Statistically and clinically significant improvements have been achieved in all major forms of childhood cancers through conduct of well-organised single institution and cooperative group clinical trials which have resulted in sequential and steady improvement in survival rates since the 1960s when curative treatments were first devised. SEER data document that the overall childhood cancer mortality rates have consistently declined throughout the 1975-95 time period.1 Documentation of the overall progress achieved by POG investigators has been reported, demonstrating significant improvements in overall survival (OS) and event-free survival (EFS) for 8 of 10 disease areas, in a sample of over 7000 children and adolescents treated between 1976 and 1989.4 Similar results have been achieved by CCG and by European national paediatric cooperative clinical trials organisations. There is also evidence that children and adolescents with acute lymphocytic leukaemia (ALL), non-Hodgkin's lymphoma (NHL), Wilm's tumour, medulloblas-toma and rhabdomyosarcoma enjoy a significant survival advantage when treated according to well-defined protocols, compared to paediatric patients not enrolled on protocols and treated outside of paediatric cancer centres.5 Most probably the inclusion benefit related to participation in clinical trials is a result of a number of factors, including the rigorous process of protocol development, incorporation of rapid pathology review and reference laboratories, defined staging practices and procedures, on-study review of radiotherapy port films, and close monitoring for toxi-city and efficacy. Some of the important advances achieved in treatment of paediatric cancers are listed in Table 7.2.
Table 7.2. Examples of important advances resulting from paediatric cancer clinical trials
• Adjuvant chemotherapy improves survival from 20% to 70% in non-metastatic osteosarcoma of the extremity.50
• Doxorubicin improves outcome when added to other chemotherapy for Ewing's sarcoma51 and the addition of ifosfamide and etoposide to vincristine, adriamycin, cyclophosphamide and actinomycin results in greater benefit.52
• Radiation therapy does not improve survival for patients receiving chemotherapy with Stage I and II, Wilm's tumour,53,54 Stage I rhabdomyosarcoma55 or localised non-Hodgkin's lymphoma.56
• Demonstration of improved event-free survival in high-risk neuroblastoma receiving myeloablative therapy in conjunction with autologous bone marrow transplantation and subsequent treatment with 13-c/s-retinoic acid compared to chemotherapy alone.57
• Attainment of 80% 4-year event-free survival rates for standard risk B-precursor ALL.58
• Achievement of 78% EFS for patients with loco-regional embryonal rhabdomyosarcoma through intensification of chemotherapy in Intergroup Rhabdomyosarcoma Study (IRS)-IV.59
Success in treatment of the most common form of paediatric malignancy, acute lymphoblastic leukaemia (ALL), has been most gratifying. Indeed, a major reason for improvements in overall survival for childhood cancer in general is due to improvement in survival rates for ALL, which accounts for roughly a third of paediatric cancer.1 With modern chemotherapy, 97-99% of children can be expected to attain complete remission, and it is not inconceivable to predict that modifications of the currently most successful protocols will boost long-term leukaemia-free survival rates to as high as 85-90%. Treatment success has been achieved through post-induction intensification/consolidation and re-induction treatments, effective treatments ('prophylaxis') for subclinical central nervous system leukaemia, and prolonged anti-metabolite-based continuation treatments of 24-36 months duration. Advances have been achieved by many single institutions and cooperative groups treating childhood leukaemias, including investigators at St. Jude Children's Research
Hospital in Memphis who pioneered a 'Total Therapy' curative approach beginning in the 1960s. It is beyond the scope of this chapter to review the treatment advances achieved through clinical trials for ALL by the BFM (Berlin-Frankfurt-MUnster) Group, POG, CCG, the Dana Farber Consortium, the Medical Research Council/UKALL, the Dutch Childhood Leukaemia Study Group, the French Acute Lymphoblastic Leukaemia Cooperative Group (FRALLE) and the Italian Association of Paediatric Haematology-Oncology (AIEOP), but the interested reader may consult reviews summarising the spectacular progress achieved in treatment of ALL.6
The lymphomas, Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL), are the third most common form of paediatric malignancy, next in frequency behind leukaemias and tumours of the central nervous system. Currently 80-90% of all children and adolescents with malignant lymphomas are curable with optimal multidis-ciplinary management, based on immunopatho-logic classification, staging for determination of disease extent, and design and selection of risk-adapted therapies. Paediatric investigators at Stanford, beginning in 1970, first pioneered combined modality treatment for children with HD and demonstrated that low-dose involved field radiotherapy combined with multiple cycles of chemotherapy (MOPP or MOPP/ABVD) resulted in cure of 90% of paediatric patients.7 Similarly outstanding rates of disease control with combined modality management of paediatric HD have since been reported by others, establishing the curability of HD in nearly all cases, such that the thrust of current trials in paediatric HD is towards reduction of serious late effects of HD treatments, such as secondary malignancies, particularly leukaemia, infertility, pulmonary fibrosis and restrictive lung disease, serious cardiac problems and premature death.
The non-Hodgkin's lymphomas occurring among children and adolescents are virtually all high-grade, diffuse malignancies, differing markedly from the distribution of histologic types typically seen among older adults. Staging systems in use for childhood and adult NHL also differ.8
Ninety percent of localised NHLs, regardless of histology, are readily cured by nine weeks of chemotherapy without radiation.9
Progress in the treatment of paediatric solid tumours has been equally striking in the last 30 years as the progress in treating childhood leukaemias and lymphomas, and may be attributable to development of accurate diagnostic methods and systems of disease staging and effective multimodal treatments combining surgery, chemotherapy and radiation. Cure rates for rhabdomyosarcoma have increased from approximately 25% in 1970 to greater than 75% currently, to 60-70% for non-metastatic bone sarcomas, to over 80% for Wilm's tumour, over 90% for retinoblastoma, over 90% for infants and children with localised neuroblastoma, and to over half of all children with brain tumours.
Aims of current trials are to increase or preserve high cure rates, decrease acute toxicity and long-term adverse sequelae of treatment, decrease costs and improve the quality of life for children with readily curable cancers. Patients with high risk or metastatic disease at diagnosis or those who recur after front-line therapies continue to pose challenges and should properly benefit from pilot trials and Phase I or II studies of new treatments.
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