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.

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.

Figure 1

Treatment design of the SIOPEL-4 study C*=cisplatin 80 mg/m² per day intravenous infusion in 24 h; on day 1 in cycle A1. C=cisplatin 70 mg/m² per day intravenous infusion in 24 h; on days 8, 15, 29, 36, 43, 57, and 64 in cycles A1–A3. D=doxorubicin 30 mg/m² per day intravenous infusion in 24 h; on days 8, 9, 36, 37, 57, and 58 in cycles A1–A3. D*=doxorubicin 25 mg/m² per day intravenous infusion in 24 h; on days 1, 2, 3, 22, 23, and 24 in cycle B. D**=doxorubicin 20 mg/m² per day intravenous infusion in 24 h; on days 1, 2, 22, 23, 43, and 44 in cycle C. CA*=carboplatin area under the curve (AUC) 10·6 mg/mL per min per day intravenous infusion in 1 h; on days 1 and 22 in cycle B. CA**=carboplatin AUC 6·6 mg/mL per min per day intravenous infusion in 1 h; on days 1, 22, and 43 in cycle C. Filled circle=assessment of response. Empty circle=assessment of response and resectability.

Figure 2

Enrolment, treatment, and outcome of patients *Withdrawn after second preoperative chemotherapy cycle (A2) because of grade 3 ototoxicity. † One toxic death, one death due to tumour rupture. ‡Withdrawn after third preoperative chemotherapy cycle (A3) with partial response. §Unresectable because of multiple lung lesions, no surgery attempted.

Figure 3

Kaplan-Meier estimates of (A) event-free and (B) overall survival for the whole study population Dotted lines show 95% CIs.