The balance between cure and late effects in childhood Hodgkin's lymphoma: The experience of the German-Austrian Study-Group since 1978

Abstract

Background : For more than 20 years now treatment strategies geared to the specific problems in children with Hodgkin's disease (HD) have been tested by different pediatric oncologic groups. In these approaches high priority was given to the reduction of late effects caused by radio- and chemotherapy, next to the goal of achieving high survival rates. Combined modality treatment as a standard option has enabled reduced dosages and fields of radiotherapy and lowered cumulative total doses of critical cytotoxic agents. Methods : In Germany and Austria more than 1.200 children and adolescents with HD have been treated in 5 consecutive multicenter studies since 1978. The main general objectives were to determine the extent to which radio- and chemotherapy can be reduced within a combined treatment concept and to find an effective chemotherapy (CT) of low long-term toxicity. Nitrogen-mustard 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 3 treatment groups (2, 4, 6 cycles, respectively) according to disease stage, and involved-field irradiation (IFI) was given instead of extended-field irradiation (EFI). Results : In study HD-82 standard doses of IFI in the 3 treatment groups (TG) after 2, 4, or 6 cycles of CT were 35, 30, or 25 Gy. In a total of 203 patients probabilities for event-free survival (pEFS) and survival (pSV) were 95% and 93% at 13 years. In the 3 TG pEFS was 97%, 92% and 85%. In an international study (SIOP-HD IV-87) 65 stage IV patients were treated according to the TG 3 schedule of HD-82(2 OPPA, 4 COPP, 20 Gy IFI). After 7 years pEFS is 77% and pSV 93%. Late effects of OPPA respectively, OPPA/COPP: The cumulative risk for secondary leukemias after 10 years is 0.5% for all patients and 0.3% for those who remained in first remission. Cardiomyopathies have not been observed (cumulative total dose of adriamycin 160 mg/m ² ). Increased FSH-levels indicating impaired spermatogenesis were found in 40% of the male patients without relapse. The frequency 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 1.000 mg/m ² ), whereas girls received OPPA again. In TG2 and 3, both boys and girls received COPP. Standard doses of IFI were reduced to 25, 25, and 20 Gy. The preliminary evaluation after nearly 5 years reveals that the reduction of radiation doses did not impair the results after OPPA and OPPA/COPP. In localized stages 2 OEPA (boys) and 2 OPPA (girls) produced the same results. In the 15–18 years age group compared to the younger patients identical values for pEFS were achieved. Conclusions : The ratio between cure rates and late effects has been favourably balanced with OPPA, respectively, OPPA/COPP plus low-dose IFI, 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 be of any significance for the treatment results with our therapy concept.