[Differentiated treatment protocols for high- and standard-risk hepatoblastoma--an interim report of the German Liver Tumor Study HB99].
BACKGROUND
Tumor-free survival from hepatoblastoma could be improved to 75 % of all patients by combining surgery with chemotherapy. This figure reaches 90 % for potentially resectable (SR, standard risk) tumors. The outcome of high risk (HR) hepatoblastomas with multifocally disseminating growth in the liver, invasion of large vessels, extrahepatic extension and metastases is still poor, especially since these tumors often rapidly develop resistance against cytotoxic drugs. In the Study HB 99 of the German Society for Pediatric Oncology and Hematology, it is attempted to reach an improved regression and thereby a better prognosis with inauguration of high dose (HD) chemotherapy. This first interim analysis shall evaluate the preliminary results of this strategy.


METHODS
53 children with a hepatoblastoma have entered the study. 8 patients were excluded from this analysis because of different or not completed therapy. 10 SR-patients with a small tumor underwent a primary complete (stage I, n = 8) or microscopically incomplete (stage II, n = 2) resection. These received two courses of ifosfamide (3 g/m2), cisplatin (100 mg/m2), and doxorubicin (adriamycin, 60 mg/m2) (IPA). 26 patients with an extended, but potentially resectable tumor (stage III SR) were preoperatively treated with three courses of IPA, followed by a tumor resection and a 4th course of IPA. 9 patients with a HR-hepatoblastoma (3 x stage III HR, 6 x stage IV) were treated with two courses of carboplatin (800 mg/m2) and etoposide (400 mg/m2) (CARBO/VP16). In case of tumor response, they received one or two courses of HD-chemotherapy with carboplatin (2000 mg/m2) and etoposide (2000 mg/m2) after sampling of peripheral stem cells, followed by resection of the primary tumor and metastases, whenever possible. IPA therapy was administered in case of inadequate response to these drugs. The preliminary therapy results were analyzed in relation to the post-surgical stages (I-IV) and to the SIOPEL-PRETEXT (Pretreatment extend of disease) -grouping system (groups I-IV, V, P, E, M). Furthermore, the response of HR-hepatoblastoma to CARBO/VP16, the achieved resectability, and the acute toxicity were evaluated.


RESULTS
40 of 45 (89%) of all hepatoblastoma patients are in remission. 34/36 (94%) SR-patients (stage I - III-SR) are tumor-free, two died of therapy complications. 6 HR-patients are tumor-free, one alive with tumor and two died. In relation to the PRETEXT-grouping, a remission was achieved in 4/4 group I, 14/16 group II, 16/16 group III, 5/6 groups I-III, V, P, E, M, and 1/3 group IV tumors. 6/9 HR-hepatoblastomas were good responders to CARBO/VP16, 5 of these are in remission. 3/9 tumors did not respond, only one could be eradicated by a liver transplantation. In 5/9 HR-patients a R0-resection was possible after chemotherapy, in one a R1-resection, one received a liver transplant, and two tumors remained inoperable. In 4/6 cases lung metastases could be completely removed or, in one case, they had vanished in the CT-scan under chemotherapy. These 4 patients remained in remission. The most frequent severe toxicity of CARBO/VP16 concerned leucopenia (23% of courses) and thrombocytopenia (85% of courses). Under HD therapy severe infections (2/7, 28%) and elevation of transaminases occurred. There was no toxic death.


CONCLUSIONS
A cure rate of over 90% can be reached by conventional cisplatin and doxorubicin containing chemotherapy and radical surgery in SR-hepatoblastoma. 50-60% of all hepatoblastomas respond to CARBO/VP16. In these cases HD-therapy with these drugs is highly efficient and enables a remission in the majority of advanced and metastasised HR-hepatoblastoma. A larger number of patients and longer follow-up have to confirm these results. Therefore, the study will be continued.
Häberle
B
B
Kinderchirurgische Abteilung, Universitätskinderspital beider Basel, Switzerland.
Bode
U
U
von Schweinitz
D
D
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D007223:Infant; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D008297:Male; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging
D005047:Etoposide; D004317:Doxorubicin; D016190:Carboplatin; D002945:Cisplatin