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What’s new in pediatric oncology?
Path. Res. Pract. 178, 425-428 (1985)
I
What's new in ...
What's New in Pediatric Oncology? Epidemiology, Treatment Principles and Prognosis in Childhood Malignancies G. Schellong* Childrens Hospital, University of Munster (Director: Prof. Dr. G. Schellong), Munster, FRG
SUMMARY
The proportion of malignancies in children differs from that in adults: Leukemias and malignant lymphomas predominate with a total of 50%, followed by tumors of the nervous system, of the kidneys, and of connective and supportive tissue. Most of these diseases respond well to cytostatic therapy. Therefore chemotherapy occupies a major role in the curative concepts for nearly all childhood malignancies. Its objective is the destruction of micrometastases as well as the reduction of primary tumor mass in inoperable cases, and it often helps to limit the extent of radical surgery. Radiotherapy, too, can be reduced under the influence of cytostatic therapy. In nearly all childhood cancers, prognosis has improved substantially over the past 10 to 15 years. Today, our aim is not the mere limited survival, but a definitive cure. Modern strategies have raised the cure rates of Hodgkin's disease to 90%, of Wilms' tumor, acute lymphoblastic leukemia and non- Hodgkin lymphomas to 70-75%, of soft tissue sarcomas and osteosarcomas to about 50%, and of acute myelogenous leukemia, neuroblastoma and medulloblastoma to 30-35%. Centralized management of childhood cancers in specially staffed hospitals is mandatory on account of their relative low frequency, the risks of chemotherapy, and the high staff workload.
Epidemiology Incidence rates of cancer are much lower in childhood than in adult life. According to statistical data from various countries the yearly rate of new cases is about 10 to 12.5 per 100000 children under 15 in white populations2,28. In the entire Federal Republic of Germany (FRG) some 11 00-1200 new cases of cancer are expected every year among the children under 15, which means an incidence rate of 11-12 per 100000. These data are derived from the Central Registry for Childhood Malignancies in * Dedicated to Prof. Dr. Dr. h.c. Franz Biichner in honor of his 90th birthday, Jan. 20, 1985. © 1985 by Gustav Fischer Verlag, Stuttgart
the FRG at the Institute for Medical Documentation and Statistics of the University of Mainz 14 • The male: female ratio is 1.26: 1; but the predominance of boys varies among different tumor types, being strongest in malignant lymphomas with a ratio of 1.6-2 : 1. Malignancies occurring in children differ principally from those found in adults with regard to type. Tumors of epithelial origin, i.e. carcinomas proper, are rarely observed. Predominant are leukemias, tumors of lymphatic or histiocytic origin (the so-called systemic diseases), and malignant tumors of nervous system, kidneys, bones, and connective tissue (socalled solid tumors), Table 1 presents a detailed listing of malignancies diagnosed in more than 4000 children in the FRG between 1980 and 1983 14 • 0344-0338/85/0179-0425$3.50/0
426 . G . Schellong
The vast majority of solid tumors originate in the prenatal phase and are therefore called embryonal neoplasms (such as neuroblastoma, nephroblastoma, medulloblastoma, retinoblastoma, rhabdomyosarcoma, germ cell tumors, hepatoblastoma). Accordingly, about 50% of tumors in childhood are diagnosed in the first four years of life. The exact age distribution, however, may show rather wide variations in the different types: Incidence rates of Hodgkin's disease and osteosarcoma rise with age; acute lymphoblastic leukemia has a peak between the ages of 3 and 6 years; in neuroblastoma, one third of all cases are diagnosed in the first year of life, another third in the second and third year.
