Part AActive Treatment

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Cancer in Children: an OverviewShai Izraeli, Gideon Rechavi

Introduction

Approximately one in every 350 children will developcancer by adulthood, and despite the remarkable curerate, cancer is still the leading cause of non-accidentaldeath in children in affluent countries after the neonatalperiod. In this Introduction we shall highlight someunique medical aspects of childhood cancer that areespecially pertinent to pediatric psycho-oncology. Formore details about specific diseases, the reader isreferred to the available textbooks in pediatric oncology.

The characteristic cancers of children are differentfrom those encountered in adults. Typically they arisein tissues and organs that develop most rapidly duringembryogenesis and the postnatal period. Indeed, it islikely that most cancers in children result fromunfortunate developmental “accidents,” often occur-ring in utero. In contrast, the typical “adult” malignan-cies arise in epithelial cells covering the surface of ductsand body cavities that are exposed for prolonged peri-ods of time to a large variety of environmental carcino-gens. Colon cancer, for example, is the end stage of aslow multistep transition from normal tissue throughbenign polyps to malignant invasive carcinomas.Colon cancer may be prevented by either modifyingdiet or by treatment with drugs such as aspirin, whichaffects the tumorogenic response of the colonic mucosato carcinogens, or by removal of benign polyps. Unlikecancers in adults, most cancers in children cannot beprevented, are not preceded by obvious pre-malignantlesions and are not amenable to early diagnosis.Indeed, several international trials of massive screeningfor pre-malignant lesions or early stages of neuroblas-toma, a childhood cancer of the sympathetic nervoussystem, have proved futile. These issues are relevantwhen dealing with the parents of a child with cancer,who are, naturally, overwhelmed by guilt and self-blame. It is important to explain to parents that to thebest of our knowledge cancers in children are not

caused by any wrongdoing of the child or his/her par-ents, nor could they have been diagnosed earlier(except, of course, in cases of clear medical neglect).

Most of the tumors arise spontaneously, althoughthere are rare familial hereditary cancer syndromes.For example, retinoblastoma, a malignant tumor ofthe retina, is often hereditary. A child with hereditaryretinoblastoma is likely to develop tumors in the othereye and later may also be diagnosed with osteo-sarcoma, a malignant bone tumor. Most of these chil-dren are cured and their chances of passing thehereditary trait are 50%. Families with hereditarycancer syndromes require therefore special lifelongattention and present the health care community withnew challenges. One of these challenges is caused bymodern genetic diagnostic techniques that enable iden-tification of individuals carrying a cancer-predisposingmutation while they are still healthy. This medicallyhelpful knowledge may also add a significant psycho-social burden to the patients and their families.

Another high-risk group is identical twins. An identi-cal twin of a child with leukemia has a 25% risk ofdeveloping the same leukemia before the age of 10.This high risk of a non-genetic disease among identicaltwins has been puzzling. The mystery has been solvedrecently. As leukemia is commonly an “accident”during embryonic development, pre-leukemic cells cancirculate from one embryonic twin to the other throughtheir common vascular channels. Other than theseexamples, in most instances there is no substantial basisfor the fear that other young members of the family willdevelop cancer as well. Moreover, the rate of cancer inoffsprings of childhood cancer survivors is not signifi-cantly higher than in the normal population. Thus, inthe majority of instances we can safely reassure thefamilies that the cancer will not spread in the family.

The most common malignancy in children involvesthe lymphoid system, especially acute lymphoblastic

Pediatric Psycho-oncology: Psychosocial Aspects and Clinical Interventions, Second Edition.Edited by Shulamith Kreitler, Myriam Weyl Ben-Arush and Andrés Martin.� 2012 John Wiley & Sons, Ltd. Published 2012 by John Wiley & Sons, Ltd.

leukemia (ALL). During embryonic development andearly childhood the normal lymphoid system has todevelop rapidly and acquire the capabilities to mountspecific immune responses against an enormous varietyof foreign antigens. For efficient diversification of thevarious immune receptors, lymphoid cells possess anunusual type of genetic instability that predisposesthem to rare genetic accidents leading to acute leuke-mia. ALL is most common in young children butoccurs throughout childhood.

The nervous system is another rapidly developingorgan that also involves substantial fine-tuned diversifi-cation and differentiation during embryogenesis andearly childhood. The frequency of tumors of the ner-vous system is almost equal to ALL and together thesemalignancies are responsible for more than half of thecancers in children. Many of these tumors are rela-tively slow-growing gliomas, often implying livingthrough childhood with slowly progressing braintumors. A large fraction of childhood brain tumorshave an embryonic and more aggressive phenotype.These include medulloblastoma, a cancer of the cere-bellum, retinoblastoma, and neuroblastoma, a malig-nant tumor of the peripheral sympathetic nervoussystem. Embryonic tumors outside the nervous systemsuch as Wilm’s tumor of the kidney, hepatoblastomaand various tumors of the gonads are also typical ofchildren.

