title: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study.
abstract: BACKGROUND
  The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma.
  
  
  METHODS
  SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1-A3: cisplatin 80 mg/m(2) per day intravenous in 24 h on day 1; cisplatin 70 mg/m(2) per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m(2) per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m(2) per day in 24 h on days 1-3 and 22-24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m(2) per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389.
  
  
  RESULTS
  We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91-100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67-88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65-87) and 3-year overall survival was 83% (73-93). 60 (97%) patients had grade 3-4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients).
  
  
  CONCLUSIONS
  The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma.
  
  
  BACKGROUND
  Cancer Research UK and Cancer Research Switzerland/Oncosuisse.
authors.affiliation: Emma Children's Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. j.zsiros@amc.uva.nl
authors.forename: József
authors.initials: J
authors.lastname: Zsiros
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugieres
authors.forename: Penelope
authors.initials: P
authors.lastname: Brock
authors.forename: Derek
authors.initials: D
authors.lastname: Roebuck
authors.forename: Rudolf
authors.initials: R
authors.lastname: Maibach
authors.forename: Arthur
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Margaret
authors.initials: M
authors.lastname: Childs
authors.forename: Daniele
authors.initials: D
authors.lastname: Pariente
authors.forename: Veronique
authors.initials: V
authors.lastname: Laithier
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Otte
authors.forename: Sophie
authors.initials: S
authors.lastname: Branchereau
authors.forename: Daniel
authors.initials: D
authors.lastname: Aronson
authors.forename: Arun
authors.initials: A
authors.lastname: Rangaswami
authors.forename: Milind
authors.initials: M
authors.lastname: Ronghe
authors.forename: Michela
authors.initials: M
authors.lastname: Casanova
authors.forename: Michael
authors.initials: M
authors.lastname: Sullivan
authors.forename: Bruce
authors.initials: B
authors.lastname: Morland
authors.forename: Piotr
authors.initials: P
authors.lastname: Czauderna
authors.forename: Giorgio
authors.initials: G
authors.lastname: Perilongo
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006498:Hepatectomy; D018197:Hepatoblastoma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008175:Lung Neoplasms / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D004317:Doxorubicin; D002945:Cisplatin