Table 1. Diagnoses of malignancies recorded in 4161 patients under 15, between 1980 and 1983. Data collected from the cooperative documentation of GPO and DAL by Institute for Medical Documentation and Statistics, University of Mainz (Prof. Dr. J. Michaelis and P. Kaatsch). Central nervous tumors are somewhat underrepresented in comparison to other documentations, which would lead us to expect a percentage of about 20. This may be due to the fact that children with brain tumors are often not treated or co-treated in pediatric clinics, but solely in departments of neurosurgery or radiotherapy not included in the cooperative documentation. Patients Leukemia Lymphoblastic Leukemia Non-lymphoblastic Leukemia Lymphomas Hodgkin's disease Malignant Non-Hodgkin-Iymphoma Histiocytoses CNS tumors Medulloblastoma Retinoblastoma Astrocytoma Ependymoma Craniopharyngeoma Others Neuroblastoma Nephroblastoma (Wilms' tumor) Bone tumors Osteosarcoma Ewing's sarcoma Cartilaginous tumors Soft tissue sarcomas Rhabdomyosarcoma Synovial sarcoma Others German cell tumors Teratoma Yellow sac tumor Others Hepatoblastoma Epithelial Neoplasms Others Sum
%
1577 1310 267 496 251 245 116
37.9 31.5 6.4 11.9 6.0 5.9 2.8
623 170 104 90 55 30 174 325 251 249 139 106 4 162 24 92
15.0 4.1 2.5 2.2 1.3 0.7 4.2 7.8 6.0 6.0 3.3 2.6 0.1 3.9 0.6 2.2
116 30 27 59 23 58 49
2.8 0.7 0.7 1.4 0.5 1.4 1.2
4161
100.0
Treatment principles Most tumors in childhood and most leukemias are strongly sensitive to cytostatic therapy. Consequently, chemotherapy occupies a high rank in the concepts of curative treatment for nearly all malignancies. In some instances it is the only, or at least the predominant therapeutic measure taken (as in leukemias, malignant lymphomas, and malignant histiocytosis); in others it is an essential part of combined strategies together with surgical and/or radiotherapeutic procedures. Within the overall concept of tumor management, surgery and radiotherapy achieve or attempt the local removal or destruction of the tumor mass, whereas chemotherapy is focused on the elimination of micro metastases that are present in lymph nodes and distant organs even at the time of diagnosis in many cases. Modern aggressive combination chemotherapy, however, exerting also a strong effect on the primary, can achieve a considerable reduction of the tumor mass in a rather high percentage of inoperable cases. In many of these, as in others where radical resection would have a severe multilating effect, initial chemotherapy may help to reduce the extent of surgery and the severity of its consequences. For instance, in rhabdomyosarcoma of the genitourinary region, exenteration of the minor pelvis is no longer advocated today 11, 2\ in certain localizations of osteosarcoma we may renounce amputation in favor of limb- preserving surgery19, 27. On principle, radical surgery is preferable whenever a tumor can be removed completely without grave multilations, and with a reasonably minor operative risk. Radiotherapy, too, may often be reduced in consequence of chemotherapeutic treatment. It can be omitted in cases with strictly localized tumors offering an approach for radical resection, such as Wilms' tumor 8, 16, neuroblastoma 3,7, rhabdomyosarcoma 11,2\ Ewing's sarcoma 13,17,20. In tumors at a more advanced stage, radiotherapy can be restricted, as compared with formerly common regimens, in terms of dosage and size of the irradiated field.
Prognosis In almost all childhood cancers prognosis could be substantially improved over the past 10 to 15 years. Not only in acute leukemia, but also in the majority of other malignancies, our foremost objective is no longer a limited stretching of the life span, but definitive cure, that is, tumorfree survival. Success, however, is of rather varying extent in different malignancies (Table 2). Using optimal modern therapy schedules, cure-rates are highest in Hodgkin's disease (90%), followed by Wilms' tumor, ALL, and non-Hodgkin lymphomas (70-75%). The next ranks are taken by the sarcomas of soft tissue and bone (about 50%). In acute myelogenous leukemia, neuroblastoma, and medulloblastoma, permanent cure is achieved today in about 30-35% of cases. Further improvement of prog-
What's New in pediatric Oncology? . 427 Table 2. Achievable cure rates in childhood malignancies, status 1984. The given percentages refer to the respective entire groups, including also the patients who die before onset of therapy, or who have metastases at the time of diagnosis References
Cure Rates
Hodgkin's disease Nephroblastoma Acute lymphoblastic leukemia Non-Hodgkin lymphomas
5,21 6,8 12,18 1,5
90% 75% 70% 70%
Osteosarcoma Rhabdomyosarcoma Ewing's sarcoma
19,26,27 11,24 13,17,20
55% 50% 50%
Acute myelogenous leukemia Neuroblastoma Medulloblastoma
22,25 3,7 4,14,23
35% 35% 30%
nosis may be expected over the next years in at least some tumors and leukemias. If we look back to the sixties when most of the diseases mentioned were still absolutely fatal, or curable in not more than a small minority of patients, current progress appears indeed remarkable. Our justified pride in rising cure rates, however, must never hide the fact that all the treatment procedures, due to their toxic side-effects and potential long-term consequences, are still full of problems and far from optimal. In fact, these problems are the greatest challenge to pediatric oncology for the future development of modes and strategies of therapy to consolidate the success achieved, but also to reduce the side-effects and long-term sequelae of radio- and chemotherapy. The treatment of childhood malignancies retains something of an experimental approach, and success is most likely to come from cooperative studies focused on the objectives described above.