The third most common type of malignancy of chil-dren is a diverse group of tumors of the musculo-skeletal and the soft tissues. These sarcomas can ariseat any age and have specific molecular, pathologicaland clinical characteristics. Many of those occur morefrequently during adolescence, a period of robust mus-culoskeletal development.

Pediatric oncology is one of the greatest medicalsuccess stories of the past four decades. The cure rateof childhood cancer has increased from about 25% inthe 1960s to more than 75% in the 1990s. This remark-able progress has occurred in almost all types of child-hood malignancies and is due to the exquisitesensitivity of these malignancies to chemotherapy andto the series of carefully conducted collaborativeempirical clinical trials in Europe and the USA.

The paradigm to this success is childhood ALL, auniformly fatal disease in the 1960s that has becomecurable in almost 80% of children today. The treatment“protocol” of childhood ALL consists of 2–3 years oftherapy utilizing up to ten chemotherapeutic drugsgiven in various combinations. Intensive remissioninduction and consolidation therapies, lasting up tohalf a year, are followed by prolonged and less inten-sive maintenance therapy. During the first half year,

the child requires frequent hospitalizations for admin-istration of drugs or for combating infectious compli-cations of chemotherapy. The child can attendkindergarten or school and function almost normallyduring the rest of the therapy.

A specific problem associated with ALL and rele-vant to the topic of this textbook is the need for preven-tion therapy to the central nervous system (CNS).Early trials with chemotherapy have failed because ofthe recurrence of the leukemia in the CNS. Apparentlydue to the poor penetration of most chemotherapeuticdrugs into the CNS it serves as a “sanctuary” haven forleukemic cells. Cure of ALL became a reality onlywhen routine irradiation of the brain was added to sys-temic chemotherapy. This success has proven to be amixed blessing as the exposure of the brain of youngchildren to a hefty dose of radiation resulted in severelong-term intellectual, behavioral and other neurologi-cal impairments. In most modern treatment protocolsof ALL, cranial irradiation has been replaced by acombination of systemic high dose methotrexate andintrathecal chemotherapy. While this approach hasbeen proven to be less toxic than irradiation, its long-term neurological implications still need to be studied.

The treatment of solid tumors combines usually atleast two modalities. Local control is achieved throughsurgery or radiotherapy. Because of the severe long-term toxicities of radiating growing tissues, surgery ispreferred when possible. Modern pediatric surgicaloncology has become much less mutilating. Thus, inmost instances, bone and soft tissue sarcomas can beremoved by limb-sparing surgery. Still, in many instan-ces, such as brain tumors, Hodgkin’s disease andinoperable sarcomas, radiation is unavoidable. It iscritically important that radiation will be delivered incenters specializing in treatment of children because ofmany specific considerations unique to these patientsthat are required to minimize the long-term side effectsand encourage conservation of symmetric growth anddevelopment.

The most significant progress in the treatment ofchildhood solid tumors occurred when the concept of“adjuvant chemotherapy” was introduced, initially fortreatment of Wilm’s tumor and osteosarcoma. In thecase of osteosarcoma, even when the tumor was local-ized to the limb, and the limb was amputated, the long-term survival was no more than 20%. Since all deathswere caused by distant metastases, the unavoidableconclusion was that micro-metastases were present inmost of the patients with localized tumors at the timeof diagnosis. The administration of “adjuvant chemo-therapy”—chemotherapy that is delivered with theintention to destroy those unseen micro-metastases, has

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led to the current 70% survival rates. Typically thesepatients today are treated first with chemotherapy, fol-lowed by surgical removal of the tumor with sparing ofthe limb, and another period of intensive chemo-therapy. The concept of adjuvant chemotherapy hasbeen also adopted by the adult oncologists for chemo-therapy-sensitive tumors such as breast cancer.

The recent decade has witnessed remarkable devel-opment in molecular biology and diagnostics. Tech-niques allowing the visualization and quantificationsof genes and gene products have enabled molecularclassification of tumors and personalized adjustmentof therapy to the biological tumor subtype. Again,pediatric oncology has shown the way. Thus, forexample, the identification of the BCR-ABL fusiongene in a child with leukemia or the detection of multi-ple copies of the NMYC oncogene in a child with neu-roblastoma led to their classification as high riskpatients and to assignment to especially intensive treat-ments that included bone marrow transplantation. Themolecular determination of minimal residual diseasehas allowed tailoring of therapy to the molecularresponse to therapy. The identification of specificmolecular abnormalities has also raised hopes fordevelopment of cancer-specific, less toxic therapies. Inthe recent years since the first edition of this book, sev-eral novel targeted therapies have been finally intro-duced for children with cancer, and others are inclinical trials. For example, the addition of inhibitorsof BCR-ABL to chemotherapy has caused such a dra-matic improvement to survival that the presence ofthis abnormality no longer constitutes an automaticindicator of stem cell transplantation. These noveltherapies are not “magic bullets” free of side effects.Indeed, many of these novel drugs target pathwaysimportant for childhood growth and development andhence have a multitude of newer side effects differentfrom those caused by chemotherapy.

