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Unlabelled: Patients with nephroblastoma have a high risk of relapse if they present with stage IV and anaplastic histology or with extraregional lymph node involvement; at time of relapse, bad prognosis is heralded by recurrence in an irradiated region, second or subsequent relapse, early first relapse (6 months after nephrectomy), relapse with adverse histology, relapse in two or more organ systems and lymph node or bone metastases at relapse. For such patients, an attempt to increase survival by high-dose chemotherapy seems to be justified. In 8 children aged 7.3 years (3.8-14.7) treated within the German Nephroblastoma Study SIOP9/GPOH, high dose chemotherapy with autologous hematopoietic rescue was instituted for the following reasons: stage IV with anaplastic histology and extra-regional lymph nodes (1), second or subsequent pulmonary relapse (3), early relapse with diffuse pleural (1) or skeletal (1) dissemination, recurrence in irradiated area (1) and lung metastases after early local relapse (1). At megatherapy, the patients were in first (1), second (2), third (2) and fourth complete (2) or in partial remission (1). The high dose regimen consisted of carboplatin, etoposide and melphalan. Treatment related toxicity, all non-lethal, included acute but reversible renal failure (1), esophagitis with need of parenteral nutrition for 6 months (1), cardiomyopathy (3; chronic in 1). After a follow-up of 2.1 years (0.5-3.7), 6/8 patients survive in complete remission; for 5 of them who are in remission since > 18 months a recurrence is unlikely. Both children with local relapse died after a further recurrence 3 and 8 months after high dose treatment., Conclusion: High dose consolidation with ASCR seems to effectively ameliorate the prognosis of patients with high risk nephroblastoma.

The therapeutic strategy of the SIOP-9 study includes pre-operative chemotherapy for all patients with nephroblastoma diagnosed by imaging methods aged between 0.5 and 16 years. By pre-operative chemotherapy the rate of radical resectable tumors should be increased and thereby the intensity of postoperative therapy, in particular of radiotherapy, diminished. Patients with nephroblastoma stage I-III were in case of tumorresponse randomised in either a 4 weeks or 8 weeks arm of pre-operative treatment with ACT D and VCR. The question was, if a prolongation of pre-operative chemotherapy could increase the relative part of stage I. Between 1/1/89 and 6/30/91 from 49 oncologic centres of former western Germany 188 patients were registered in the SIOP-9/GPO. From the stage I-III patients between 0.5 and 16 years 80.1% were pretreated with cytostatic agents. Only 53.9% of the patients with tumorresponse were randomised. The relative frequency of intraoperative ruptures was with 3% lower in the group of pretreated patients than in the primary operated (15.3%). The stage distribution for all Wilms' tumor patients showed a prevalence of stage I with 43.3% (after pre-operative treatment 59%; after primary operation 28%). Abdominal radiotherapy was performed in 22.4%. The event-free survival rate of all nephroblastoma lay at 85% 3 years after diagnosis (stage I standard 96%; unfavorable histology all stages 45%). 7.3% of the patients developed a hepatopathy under treatment and 7.8% even a VOD according to the criteria of McDonald.(ABSTRACT TRUNCATED AT 250 WORDS)

According to the international SIOP 9 study preoperative chemotherapy for patients between 6 months and 16 years old is a major component of the therapeutic management of Wilms' tumour. Prior to treatment, the diagnosis is established by diagnostic imaging alone, without biopsy. This study was therefore undertaken to verify the accuracy of diagnostic imaging in the German GPO study group. Between July 1988 and November 1990, 156 patients with known histology were registered in the study centre. Of these patients, 67% (105/156) received preoperative chemotherapy. The diagnosis was initially established by US, TVP and CT, and in some cases MRT without prior biopsy. Of these preoperatively treated patients, 92.4% (97/105) had Wilms' tumour or one of its variants. Five patients had a different malignant tumour. Three cases, i.e. 2.8% of the preoperatively treated patients or 1.9% of all registered patients with known histology, had benign tumours of the kidney. Morphologically, the Wilms' tumour was revealed by a characteristic inhomogeneity in sonography and the CT scan. The inhomogeneity in the CT scan increased following injection of contrast medium. Intratumoral bleeding and cystic areas were observed frequently in the native scan. Calcifications were seen in 5% of the cases. The predictive value of pretherapeutic diagnostic imaging was good enough to justify instituting chemotherapy without diagnostic biopsy. It is still difficult in diagnostic imaging to differentiate the very rare benign cystic nephroma from malignant nephroblastoma. Intravenous pyelography proved to be the best method for distinguishing extrarenal from renal tumours.