Centralized Therapeutic Management In view of the relatively low case numbers of childhood tumors and leukemias, and especially of the complicated and highly specialized protocols of modern therapeutic strategies centralization of pediatric oncology in a limited number of clinics with experienced staff is indispensable. The extent of cure rates as well as the effective control of therapeutic risks, will depend essentially on the quality of therapeutic management and on the competence and experience of medical and nursing staff. Close interdisciplinary cooperation with other specialists within and outside the discipline of prediatrics is of the highest importance. In the FRG, the organization of centralized management for children with malignant diseases has attained a remarkable standard. About 75% of all new cases are treated in 20 clinics. Supraregional cooperation is organized by two societies: "Gesellschaft fur Padiatrische Onkologie" (GPO) (Society of Pediatric Oncology) and
"Deutsche Arbeitsgemeinschaft fur Leukamie-Forschung und -Behandlung im Kindesalter" (DAL) (German Work Group for Research and Treatment of Childhood Leukemia). The two societies run a joint central pathoanatomical registry of childhood tumors under the direction of D. Harms, Institute of Pathology of Kiel University9,10, and a cooperative project of documentation of childhood malignancies 14 • Numerous interdisciplinary work groups on different tumor types have been instituted to plan multicentric therapy studies, organize and monitor their impementation and evaluation, and update the protocols every few years. These activities resulted in effectively including most of the children with tumors or leukemias in the FRG (and partly Austria) in these national therapy studies. The benefits of centralized treatment are seen not only in the continuous collection of important research data for future therapeutic procedures, but also the practical improvement of patient care for children suffering from malignant diseases.
References 1 Anderson JR, Wilson JF, Jenkin RDT, Meadows AT, Kersey ], Chilcote RR, Coccia P, Exelby P, Kushner J, Siegel S, Hammond D (1983) Childhood Non-Hodgkin's Lymphoma, The Results of a Randomized Therapeutic Trial Comparing a 4-Drug Regimen (COMP) with a 10-Drug Regimen (LSAr L2). Eng J of Medicine 308: 559 2 Aurich G, Fuchs D, Herold HJ, Plenert W, Zintl F (1976) Untersuchungen zur Epidemiologie von malignen Tumoren, Systemerkrankungen und Leukiimien im Kindesalter. Arch Geschwulstforsch 46: 116-128 3 Berthold F, Treuner J, Brandeis WE, Evers G, Haas RJ, Harms D, Jurgens H, Kaatsch P, Michaelis J, Niethammer D, Prindull G, Riehm H, Winkler K, Lampert F (1982) Neuroblastomstudie NBL 79 der Gesellschaft fUr Piidiatrische Onkologie Zwischenbericht nach 2 Jahren. Klin Piidiat 194: 262-269 4 Bloom HJG, Thornton H, Schweisguth 0 (1982) SlOP medulloblastoma and high-grade ependymoma therapeutic clinical trial: preliminary results (1975-1981) In: Raybaud C, Clement R, Lebreuil G (Eds) Pediatric Onkology. Amsterdam Oxford - Princeton: Excerpta Medica International Congress Series Nr. 570, pp 309-322 5 Breu H, Schellong G, Grosch-Worner I, Jobke A, Riehm H, Ritter J, Treuner J, Schwarze EW, Wannenmacher M (1982) Abgestufte Chemotherapie und reduzierte Strahlendosis beim Morbus Hodgkin im Kindesalter - Ein Bericht uber 170 Patienten der kooperativen Therapiestudie HD 78. Klin Piidiat 194: 233-241 6 D'Angio GJ, Evans A, Breslow N, Beckwith B, Bishop H, Farewell V, Goodwin W, Leape L, Palmer N, Sinks L, Sutow W, Tefft M, Wolff J (1981) The Treatment of Wilms' Tumor; Results of the Second National Wilm's Tumor Study. Cancer 47: 2302-2311 7 Evans AE (1980) Staging and treatment of neuroblastoma. Cancer 45: 1799-1802 8 Gutjahr P (1981) Wilmstumoren - Eine Standortbestimmung. Klin Piidiat 193: 119-135 9 Harms D (1982) Pathologische Anatomie der soliden Tumoren des Kindesalters unter Berucksichtigung ihres biologischen Verhaltens. Pathologe 3: 66-76
