11 Treatment of children and adolescents with Hodgkin's disease: the experience of the German-Austrian Paediatric study group

Abstract

In treatment strategies adapted to the specific problems in children with Hodgkin's disease (HD) high priority has been given to the reduction of late effects caused by radio- and chemotherapy, without sacrificing high survival rates. Combined modality treatment, as a standard option, has enabled reduced doses and fields of radiotherapy and lower cumulative total doses of critical cytotoxic agents. In Germany and Austria 1242 children and adolescents with HD have been treated in five consecutive multicentre studies since 1978. The main general objectives were to determine the extent to which radio- and chemotherapy can be reduced within a combined modality treatment concept and to find an effective chemotherapy of low long-term toxicity. Mechlorethamine in MOPP was replaced by adriamycin (OPPA) in the first 2 cycles of CT and by cyclophosphamide (COPP) in the additional cycles. The total number of cycles was reduced for early and intermediate stages. From the second study (HD-82) onward, patients were allocated to three treatment groups (2, 4 or 6 cycles, respectively) according to disease stage, and involved-field instead of extended-field irradiation was given. With radiation doses of 35, 30 and 25 Gy, high rates for event-free survival (97, 92 and 85%, respectively) at 14 years were achieved, demonstrating that microfoci in adjacent fields are safely eradicated by the chemotherapy used. Late effects of OPPA and OPPA/COPP: the cumulative risk of secondary leukaemias in 686 patients after 15 years was 0.9% for all patients and 0.8% for those who remained in first remission. Cardiomyopathies have not been observed (cumulative total dose of adriamycin 160 mg/m2). Increased FSH-levels indicating impaired spermatogenesis were found in 40% of the male patients without relapse. The prevalence was related to the number of procarbazine containing cycles (29% after 2 cycles, 46% after 4, and 63% after 6). In study HD-90, procarbazine in OPPA was replaced by etoposide (OEPA) for the boys (cumulative dose 1000 mg/m2), whereas girls received OPPA again. In TGs 2 and 3, both boys and girls received an additional 2 or 4 COPP cycles. Standard doses of involved-field irradiation were reduced to 25, 25 and 20 Gy. The preliminary evaluation after nearly 5 years reveals that the reduction in radiation doses did not affect the results with OPPA and OPPA/COPP chemotherapy. In localized stages, 2 OEPA (boys) and 2 OPPA (girls) cycles produced identical results. An additional objective of the German-Austrian trials was to re-evaluate the relevance of exploratory laparotomy and splenectomy within a combined modality treatment concept for all patients. While all children were laparotomized and splenectomized in the first study, the frequency of splenectomy and laparotomy was reduced step by step on the basis of retrospective analyses of the study data regarding infra-diaphragmatic involvement. Splenectomy has been completely abandoned since 1990. In conclusion, the ratio of cure rates and late effects has been favourably balanced with OPPA and OPPA/COPP plus low-dose involved-field irradiation, especially in female patients. In boys, the risk of testicular dysfunction can be further reduced by substituting OEPA for OPPA. Age up to 18 years does not appear to bear any prognostic significance for the treatment results under the conditions of the therapy concept described.