86 patients with Wilms' tumor were treated in Heidelberg between 1951 and 1980. Using the histopathologic grading according to Hardwick and Stowens the sarcomatous tumor type has an unfavorable prognosis. All the patients in stage III to V developed metastases. In contrast to other types of Wilms' tumor these sarcomatous tumors do metastasize to bones, not primarily to the lung. Boys up to 5 years are mostly affected by the tumor. These were "cold" lesions in bone scan using different radionuclides on skeletal osteolytic metastases, which is limiting the application of scans to detect bone metastases in Wilms' tumor. A more aggressive chemotherapy should be given to improve prognosis of the sarcomatous type of Wilms' tumor.

Unlabelled: It was the aim of the cooperative therapy study HD-82 for children with Hodgkin's disease to reduce chemo- and radiotherapy and to investigate of a strategy for selective splenectomy previously developed in the Hodgkin study HD-78. Between December 1981 and December 1984 207 patients (131 boys and 76 girls) below 16 years of age were enrolled in this study. In 174 out of 207 patients (84.1%) the criteria for selective splenectomy were applied i.e. the spleen was only removed when the splenic surface was nodular or when the lymphnodes at the splenic hilus and/or the pancreatic tail were enlarged. 69 out of 174 patients (39.7%) had a splenectomy. 50 of the removed 69 spleens (72%) showed histological evidence of Hodgkin's disease. These results were comparable to the 36% and 73% predicted from the retrospective analysis in the HD-78 study. According to the stage of Hodgkin's disease three different treatment groups with 2, 4 and 6 cycles of OPPA/COPP were formed (stage I/IIA, IIB/IIIA and IIIB/IV). Radiation therapy was given as involved field irradiation with a total dose of 35, 30 and 25 Gy depending on the extent of the chemotherapy. 203 patients were treated according to the protocol. Until the 30th of November 1985 3 patients died from intercurrent disease during a follow-up period of 11 to 47 months (median 29 months). 5 patients relapsed. The probability for disease-free survival after 3 1/2 years is 96% for the total group and 99%, 96% and 87% for the three treatment groups including 100, 53 and 50 patients in each group respectively., Conclusions: 1. The OPPA/COPP chemotherapy eliminates reliably occult microfoci. 2. The radiation doses in combination with the chemotherapy are sufficient to prevent local recurrences. 3. The decisional model for selective splenectomy has proved to be extremely valuable prospectively.

Local relapses in mediastinal non-Hodgkin's lymphomas in childhood are rare. Of the 15 children treated in our hospital during the last 11 years, 2 had early local or pleural relapses. At presentation both had extensive pleural effusions, and after completion of induction therapy still some fluid in the pleural space was present. A local irradiation was not performed initially. Be review of the literature for risks and benefit of local irradiation in mediastinal non-Hodgkin's lymphoma, local irradiation in children receiving aggressive chemotherapy should only be considered in few patients; preferentially in those, with incomplete disappearance of the mediastinal tumor or, as we may conclude from our patients, incomplete disappearance of pleural effusion.

An increasing number of children with acute leukemia show cerebral complications. 10 out of 78 children treated in our hospital for acute lymphoblastic leukemia or non-Hodgkin's lymphoma who underwent remission induction therapy or were in continuous complete remission developed central nervous system complications. During intensive initial therapy, intracerebral hemorrhages (2) and metabolic disturbances with concomitant cerebral convulsions (3) were seen. Unusual central-nervous infections occured in each treatment period (3). Cerebral degenerations could be observed only during the maintenance therapy (2). Cerebral convulsions were the leading symptom in 7 children. With intensive control of the coagulation system and the metabolic parameters central nervous system complications in the treatment of acute lymphoblastic leukemia should be reduced significantly.

The influence of fractionated cranial irradiation with 24 Gy on blood-CSF and blood-brain barrier permeability for methotrexate (MTX) and serum proteins was studied in young rabbits. In unirradiated control animals and 1, 4, 14 and 26 weeks following cranial irradiation MTX 57.5 mg/kg body weight was given by an infusion. 24 hours after the start of the MTX-infusion blood, CSF and brain was collected. MTX was measured by a radioimmunoassay, albumin and IgG by immunnephelometry. MTX in serum and brain tissue did not change significantly in the different groups before and after cranial irradiation. MTX in CSF was significantly higher 4 and 14 weeks following cranial irradiation compared to the unirradiated control group, demonstrating a significant blood-CSF barrier disturbance without blood-brain barrier disturbance. Increased MTX concentration were paralleled by significantly increased albumin concentrations in the CSF. IgG penetration across the blood-CSF barrier remained unchanged after irradiation.