428 . G. Schellong 10 Harms D, Gottschalk I, Hedderich J (1983) 5 Jahre zentrales Tumorregister bei der Gesellschah rur Piidiatrische Onkologie. The first five years of the central Tumor Registry of the (German) Society of Pediatric Oncology. Verh Dtsch Krebs Ges 4: 171-181, Gustav Fischer Verlag Stuttgart, New York 11 Hays DM (1980) The Management of Rhabdomyosarcoma in Children and Young Adults. World J Surg 4: 15-28 12 Henze G, Langermann H], Fengler R, Brandeis M, Evers KG, Gadner H, Hinderfeld L, Jobke A, Kornhuber B, Lampert F, Lasson U, Ludwig R, MiiIler-Weihrich S, Neidhardt M, Nessler G, Niethammer D, Rister M, Ritter J, Schaaff A, Schellong G, Stollmann B, Treuner J, Wahlen W, Weinel P, Wehinger H, Riehm H (1982) Therapiestudie BFM 79/81 zur Behandlung der akuten lymphoblastischen Leukiimie bei Kindern und Jugendlichen: intensivierte Reinduktionstherapie rur Patientengruppen mit unterschiedlichem Rezidivrisiko. Klin Piidiat 194: 195-203 13 Jiirgens H, Cserhati M, Gobel U, Gutjahr P, Jobke A, Kaatsch P, Kiihl J, Kotz R, Winkler K (1983) Die Kooperative Ewing-Sarkom-Studie CESS 81 der GPO: Zwischenbericht. Klin Piidiat 195: 207-213 14 Kaatsch P, Michaelis J (1983) Bericht iiber drei Jahre kooperative Dokumentation von Malignomen im Kindesalter. Technischer Bericht 1/83 des Institus fiir Medizinische Statistik und Dokumentation der Universitiit Mainz 15 MiilIer-Weihrich St, Beck J, Henze G, Jobke A, Kornhuber B, Lampert F, Ludwig R, Prindull G, Schellong G, Spaar HJ, Stoll mann B, Treuner J, Wahlen W, Weinel P, Riehm H (1984) BFM-Studie 1981/83 zur Behandlung hochmaligner Non-Hodgkin-Lymphome bei Kindern: Ergebnisse einer nach histologischimmunologischem Typ und Ausbreitungsstadium stratefizierten Therapie. Klin Piidiat 196: 135 16 Neidhardt M (1982) Die Behandlung des Medulloblastoms aus piidiatrisch-onkologischer Sicht. Strahlentherapie 158: 76 17 Razek A, Perez CA, Tefft M, Nesbit M, Vietti T, Burgert EO, Kissane J, Pritchard DJ, Gehan EA (1980) Intergroup Ewing's Sarcoma Study Local Control Related to Radiation Dose, Volume, and Site of Primary Lesion in Ewing's Sarcoma. Cancer 46: 516-521 18 Riehm H, Gadner H, Henze G, Kornhuber B, Langermann HJ, MiiIler-Weihrich St, Schellong G (1983) Acute Lymphoblastic Leukemia: Treatment Results in Three BFM Studies (1970-1981). In: Murphy SB, Gilbert JR (Eds) Leukemia Research: Advances in Cell Biology and Treatment. Elsevier Science Pub co Inc
19 Rosen G, Caparros B, Huvas AG, Kosloff C, Nierenberg A, Cacavio A, Marcove RC, Lane JM, Metha B, Urban C (1982) Preoperative Chemotherapy for Osteogenic Sarcoma: Selection of Postoperative Adjuvant Chemotherapy Based on the Response of the Primary Tumor to Preoperative Chemotherapy. Cancer 49: 1221-1230 20 Rosen G, Caparros B, Nierenberg A, Marcove RC, Huvas AG, Kosloff C, Lane], Murphy L (1981) Ewing-Sarcoma: TenYear Experience with Adjuvant Chemotherapy. Cancer 47: 2204-2213 21 Schellong G, Breu H, Grosch-Worner I, Jobke A, Lennert