Hepatotoxicity in patients treated according to the nephroblastoma trial and study SIOP-9/GPOH

Background, A major problem far children receiving Wilms tumor (WT) chemoth erapy is hepatotoxicity, which may even be life-threatening. Dactinomycin ( AMD) has been shown to be an important factor, as has abdominal irradiation . Procedure. In the nephroblastoma trial and study SIOP-9 (SIOP-9) two diff erent regimens for the application of AMD were used (standard dose over 3-5 days vs. double dose on a single day). In children at increased risk for l ocal relapse,postoperative abdominal irradiation was given. We analyzed the influence of AMD and radiotherapy on the development of hepatotoxicity in 481 children treated in centers of the German Paediatric Oncology and Haema tology Society (GPOH). A special questionnaire was sent out for all patient s with reduced treatment or delay of more than 1 week because of hepatotoxi city. Because SIOP and the National Wilms Tumor Study (NWTS) used different criteria to asses hepatotoxicity,we applied both definitions. Results, All 72 cases of mild or severe hepatotoxicity occurred during treatment with A MD over 3-5 days with the standard dose (9.4-22.5 mu g/kg/week) compared to none in the group receiving a double dose on 1 day(3.75-8 mu g/kg/week; P < 0.001). Irradiation of the right abdomen, including parts of the liver, e nhanced liver toxicity significantly, with a relative risk (RR) of 2.6 (P < 0.003). Preoperative liver toxicity was more frequent in smaller children (P = 0.02) and especially if no dose reduction was done in children with bo dy weight of less than 12 kg (RR 5.3, P = 0.01). If severe liver toxicity w as defined according to NWTS criteria, 10% of ail treated patients were aff ected compared to 4.8% if McDonald's criteria for hepatic veno-occlusive di sease (VOD) were applied. Conclusions. To diminish the hepatotoxicity of WT treatment, AMD dose intensity should be reduced (below 10 mu g/kg per week ), especially in smaller children or when the liver is irradiated. (C) 1999 Wiley-Liss. Inc.