In therapy study ALL-BFM 83 a total of 630 patients with acute lymphoblastic leukemia (ALL) have prospectively been evaluated for initial response on therapy with corticosteroids. It was the aim to qualify the in vivo cytoreduction as a new predictor for therapy failure. All patients were exposed for 7 days to prednisone before combination chemotherapy at day 8 has been started. At day 0 one additional dose of Methotrexate was given intrathecally. Therapy for all patients with non-B-ALL has been stratified according to initial tumor burden (risk factor) providing four therapy branches: standard risk low (SR-L), standard risk high (SR-H), medium risk (MR), high risk (HR). After a median duration of study of 21 months, event-free survival (EFS) is for all 630 patients 73%, 81% for SR-L, 76% for SR-H, 69% for MR, and 35% for HR patients (date of evaluation Jan. 1, 1987). In this prospective study, a small subgroup of patients (n = 48; 7.6% of total group) is characterized by greater than 1000 leukemic blasts/mm3 peripheral blood at day 8 after exposure to prednisone. In this subgroup the EFS is only 43% in contrast to 76% in the complementary group of 582 patients with less than 1000 leukemic blasts/mm3 peripheral blood at day 8. Patients of that risk group are derived from therapy branches SR-H, M and HR, the latter contributing relatively most patients. In this negatively selected group all patients with an initial high white blood count, CNS disease at diagnosis, immune subtypes as prae-T-ALL (n = 6), T-ALL (n = 18), null-ALL (n = 5), and males clearly dominate. Of 48 patients with greater than 1000 blasts/mm3 at day 8 4 subsequently failed to enter remission and 8 were qualified as lateresponders. 18 patients relapsed, most of them earlier compared to those of the complementary group. The initial in vivo response on corticosteroid therapy is considered a supplementary prognostic predictor for early failure. It will be utilized in trial ALL/NHL-BFM 86 to qualify patients at the highest risk for relapse. This group of patients is supplemented in addition by non- and lateresponders and children with acute undifferentiated leukemia (AUL). The in vivo corticosteroid test is simple, generates early and reliable results and can be obtained almost always. Thus it may be recommended for use in a multicenter trial.

It was the objective of the DAL study HD-85 to examine the possibility of a reduction of chemotherapy, compared to the study HD-82 which had applied a combined treatment strategy resulting in a relapse rate of only 2.5% after 4 years, and a proportion of intercurrent deaths of 1.5%, in a total of 203 patients. Procarbazine was eliminated in the OPPA-therapy (OPA) and replaced by methotrexate in the COPP-cycles (COMP). Chemotherapy consisted in 2 cycles of OPA for stage I/IIA (group 1), 2 cycles of OPA and 2 cycles of COMP for stage IIB/IIIA (including IEA/IIEA) (group 2), and 2 cycles of OPA and 4 cycles of COMP for stage IIIB/IV (group 3). The subsequent radiotherapy was limited to the initially involved fields, the dosage of 35, 30 or 25 Gy depending on the extent of chemotherapy. Regions showing incomplete tumor regression after chemotherapy received another 5 Gy, in patients of groups 2 and 3. Between Jan. 1985 to Nov. 1986, 103 children with Hodgkin's disease from 42 participating hospitals were enrolled in this study. 98 patients were treated according to protocol (59 boys, 39 girls). A specific strategy for the selective indication of laparotomy and splenectomy was applied. With this strategy no laparotomy was performed in 39/98 patients (40%). 67 patients (68%) retained their spleen. 4 patients showed progression of the disease under chemotherapy, all others achieved remission. 16 patients relapsed before Dec. 31, 1987. So far no child of this study has died.(ABSTRACT TRUNCATED AT 250 WORDS)