K, Riehm H, Ritter J, Treuner J, Schwarze EW, Wannenmacher M (1983) Morbus Hodgkin bei Kindern: Kombinierte Behandlungsstrategie mit abgestuher Chemotherapie und reduzierter Strahlendosis nach Staging-Laparotomie. Eine kooperative random isierte Studie. Verh Dtsch Krebsges Vol 4: 193-206 Gustav Fischer Verlag, Stuttgart - New York 22 Schellong G, Creutzig U, Ritter J (1984) Therapie der akuten myeloischen Leukiimie bei Kindern. In: Biichner Th, Urbanitz D, v. d. Loo J (Eds) Therapie der akuten Leukiimien. Springer Berlin, Heidelberg, New York, Tokio 23 Schweisguth 0 (1983) Solide Tumoren im Kindesalter. Ferdinand-Enke-Verlag Stuttgart, S. 218 24 Treuner J, Niethammer D (1984) Rhabdomyosarkom. In: Kornhuber B (Ed) Onkologie in der Piidiatrie 103-133 Thieme Verlag 25 Weinstein HJ, Mayer RJ, Rosenthal DS, Coral FS, Camitta BM, Gelber RD (1983) Chemotherapy for acute myelogenous leukemia in children and adults: VAPA up date. Blood 62: 315-319 26 Winkler K, Beron G, Schellong G, Stollmann B, Prindull G, Lasson U, Brandeis W, Henze G, Ritter J, Russe W, StengelRutkowski L, Treuner J, Landbeck G (1982) Kooperative Osteosarkomstudie COSS-77: Ergebnisse nach iiber 4 Jahren. Klin Piidiat 194: 251-256 27 Winkler K, Beron G, Kotz R, Salzer-Kuntschik M, Beck J, Beck W, Brandeis W, Ebell W, Erttmann R, Gobel U, Havers W, Henze G, Hinderfeld L, Hocker P, Jobke A, Jiirgens H, Kabisch H, Preusser P, Prindull G, Ramach W, Ritter J, Sekera J, Treuner J, Wiist G, Landbeck G (1984) Neoadjuvant chemotherapy for osteogenic sarcoma: results of a cooperative German/Austria study (COSS 80). J Clin One (in press) 28 YoungJL, Miller RW (1975) Incidence of malignant tumors in U. S. children. J Pediat 86: 254-258
Received March 23, 1984· Accepted April 9, 1984
Key words: Childhood malignancies - Leukemia - Therapy of childhood cancer Prof. Dr. G. Schellong, Universitiits-Kinderklinik, Robert-Koch-StrafSe 31, D-4400 Miinster, FRG
I
What's new in ...
What's New in Pediatric Oncology? Epidemiology, Treatment Principles and Prognosis in Childhood Malignancies G. Schellong* Childrens Hospital, University of Munster (Director: Prof. Dr. G. Schellong), Munster, FRG
SUMMARY
The proportion of malignancies in children differs from that in adults: Leukemias and malignant lymphomas predominate with a total of 50%, followed by tumors of the nervous system, of the kidneys, and of connective and supportive tissue. Most of these diseases respond well to cytostatic therapy. Therefore chemotherapy occupies a major role in the curative concepts for nearly all childhood malignancies. Its objective is the destruction of micrometastases as well as the reduction of primary tumor mass in inoperable cases, and it often helps to limit the extent of radical surgery. Radiotherapy, too, can be reduced under the influence of cytostatic therapy. In nearly all childhood cancers, prognosis has improved substantially over the past 10 to 15 years. Today, our aim is not the mere limited survival, but a definitive cure. Modern strategies have raised the cure rates of Hodgkin's disease to 90%, of Wilms' tumor, acute lymphoblastic leukemia and non- Hodgkin lymphomas to 70-75%, of soft tissue sarcomas and osteosarcomas to about 50%, and of acute myelogenous leukemia, neuroblastoma and medulloblastoma to 30-35%. Centralized management of childhood cancers in specially staffed hospitals is mandatory on account of their relative low frequency, the risks of chemotherapy, and the high staff workload.
