Risk-adapted treatment for childhood hepatoblastoma

Abstract

SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors (‘standard-risk (SR) HB’), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread ‘high-risk (HR) HB’. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m² every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m², and doxorubicin (DOXO), 60 mg/m². Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80–96%) and 78% (95% CI 65–87%), and resection rates were 97% (95% CI 87–99%) and 67% (95% CI 54–79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (±7%) and 89% (±7%) and for the HR-HB group 53% (±13%) and 48% (±13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO (‘PLADO') combination are now being compared in a prospective randomised trial (SIOPEL 3).

Introduction

SIOPEL 1, the first prospective international clinical trial on childhood hepatoblastoma (HB), run by the Childhood Liver Tumor Strategy Group of the International Society of Pediatric Oncology (SIOPEL), aimed inter alia to investigate the prognostic significance of several pretreatment characteristics, both of patients and of their tumours 1, 2, 3. In SIOPEL 1, there was no stratification by clinical and histological characteristics and all patients received similar therapy. The treatment strategy in SIOPEL 1 used preoperative chemotherapy, with a combination of cisplatin (CDDP) and doxorubicin (DOXO) (the ‘PLADO’ regimen), then delayed resection of the primary tumour. Before treatment, both the extent of intrahepatic disease, as defined by the pretreatment extension of disease (PRETEXT) system (see below), and the presence of lung metastases were identified as prognostic factors for 5-year event-free survival (EFS), but in multivariate analysis the PRETEXT category was the only statistically significant prognostic factor for 5-year overall survival (OS) [1]. Based on these findings, the SIOPEL group decided, for the subsequent SIOPEL 2 trial, to stratify treatment according to the intrahepatic extent of the disease (as expressed by the PRETEXT system) and the presence of lung metastases. More precisely, we decided to investigate whether intensification of therapy would improve the prognosis of those children affected by HB involving all four hepatic sectors (PRETEXT IV) and/or those with metastases and if it would be possible to reduce therapy, without jeopardising the overall outcome, in those patients whose tumour was completely confined to the liver and involved, at most, three hepatic sectors. The first group of HB were designated ‘high-risk’ (HR) tumours and the second ‘standard-risk’ (SR) tumours. Within the HR group, patients with intra-abdominal extension of the tumour beyond the liver were also included, even though there was no definite evidence that these factors worsened prognosis.

Concerns about the short- and long-term cardiotoxicity of DOXO, as well as the belief that CDDP is probably the most effective drug for HB 4, 5, motivated us to investigate whether SR-HB patients could be cured with a treatment strategy based on surgery and CDDP alone (CDDP ‘monotherapy’). For HR-HB patients, it was decided to intensify the treatment by adding carboplatin (CARBO) to the PLADO regimen using the three drugs in a rapidly alternating sequence. Data indicating that CARBO had some activity in HB were available at the time the study was launched 6, 7.

The relatively high proportion (70%) of patients with SR-HB in SIOPEL 1 meant that it was possible to conduct a prospective randomised trial of the efficacy of treatment with surgery and CDDP versus that of surgery and PLADO. However, before launching this trial, a pilot study was deemed essential (i) to substantiate existing data on the efficacy of CDDP monotherapy, (ii) to alleviate concerns about treating this malignancy with just one agent, and (iii) to investigate the toxicity of the proposed rapid (every 15 days) schedule for administering CDDP. By contrast, the cohort of HR-HB patients is smaller (30%) and randomised controlled trials more difficult to mount, and a cohort study was designed instead. In summary, SIOPEL 2 was a pilot study whose principal aims were to investigate the efficacy and toxicity of two new therapeutic strategies: (i) a regimen based on CDDP monotherapy and surgery directed at a selected cohort of HB with favourable presenting features, and (ii) an intensified multi-agent regimen directed at a group of HB with unfavourable clinical characteristics. The trial should also provide data to help determine whether the notion of clustering patients into two ‘risk groups’ was valid and helpful.