From 1970 to 1979, two subsequent BFM studies were performed with different modalities of systemic chemotherapy and preventive central nervous system (CNS) therapy. Eighteen out of 275 children experienced isolated CNS relapses within 2 years after diagnosis. The present analysis should clarify the following questions: 1. Could the risk for CNS relapse be assessed by initial diagnostic findings? 2. Is the CNS relapse rate influenced by more intensive systemic chemotherapy? 3. Is the CNS relapse rate altered by different doses of radiation therapy? The risk for relapse was assessed using a risk index (RI) based on findings at diagnosis. All patients were treated with an 8 weeks induction and consolidation chemotherapy protocol. In part, children with increased risk for relapse (RI greater than = 3) received an additional 6 weeks reinduction protocol within the first six months after diagnosis. Preventive treatment to the CNS consisted of radiotherapy at doses of less than = 18 Gy or 24 Gy and intrathecal methotrexate given during the consolidation phase. The results are as follows: 1. The RI proved to be predictive also for the risk of CNS relapse. However, CNS relapse rates were not substantially higher in children with RI greater than = 3 when they had been exposed to radiation doses of 24 Gy instead of less than = 18 Gy. 2. Intensive systemic reinduction therapy did not influence the CNS relapse rate in children with RI greater than = 3. 3. Three percent of children with RI less than = 2 experienced CNS relapses, irrespectively of lower or higher radiation doses. In patients with RI greater than = 3, however, irradiation at doses of less than = 18 Gy instead of 24 Gy led to a 3-4 fold higher incidence of CNS relapses, irrespectively of chemotherapy. We conclude that radiation doses of less than = 18 Gy are capable of preventing CNS relapses effectively in children with RI less than = 2. The exposure of patients with RI greater tha = 3 to doses of 24 Gy is justified.

Twelve children with their first relapse of acute lymphoblastic leukemia who had the same initial therapy were treated on an out-patient basis. After 28 days all entered second remission. Medium remission duration was 11 months. At the end of the study seven patients were in continuous complete remission. Of the twelve children seven suffered bone marrow, two meningeal, two testicular relapses and one a combined bone marrow and meningeal relapse. Side effects were compatible with an out-patient treatment.

Biclonal leukemia was diagnosed in an 8 months old girl, combining lymphoblastic (FAB L1) and monoblastic (FAB M 5) phenotypes which were classified as O-ALL and AMol by immunological examination of surface-antigens. Chemotherapy for one cell type resulted in predominance or relapse of the other one. Chromosomal abnormalities diagnosed in the lymphoblastic clone consisted of translocation t(11;19)(q23;p13) and triple X. The breakpoint 11q23 neighbouring one well known oncogene (ets) is not strictly associated with special leukemic phenotypes. But it is often found in infants and usually correlated with a poor prognosis. The data of 18 patients with hybrid leukemias registered in the BFM studies strongly support the fatal course of the disease. 12 months after diagnosis approximately 1 out of 10 children is expected to survive disease-free.

99 children with non-Hodgkin's lymphoma entered the prospective, multicenter BFM study 81/83. They were treated with a four-fold stratified therapy according to clinical stage and origin of the lymphoma from B- or non-B-lymphocytes. In the BFM study 75/81, these criteria had been proven to be most relevant for prognosis. Therapy of non-B-NHL was very similar to the therapeutic concept as applied in acute lymphoblastic leukemias by the BFM group. For the NHL of B-type, a new therapeutic regimen was developed. Cytostatic drugs applied in this group were: medium dose methotrexate, cyclophosphamide in a fractionated manner of application, adriamycin, cytarabine, VM 26 and prednisone. The probability of disease-free survival was 80% after nearly 3 years for all patients. In non-B-NHL it was 89% in localized, and 79% in disseminated disease. All patients with localized B-NHL are surviving without relapse, while the probability of disease-free survival in patients with disseminated B-NHL was 67%. Thus, the therapy result in the latter group was doubled as compared to the result of the BFM study 75/81.

In 1979/80 meta-iodobenzylguanidine (MIBG) was introduced as a radiopharmaceutical agent with high affinity to the adrenal medulla. It could be shown, that scintigraphic imaging with 131J labeled MIBG is a sensitive and highly specific method for localization of pheochromocytoma. In this connection we could demonstrate in 1983 that neuroblastoma can be visualized scintigraphically with MIBG as well. Until now 13 patients were examined with 131J-MIBG by our group: In 10 children with histologically proven neuroblastoma we found a specific enrichment in the tumor area. Besides the primary tumor local recurrence and metastases to bones, bone marrow and brain were detected. There was no neuroblastoma manifestation without MIBG uptake. In 3 patients with tumors other than neuroblastoma no uptake of MIBG was noticed. The results agree with those of other studies: If the physiological pattern of distribution is taken into consideration and if the proper imaging technique is adapted, 131J-MIBG scintigraphy is a highly sensitive and specific method for staging, monitoring of disease and follow-up of neuroblastoma.