Epidemiology Incidence rates of cancer are much lower in childhood than in adult life. According to statistical data from various countries the yearly rate of new cases is about 10 to 12.5 per 100000 children under 15 in white populations2,28. In the entire Federal Republic of Germany (FRG) some 11 00-1200 new cases of cancer are expected every year among the children under 15, which means an incidence rate of 11-12 per 100000. These data are derived from the Central Registry for Childhood Malignancies in * Dedicated to Prof. Dr. Dr. h.c. Franz Biichner in honor of his 90th birthday, Jan. 20, 1985. © 1985 by Gustav Fischer Verlag, Stuttgart
the FRG at the Institute for Medical Documentation and Statistics of the University of Mainz 14 • The male: female ratio is 1.26: 1; but the predominance of boys varies among different tumor types, being strongest in malignant lymphomas with a ratio of 1.6-2 : 1. Malignancies occurring in children differ principally from those found in adults with regard to type. Tumors of epithelial origin, i.e. carcinomas proper, are rarely observed. Predominant are leukemias, tumors of lymphatic or histiocytic origin (the so-called systemic diseases), and malignant tumors of nervous system, kidneys, bones, and connective tissue (socalled solid tumors), Table 1 presents a detailed listing of malignancies diagnosed in more than 4000 children in the FRG between 1980 and 1983 14 • 0344-0338/85/0179-0425$3.50/0
426 . G . Schellong
The vast majority of solid tumors originate in the prenatal phase and are therefore called embryonal neoplasms (such as neuroblastoma, nephroblastoma, medulloblastoma, retinoblastoma, rhabdomyosarcoma, germ cell tumors, hepatoblastoma). Accordingly, about 50% of tumors in childhood are diagnosed in the first four years of life. The exact age distribution, however, may show rather wide variations in the different types: Incidence rates of Hodgkin's disease and osteosarcoma rise with age; acute lymphoblastic leukemia has a peak between the ages of 3 and 6 years; in neuroblastoma, one third of all cases are diagnosed in the first year of life, another third in the second and third year.
Table 1. Diagnoses of malignancies recorded in 4161 patients under 15, between 1980 and 1983. Data collected from the cooperative documentation of GPO and DAL by Institute for Medical Documentation and Statistics, University of Mainz (Prof. Dr. J. Michaelis and P. Kaatsch). Central nervous tumors are somewhat underrepresented in comparison to other documentations, which would lead us to expect a percentage of about 20. This may be due to the fact that children with brain tumors are often not treated or co-treated in pediatric clinics, but solely in departments of neurosurgery or radiotherapy not included in the cooperative documentation. Patients Leukemia Lymphoblastic Leukemia Non-lymphoblastic Leukemia Lymphomas Hodgkin's disease Malignant Non-Hodgkin-Iymphoma Histiocytoses CNS tumors Medulloblastoma Retinoblastoma Astrocytoma Ependymoma Craniopharyngeoma Others Neuroblastoma Nephroblastoma (Wilms' tumor) Bone tumors Osteosarcoma Ewing's sarcoma Cartilaginous tumors Soft tissue sarcomas Rhabdomyosarcoma Synovial sarcoma Others German cell tumors Teratoma Yellow sac tumor Others Hepatoblastoma Epithelial Neoplasms Others Sum
%
1577 1310 267 496 251 245 116
37.9 31.5 6.4 11.9 6.0 5.9 2.8
623 170 104 90 55 30 174 325 251 249 139 106 4 162 24 92
15.0 4.1 2.5 2.2 1.3 0.7 4.2 7.8 6.0 6.0 3.3 2.6 0.1 3.9 0.6 2.2
116 30 27 59 23 58 49
2.8 0.7 0.7 1.4 0.5 1.4 1.2
4161
100.0
