![]()
Part A
Active Treatment
![]()
Chapter 1
Cancer in Children: an Overview
Shai Izraeli, Gideon Rechavi
Introduction
Approximately one in every 350 children will develop cancer by adulthood, and despite the remarkable cure rate, cancer is still the leading cause of non-accidental death in children in affluent countries after the neonatal period. In this Introduction we shall highlight some unique medical aspects of childhood cancer that are especially pertinent to pediatric psycho-oncology. For more details about specific diseases, the reader is referred to the available textbooks in pediatric oncology.
The characteristic cancers of children are different from those encountered in adults. Typically they arise in tissues and organs that develop most rapidly during embryogenesis and the postnatal period. Indeed, it is likely that most cancers in children result from unfortunate developmental “accidents,” often occurring in utero. In contrast, the typical “adult” malignancies arise in epithelial cells covering the surface of ducts and body cavities that are exposed for prolonged periods of time to a large variety of environmental carcinogens. Colon cancer, for example, is the end stage of a slow multistep transition from normal tissue through benign polyps to malignant invasive carcinomas. Colon cancer may be prevented by either modifying diet or by treatment with drugs such as aspirin, which affects the tumorogenic response of the colonic mucosa to carcinogens, or by removal of benign polyps. Unlike cancers in adults, most cancers in children cannot be prevented, are not preceded by obvious pre-malignant lesions and are not amenable to early diagnosis. Indeed, several international trials of massive screening for pre-malignant lesions or early stages of neuroblastoma, a childhood cancer of the sympathetic nervous system, have proved futile. These issues are relevant when 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 the best of our knowledge cancers in children are not caused by any wrongdoing of the child or his/her parents, nor could they have been diagnosed earlier (except, of course, in cases of clear medical neglect).
Most of the tumors arise spontaneously, although there are rare familial hereditary cancer syndromes. For example, retinoblastoma, a malignant tumor of the retina, is often hereditary. A child with hereditary retinoblastoma is likely to develop tumors in the other eye and later may also be diagnosed with osteosarcoma, a malignant bone tumor. Most of these children are cured and their chances of passing the hereditary trait are 50%. Families with hereditary cancer syndromes require therefore special lifelong attention and present the health care community with new challenges. One of these challenges is caused by modern genetic diagnostic techniques that enable identification of individuals carrying a cancer-predisposing mutation while they are still healthy. This medically helpful knowledge may also add a significant psychosocial burden to the patients and their families.
Another high-risk group is identical twins. An identical twin of a child with leukemia has a 25% risk of developing the same leukemia before the age of 10. This high risk of a non-genetic disease among identical twins has been puzzling. The mystery has been solved recently. As leukemia is commonly an “accident” during embryonic development, pre-leukemic cells can circulate from one embryonic twin to the other through their common vascular channels. Other than these examples, in most instances there is no substantial basis for the fear that other young members of the family will develop cancer as well. Moreover, the rate of cancer in offsprings of childhood cancer survivors is not significantly higher than in the normal population. Thus, in the majority of instances we can safely reassure the families that the cancer will not spread in the family.
The most common malignancy in children involves the lymphoid system, especially acute lymphoblastic leukemia (ALL). During embryonic development and early childhood the normal lymphoid system has to develop rapidly and acquire the capabilities to mount specific immune responses against an enormous variety of foreign antigens. For efficient diversification of the various immune receptors, lymphoid cells possess an unusual type of genetic instability that predisposes them to rare genetic accidents leading to acute leukemia. ALL is most common in young children but occurs throughout childhood.
The nervous system is another rapidly developing organ that also involves substantial fine-tuned diversification and differentiation during embryogenesis and early childhood. The frequency of tumors of the nervous system is almost equal to ALL and together these malignancies are responsible for more than half of the cancers in children. Many of these tumors are relatively slow-growing gliomas, often implying living through childhood with slowly progressing brain tumors. A large fraction of childhood brain tumors have an embryonic and more aggressive phenotype. These include medulloblastoma, a cancer of the cerebellum, retinoblastoma, and neuroblastoma, a malignant tumor of the peripheral sympathetic nervous system. Embryonic tumors outside the nervous system such as Wilm's tumor of the kidney, hepatoblastoma and various tumors of the gonads are also typical of children.
The third most common type of malignancy of children is a diverse group of tumors of the musculoskeletal and the soft tissues. These sarcomas can arise at any age and have specific molecular, pathological and clinical characteristics. Many of those occur more frequently during adolescence, a period of robust musculoskeletal development.
