HEPATOTOXICITY IN IRRADIATED NEPHROBLASTOMA PATIENTS DURING POSTOPERATIVE TREATMENT ACCORDING TO SIOP9/GPOH

This report describes liver toxicity in the risk group qualifying for combined postoperative irradiation and chemotherapy according to SIOP9/GPOH and diagnosed between January 1989 and June 1992 in hospitals participating in the GPOH studies (German Pediatric Oncology Hematology Group). Of 269 Wilms' tumor patients receiving postoperative treatment, 58 had abdominal irradiation (local SIOP, Stages II N+ and III standard histology [SH, n = 42]; and local Stages II and III, unfavorable histology [UH, n=16]). Age was between 6 months and 22 years. Parallel to abdominal irradiation the patients were treated with polychemotherapy of differing combination depending on surgical stage and histology. All of them received actinomycin D (ACT D) and vincristine. However, ACT D was given according to protocol for standard histology Stage II and III in a dose of 15 mu g/kg on 5 consecutive days and as single injection of 30 mu g/kg in Stage IV standard and in unfavorable histology. For 37/58 children the major part (> 50%) of the liver was within the irradiation portals and 28/37 had whole liver irradiation. Doses ranged between 12 and 22.5 Gy and in 9 children parts of the liver received additional irradiation up to a total of 30 Gy. Eleven of 58 children (18%) developed hepatotoxicity and 4 of them veno-occlusive disease (VOD). Liver toxicity in irradiated patients occurred at a median of 6.5 weeks after start of postoperative treatment. The rate of toxicity was 4/14 versus 7/23 in patients receiving > 20 versus <20 Gy to the major part of the liver. However, all cases with VOD had been irradiated with doses >20 Gy. No patient (0/13) with single dose versus 11/24 with ACT D on 5 consecutive days developed liver toxicity. Further analysis of treatment compliance revealed that in 7 of the 11 patients with hepatotoxicity protocol deviations resulting in omission of ACT D reduction during the first course after radiotherapy were present. Postoperative irradiation combined with polychemotherapy leads to an increased probability of hepatotoxicity in Wilms' tumor patients, if major parts of the liver are included. However, type, timing and dosage of chemotherapy have been major risk factors in the combined treatment.