Treatment principles Most tumors in childhood and most leukemias are strongly sensitive to cytostatic therapy. Consequently, chemotherapy occupies a high rank in the concepts of curative treatment for nearly all malignancies. In some instances it is the only, or at least the predominant therapeutic measure taken (as in leukemias, malignant lymphomas, and malignant histiocytosis); in others it is an essential part of combined strategies together with surgical and/or radiotherapeutic procedures. Within the overall concept of tumor management, surgery and radiotherapy achieve or attempt the local removal or destruction of the tumor mass, whereas chemotherapy is focused on the elimination of micro metastases that are present in lymph nodes and distant organs even at the time of diagnosis in many cases. Modern aggressive combination chemotherapy, however, exerting also a strong effect on the primary, can achieve a considerable reduction of the tumor mass in a rather high percentage of inoperable cases. In many of these, as in others where radical resection would have a severe multilating effect, initial chemotherapy may help to reduce the extent of surgery and the severity of its consequences. For instance, in rhabdomyosarcoma of the genitourinary region, exenteration of the minor pelvis is no longer advocated today 11, 2\ in certain localizations of osteosarcoma we may renounce amputation in favor of limb- preserving surgery19, 27. On principle, radical surgery is preferable whenever a tumor can be removed completely without grave multilations, and with a reasonably minor operative risk. Radiotherapy, too, may often be reduced in consequence of chemotherapeutic treatment. It can be omitted in cases with strictly localized tumors offering an approach for radical resection, such as Wilms' tumor 8, 16, neuroblastoma 3,7, rhabdomyosarcoma 11,2\ Ewing's sarcoma 13,17,20. In tumors at a more advanced stage, radiotherapy can be restricted, as compared with formerly common regimens, in terms of dosage and size of the irradiated field.
Prognosis In almost all childhood cancers prognosis could be substantially improved over the past 10 to 15 years. Not only in acute leukemia, but also in the majority of other malignancies, our foremost objective is no longer a limited stretching of the life span, but definitive cure, that is, tumorfree survival. Success, however, is of rather varying extent in different malignancies (Table 2). Using optimal modern therapy schedules, cure-rates are highest in Hodgkin's disease (90%), followed by Wilms' tumor, ALL, and non-Hodgkin lymphomas (70-75%). The next ranks are taken by the sarcomas of soft tissue and bone (about 50%). In acute myelogenous leukemia, neuroblastoma, and medulloblastoma, permanent cure is achieved today in about 30-35% of cases. Further improvement of prog-
What's New in pediatric Oncology? . 427 Table 2. Achievable cure rates in childhood malignancies, status 1984. The given percentages refer to the respective entire groups, including also the patients who die before onset of therapy, or who have metastases at the time of diagnosis References
Cure Rates
Hodgkin's disease Nephroblastoma Acute lymphoblastic leukemia Non-Hodgkin lymphomas
5,21 6,8 12,18 1,5
90% 75% 70% 70%
Osteosarcoma Rhabdomyosarcoma Ewing's sarcoma
19,26,27 11,24 13,17,20
55% 50% 50%
Acute myelogenous leukemia Neuroblastoma Medulloblastoma
22,25 3,7 4,14,23
35% 35% 30%
nosis may be expected over the next years in at least some tumors and leukemias. If we look back to the sixties when most of the diseases mentioned were still absolutely fatal, or curable in not more than a small minority of patients, current progress appears indeed remarkable. Our justified pride in rising cure rates, however, must never hide the fact that all the treatment procedures, due to their toxic side-effects and potential long-term consequences, are still full of problems and far from optimal. In fact, these problems are the greatest challenge to pediatric oncology for the future development of modes and strategies of therapy to consolidate the success achieved, but also to reduce the side-effects and long-term sequelae of radio- and chemotherapy. The treatment of childhood malignancies retains something of an experimental approach, and success is most likely to come from cooperative studies focused on the objectives described above.
