planning and delivery processes, and structures traversed by the beam can bevisualized with the eye of the beam; and (4) the distributionof doses received by the tumor volume and any normaltissue is computable on a point-by-point basis in three-dimensional space. Several different methods of deliveringimage-guided photon radiation are currently in use and arediscussed here.

Conformal Radiation Therapy

The delivery of three-dimensional conformal radiation

therapy allows specific targeting of tumor volumes on thebasis of imaging studies performed with the patient in thetreatment position. This method of delivery uses multiplefields or portals, with each beam aperture shaped to the tumorvolume, and it is performed daily. Beam modifiers, such aswedges, are used to conform the radiation beam to the tumorand to ensure that the tumor volume receives a homogeneousdose. Conformal radiation therapy has been intensively stud-ied in adults with head and neck cancer, lung cancer, andprostate cancer and has been shown to excel when the targetvolume is convex and crucial structures do not invaginate thetarget volume. Available data demonstrate that it has low tox-icity despite high doses of radiation to the target volume.112

Intensity-Modulated Radiation Therapy

Intensity-modulated radiation therapy is another method of delivering external beam radiation that requires imaging of the patient in the treatment position and delineation of targetvolumes and normal tissues. Radiation is delivered to the tar-get as multiple small fields that do not encompass the entiretarget volume but collectively deliver the prescribed daily dose. Intensity-modulated radiation therapy differs fromconformal radiation therapy in that it (1) increases the com-plexity and time required for the planning and delivery of treatment, (2) increases the amount of quality-assurance workrequired before treatment is delivered, (3) increases doseheterogeneity within the target volume such that some intrale-sional areas receive a relatively high dose, and (4) can be used

to treat concave targets while sparing crucial structures thatinvaginate the target volume. The last point holds promisefor better protecting normal tissue and reducing late toxiceffects. Preliminary data from adult patients given intensity-modulated radiation therapy demonstrate its potential forreducing treatment toxicity when applied to pediatric braintumors and other adult tumors.113

Proton Beam Radiation Therapy

Proton radiation therapy and other approaches using heavy charged particles have been investigated at a limited numberof centers. The primary benefit of therapywith proton or other

heavy charged particle beams is the capacity to end the radi-ation beam at a specific and controllable depth. This mayallow the protection of healthy, normal tissues directly adja-cent to tumor-bearing tissues.114 However, the use of protontherapy has been limited because of the expense of construct-ing a suitable treatment facility. Several new facilities haveopened in the United States, and pediatric malignancies arealways noted as one of the tumors systems on which the

centers will focus their research efforts. With appropriatelydesigned studies and comparisons with current state-of-the-art focal radiation therapy delivered with photon beamsa determination of the potential benefits of this treatmentmodality may be made.

Brachytherapy

Brachytherapy is a method of delivering radiation to atumor or tumor bed by placing radioactive sources withinor adjacent to the target volume, usually at the time of surgicalresection and under direct vision. Planning of the dose to bedelivered to the target vol

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