Pediatric oncology is one of the greatest medical success stories of the past four decades. The cure rate of childhood cancer has increased from about 25% in the 1960s to more than 75% in the 1990s. This remarkable progress has occurred in almost all types of childhood malignancies and is due to the exquisite sensitivity of these malignancies to chemotherapy and to the series of carefully conducted collaborative empirical clinical trials in Europe and the USA.
The paradigm to this success is childhood ALL, a uniformly fatal disease in the 1960s that has become curable in almost 80% of children today. The treatment “protocol” of childhood ALL consists of 2–3 years of therapy utilizing up to ten chemotherapeutic drugs given in various combinations. Intensive remission induction and consolidation therapies, lasting up to half a year, are followed by prolonged and less intensive maintenance therapy. During the first half year, the child requires frequent hospitalizations for administration of drugs or for combating infectious complications of chemotherapy. The child can attend kindergarten or school and function almost normally during the rest of the therapy.
A specific problem associated with ALL and relevant to the topic of this textbook is the need for prevention therapy to the central nervous system (CNS). Early trials with chemotherapy have failed because of the recurrence of the leukemia in the CNS. Apparently due to the poor penetration of most chemotherapeutic drugs into the CNS it serves as a “sanctuary” haven for leukemic cells. Cure of ALL became a reality only when routine irradiation of the brain was added to systemic chemotherapy. This success has proven to be a mixed blessing as the exposure of the brain of young children to a hefty dose of radiation resulted in severe long-term intellectual, behavioral and other neurological impairments. In most modern treatment protocols of ALL, cranial irradiation has been replaced by a combination of systemic high dose methotrexate and intrathecal chemotherapy. While this approach has been proven to be less toxic than irradiation, its long-term neurological implications still need to be studied.
The treatment of solid tumors combines usually at least two modalities. Local control is achieved through surgery or radiotherapy. Because of the severe long-term toxicities of radiating growing tissues, surgery is preferred when possible. Modern pediatric surgical oncology has become much less mutilating. Thus, in most instances, bone and soft tissue sarcomas can be removed by limb-sparing surgery. Still, in many instances, such as brain tumors, Hodgkin's disease and inoperable sarcomas, radiation is unavoidable. It is critically important that radiation will be delivered in centers specializing in treatment of children because of many specific considerations unique to these patients that are required to minimize the long-term side effects and encourage conservation of symmetric growth and development.
The most significant progress in the treatment of childhood solid tumors occurred when the concept of “adjuvant chemotherapy” was introduced, initially for treatment of Wilm's tumor and osteosarcoma. In the case of osteosarcoma, even when the tumor was localized to the limb, and the limb was amputated, the long-term survival was no more than 20%. Since all deaths were caused by distant metastases, the unavoidable conclusion was that micro-metastases were present in most of the patients with localized tumors at the time of diagnosis. The administration of “adjuvant chemotherapy”—chemotherapy that is delivered with the intention to destroy those unseen micro-metastases, has led to the current 70% survival rates. Typically these patients today are treated first with chemotherapy, followed by surgical removal of the tumor with sparing of the limb, and another period of intensive chemotherapy. The concept of adjuvant chemotherapy has been also adopted by the adult oncologists for chemotherapy-sensitive tumors such as breast cancer.
The recent decade has witnessed remarkable development in molecular biology and diagnostics. Techniques allowing the visualization and quantifications of genes and gene products have enabled molecular classification of tumors and personalized adjustment of therapy to the biological tumor subtype. Again, pediatric oncology has shown the way. Thus, for example, the identification of the BCR-ABL fusion gene in a child with leukemia or the detection of multiple copies of the NMYC oncogene in a child with neuroblastoma led to their classification as high risk patients and to assignment to especially intensive treatments that included bone marrow transplantation. The molecular determination of minimal residual disease has allowed tailoring of therapy to the molecular response to therapy. The identification of specific molecular abnormalities has also raised hopes for development of cancer-specific, less toxic therapies. In the recent years since the first edition of this book, several novel targeted therapies have been finally introduced for children with cancer, and others are in clinical trials. For example, the addition of inhibitors of BCR-ABL to chemotherapy has caused such a dramatic improvement to survival that the presence of this abnormality no longer constitutes an automatic indicator of stem cell transplantation. These novel therapies are not “magic bullets” free of side effects. Indeed, many of these novel drugs target pathways important for childhood growth and development and hence have a multitude of newer side effects different from those caused by chemotherapy.
While childhood cancer is a relatively rare disease, its high cure rate is having a significant...