Centralized Therapeutic Management In view of the relatively low case numbers of childhood tumors and leukemias, and especially of the complicated and highly specialized protocols of modern therapeutic strategies centralization of pediatric oncology in a limited number of clinics with experienced staff is indispensable. The extent of cure rates as well as the effective control of therapeutic risks, will depend essentially on the quality of therapeutic management and on the competence and experience of medical and nursing staff. Close interdisciplinary cooperation with other specialists within and outside the discipline of prediatrics is of the highest importance. In the FRG, the organization of centralized management for children with malignant diseases has attained a remarkable standard. About 75% of all new cases are treated in 20 clinics. Supraregional cooperation is organized by two societies: "Gesellschaft fur Padiatrische Onkologie" (GPO) (Society of Pediatric Oncology) and
"Deutsche Arbeitsgemeinschaft fur Leukamie-Forschung und -Behandlung im Kindesalter" (DAL) (German Work Group for Research and Treatment of Childhood Leukemia). The two societies run a joint central pathoanatomical registry of childhood tumors under the direction of D. Harms, Institute of Pathology of Kiel University9,10, and a cooperative project of documentation of childhood malignancies 14 • Numerous interdisciplinary work groups on different tumor types have been instituted to plan multicentric therapy studies, organize and monitor their impementation and evaluation, and update the protocols every few years. These activities resulted in effectively including most of the children with tumors or leukemias in the FRG (and partly Austria) in these national therapy studies. The benefits of centralized treatment are seen not only in the continuous collection of important research data for future therapeutic procedures, but also the practical improvement of patient care for children suffering from malignant diseases.
References 1 Anderson JR, Wilson JF, Jenkin RDT, Meadows AT, Kersey ], Chilcote RR, Coccia P, Exelby P, Kushner J, Siegel S, Hammond D (1983) Childhood Non-Hodgkin's Lymphoma, The Results of a Randomized Therapeutic Trial Comparing a 4-Drug Regimen (COMP) with a 10-Drug Regimen (LSAr L2). Eng J of Medicine 308: 559 2 Aurich G, Fuchs D, Herold HJ, Plenert W, Zintl F (1976) Untersuchungen zur Epidemiologie von malignen Tumoren, Systemerkrankungen und Leukiimien im Kindesalter. Arch Geschwulstforsch 46: 116-128 3 Berthold F, Treuner J, Brandeis WE, Evers G, Haas RJ, Harms D, Jurgens H, Kaatsch P, Michaelis J, Niethammer D, Prindull G, Riehm H, Winkler K, Lampert F (1982) Neuroblastomstudie NBL 79 der Gesellschaft fUr Piidiatrische Onkologie Zwischenbericht nach 2 Jahren. Klin Piidiat 194: 262-269 4 Bloom HJG, Thornton H, Schweisguth 0 (1982) SlOP medulloblastoma and high-grade ependymoma therapeutic clinical trial: preliminary results (1975-1981) In: Raybaud C, Clement R, Lebreuil G (Eds) Pediatric Onkology. Amsterdam Oxford - Princeton: Excerpta Medica International Congress Series Nr. 570, pp 309-322 5 Breu H, Schellong G, Grosch-Worner I, Jobke A, Riehm H, Ritter J, Treuner J, Schwarze EW, Wannenmacher M (1982) Abgestufte Chemotherapie und reduzierte Strahlendosis beim Morbus Hodgkin im Kindesalter - Ein Bericht uber 170 Patienten der kooperativen Therapiestudie HD 78. Klin Piidiat 194: 233-241 6 D'Angio GJ, Evans A, Breslow N, Beckwith B, Bishop H, Farewell V, Goodwin W, Leape L, Palmer N, Sinks L, Sutow W, Tefft M, Wolff J (1981) The Treatment of Wilms' Tumor; Results of the Second National Wilm's Tumor Study. Cancer 47: 2302-2311 7 Evans AE (1980) Staging and treatment of neuroblastoma. Cancer 45: 1799-1802 8 Gutjahr P (1981) Wilmstumoren - Eine Standortbestimmung. Klin Piidiat 193: 119-135 9 Harms D (1982) Pathologische Anatomie der soliden Tumoren des Kindesalters unter Berucksichtigung ihres biologischen Verhaltens. Pathologe 3: 66-76
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Received March 23, 1984· Accepted April 9, 1984
Key words: Childhood malignancies - Leukemia - Therapy of childhood cancer Prof. Dr. G. Schellong, Universitiits-Kinderklinik, Robert-Koch-StrafSe 31, D-4400 Miinster, FRG