Pediatric Hodgkin's disease: treatment in the late 1990s

For two decades now combined chemo-radiotherapy has been preferred in most of the studies on childhood Hodgkin's disease (HD), because combined modality is the precondition for (1) reducing the radiation dose, (2) reducing the radiation fields, (3) shortening chemotherapy, (4) omitting splenectomy and laparotomy, and thus, for optimizing the benefit/risk ratio between cure rates and late effects. Recently, the rationale for this approach was strengthened by worrisome data about the increasing incidence of secondary breast cancer in women treated for HD in childhood, adolescence or adult age < 30 years. Nearly all breast cancers were localized in the former radiation field, and the relative risk was much higher after doses > 40 Gy than after lower doses. These findings suggest that pediatric therapy approaches abandoning radiotherapy alone with its high doses and large fields should be extended to adolescents treated outside of pediatric studies and to adults younger than 30. The risk of chemotherapy-related secondary leukemias can be limited to < 1% by omitting mechlorethamine and restricting the cumulative doses of other drugs with leukemogenic potential, as demonstrated by the experience with ABVD and the recently published data of the German-Austrian pediatric group.

The updated results of the German-Austrian multicenter study HD-90 are presented in this paper (578 patients < 18 years, follow-up: median 4 years, maximum 7 years). Patients were allocated to three treatment groups (TG) according to disease stage. In all three TG, induction procarbazine, prednisone, adriamycin) for girls and two cycles of OEPA (etoposide instead of procarbazine) for boys. Patients of TG 2 and 3 additionally received two or four cycles of COPP (C, cyclophosphamide), respectively. CT was followed by radiotherapy to the involved sites (reduced fields if possible) of 25, 25 and 20 Gy in the 3 TG, respectively.

For the total group of 578 pats, overall survival (OS) at 5 years is 98% and event-free survival (EFS) 91%. In TG 1, EFS for girls (2 OPPA) is 96%, and for boys (OEPA), 94%, in TG 2 and 3 (combined), 92% and 86%, respectively. Secondary leukemias were not observed so far, thirty-one male patients of TG 1 who were tested endocrinologically showed normal FSH levels.

The especially high efficacy of OPPA and OPPA/COPP could be confirmed in study HD-90 with reduced radiation doses and fields. OEPA and OEPA/COPP CT also produced very favorable results, not significantly different from those with OPPA and OPPA/COPP. It may be anticipated that the ratio between cure rates and risks of late effects of study HD-90 will compare favorably to approaches of other groups. It would be useful for the future continued optimization of HD therapy to attain a rough consensus at an international level about principles which should be considered for pediatric approaches. Some proposals have been made for treatment of early stages.