While childhood cancer is a relatively rare disease,its high cure rate is having a significant impact in devel-oped societies. Currently, one in every 900 young (lessthan 45-year-old) Americans has been cured of child-hood cancer. It is estimated that within 20 years thisrate will increase to more than one in every 400. Unlikeadult cancer, occurring mostly in the post-retirementage, children cured from cancer are expected to livemany more productive years. Thus the quality of life ofchildhood cancer survivors and late effects of the can-cer and its treatment have become a major focus ofmodern pediatric oncology and are particularly rele-vant for the field of psycho-oncology.

Although children tolerate the acute toxicities ofchemotherapy better than adults, growing children are

more vulnerable to the delayed effects of cancer ther-apy such as effects on growth, the endocrine system,fertility, the myocardium, neuropsychological func-tion, and the occurrence of secondary cancers. More-over, because children tolerate chemotherapy betterthan adults, they often receive far greater dose-inten-sity and are therefore more likely to develop latesequelae. Of the different therapeutic modalities, radia-tion is associated with the highest rates of late effects inchildren.

Most relevant for this textbook are the late neuro-psychological sequelae of childhood cancer therapy.Long-term neurological impairments are associatedwith leukemia and brain tumors, the two most com-mon malignancies of children. Learning difficultieshave been most commonly attributed to cranialirradiation and are related to the dose and the age atthe time of irradiation. For example, cranialirradiation with 3,600 cGy of children with braintumors who are younger than 36m is universally asso-ciated with marked decreases in I.Q. Newer therapeu-tic protocols are attempting to delay radiation andlower the dose in young children.

Although radiation doses in children with ALL aresignificantly lower than those used for children withbrain tumors, they are still likely to have long-termneuropsychological sequelae. These effects are mainlyin attention capacities and other nonverbal cognitiveprocessing skills and not in the global IQ. These deficitscorrelate with focal findings in magnetic resonanceimaging (MRI) of the brain and neurophysiologicalstudies. As with brain tumors, the extent and timing ofthe deficits are related to the radiation dose and the ageat the time of radiation. Girls less than 5 years old aremost vulnerable. At the extreme end of the spectrum ofneurological toxicity is progressive necrotizing leu-koencephalopathy, a rare and devastating complica-tion, occurring mainly in patients who have received acombination of higher dose radiotherapy and intra-thecal methotrexate. Although significantly less neuro-logical impairment is seen in children with ALL treatedwith intrathecal therapy only, it is premature to con-clude that no neuropsychological deficits are expected.Indeed, minor abnormalities in brain imaging are com-monly detected and the long-term significance of thesechanges is presently unknown.

It is impossible to write an introduction to a book onpsychology of children without relating to adolescence.Surviving normal adolescence is a challenge to chil-dren, their parents and educators and provides the live-lihood of pediatric psychologists. Cancer in this lifeperiod is extraordinarily more challenging. Adoles-cents tend to delay bringing medical problems to

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attention and are less compliant with therapy. Forexample, it has been clearly shown that adolescentswith ALL tend to be less adherent to the oral chemo-therapy regimen during the maintenance period andthat their prognosis directly correlates with their degreeof compliance. There are also some unique medicalissues such as preservation of fertility, and a large listof psychosocial issues. Because of these issues, the needof a specific discipline for adolescent and young adultsoncology is being considered now in the USA andEurope.

The final issue relates to the topic we all try to avoid.Despite the enormous success, one in every five chil-dren with cancer will die from the disease. The grimoutlook of a particular child is often known soon afterdiagnosis. Yet studies have repeatedly shown that theprospect of dying is usually, if at all, addressed onlyvery shortly before death. Even in the most hopelesscases, treatment is usually characterized by intensiveattempts to cure and by ignoring the option of pallia-tive care. This is one area where we, who deal with

childhood cancer, can learn from our colleagues in theadult oncology field. Hospice and palliative care arenew and much needed concepts in pediatric oncologythat, naturally, combine medical and psychosocialapproaches. And after the death, there are bereavedparents, siblings, and friends. They often cling to thepediatric oncology department and look for comfortand help. The “end of life” issue is a chapter in pediat-ric oncology waiting to be defined and written.

Pediatric oncology meets childhood psychology atthe time of the diagnosis of these devastating diseases,during the difficulties associated with the toxicities ofintensive chemotherapy, the rehabilitation period, dur-ing the follow-up of the majority who are long-termsurvivors, and the bereavement of those who lost themost precious of all. Although the child is the one withthe cancer, the pediatric oncology team interacts inten-sively with the siblings, parents, grandparents, friends,schoolteachers and more. It becomes a communityaffair in which the pediatric oncology team is atthe center.

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