Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study

József Zsiros, Laurence Brugieres, Penelope Brock, Derek Roebuck, Rudolf Maibach, Arthur Zimmermann, Margaret Childs, Daniele Pariente, Veronique Laithier, Jean Bernard Otte, Sophie Branchereau, Daniel Aronson, Arun Rangaswami, Milind Ronghe, Michela Casanova, Michael Sullivan, Bruce Morland, Piotr Czauderna, Giorgio Perilongo

Research output: Contribution to journalArticle

92 Citations (Scopus)

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/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 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/m2 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/m2 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. Findings: 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). Interpretation: The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding: Cancer Research UK and Cancer Research Switzerland/Oncosuisse.

Original languageEnglish
Pages (from-to)834-842
Number of pages9
JournalThe Lancet Oncology
Volume14
Issue number9
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Hepatoblastoma
Feasibility Studies
Cisplatin
Drug Therapy
Neoplasms
Doxorubicin
Carboplatin
Neutropenia
Area Under Curve
Therapeutics
Metastasectomy
Fetal Proteins
Febrile Neutropenia
Mucositis
Intention to Treat Analysis
Mycoses
Anorexia
Hepatectomy
Switzerland
Vascular Diseases

ASJC Scopus subject areas

  • Oncology

Cite this

Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4) : A prospective, single-arm, feasibility study. / Zsiros, József; Brugieres, Laurence; Brock, Penelope; Roebuck, Derek; Maibach, Rudolf; Zimmermann, Arthur; Childs, Margaret; Pariente, Daniele; Laithier, Veronique; Otte, Jean Bernard; Branchereau, Sophie; Aronson, Daniel; Rangaswami, Arun; Ronghe, Milind; Casanova, Michela; Sullivan, Michael; Morland, Bruce; Czauderna, Piotr; Perilongo, Giorgio.

In: The Lancet Oncology, Vol. 14, No. 9, 08.2013, p. 834-842.

Research output: Contribution to journalArticle

Zsiros, J, Brugieres, L, Brock, P, Roebuck, D, Maibach, R, Zimmermann, A, Childs, M, Pariente, D, Laithier, V, Otte, JB, Branchereau, S, Aronson, D, Rangaswami, A, Ronghe, M, Casanova, M, Sullivan, M, Morland, B, Czauderna, P & Perilongo, G 2013, 'Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study', The Lancet Oncology, vol. 14, no. 9, pp. 834-842. https://doi.org/10.1016/S1470-2045(13)70272-9
Zsiros, József ; Brugieres, Laurence ; Brock, Penelope ; Roebuck, Derek ; Maibach, Rudolf ; Zimmermann, Arthur ; Childs, Margaret ; Pariente, Daniele ; Laithier, Veronique ; Otte, Jean Bernard ; Branchereau, Sophie ; Aronson, Daniel ; Rangaswami, Arun ; Ronghe, Milind ; Casanova, Michela ; Sullivan, Michael ; Morland, Bruce ; Czauderna, Piotr ; Perilongo, Giorgio. / Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4) : A prospective, single-arm, feasibility study. In: The Lancet Oncology. 2013 ; Vol. 14, No. 9. pp. 834-842.
@article{e94ef7cdb709430aae0a6cda05ca9b0c,
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/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 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/m2 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/m2 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. Findings: 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). Interpretation: The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding: Cancer Research UK and Cancer Research Switzerland/Oncosuisse.",
author = "J{\'o}zsef Zsiros and Laurence Brugieres and Penelope Brock and Derek Roebuck and Rudolf Maibach and Arthur Zimmermann and Margaret Childs and Daniele Pariente and Veronique Laithier and Otte, {Jean Bernard} and Sophie Branchereau and Daniel Aronson and Arun Rangaswami and Milind Ronghe and Michela Casanova and Michael Sullivan and Bruce Morland and Piotr Czauderna and Giorgio Perilongo",
year = "2013",
month = "8",
doi = "10.1016/S1470-2045(13)70272-9",
language = "English",
volume = "14",
pages = "834--842",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "9",

}

TY - JOUR

T1 - Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4)

T2 - A prospective, single-arm, feasibility study

AU - Zsiros, József

AU - Brugieres, Laurence

AU - Brock, Penelope

AU - Roebuck, Derek

AU - Maibach, Rudolf

AU - Zimmermann, Arthur

AU - Childs, Margaret

AU - Pariente, Daniele

AU - Laithier, Veronique

AU - Otte, Jean Bernard

AU - Branchereau, Sophie

AU - Aronson, Daniel

AU - Rangaswami, Arun

AU - Ronghe, Milind

AU - Casanova, Michela

AU - Sullivan, Michael

AU - Morland, Bruce

AU - Czauderna, Piotr

AU - Perilongo, Giorgio

PY - 2013/8

Y1 - 2013/8

N2 - 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/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 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/m2 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/m2 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. Findings: 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). Interpretation: The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding: Cancer Research UK and Cancer Research Switzerland/Oncosuisse.

AB - 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/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 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/m2 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/m2 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. Findings: 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). Interpretation: The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding: Cancer Research UK and Cancer Research Switzerland/Oncosuisse.

UR - http://www.scopus.com/inward/record.url?scp=84880844862&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880844862&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(13)70272-9

DO - 10.1016/S1470-2045(13)70272-9

M3 - Article

C2 - 23831416

AN - SCOPUS:84880844862

VL - 14

SP - 834

EP - 842

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 9

ER -