Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma.

BACKGROUND: Preoperative cisplatin alone may be as effective as cisplatin plus doxorubicin in standard-risk hepatoblastoma (a tumor involving three or fewer sectors of the liver that is associated with an alpha-fetoprotein level of >100 ng per milliliter). METHODS: Children with standard-risk hepatoblastoma who were younger than 16 years of age were eligible for inclusion in the study. After they received one cycle of cisplatin (80 mg per square meter of body-surface area per 24 hours), we randomly assigned patients to receive cisplatin (every 14 days) or cisplatin plus doxorubicin administered in three preoperative cycles and two postoperative cycles. The primary outcome was the rate of complete resection, and the trial was powered to test the noninferiority of cisplatin alone (<10% difference in the rate of complete resection). RESULTS: Between June 1998 and December 2006, 126 patients were randomly assigned to receive cisplatin and 129 were randomly assigned to receive cisplatin plus doxorubicin. The rate of complete resection was 95% in the cisplatin-alone group and 93% in the cisplatin-doxorubicin group in the intention-to-treat analysis (difference, 1.4%; 95% confidence interval [CI], -4.1 to 7.0); these rates were 99% and 95%, respectively, in the per-protocol analysis. Three-year event-free survival and overall survival were, respectively, 83% (95% CI, 77 to 90) and 95% (95% CI, 91 to 99) in the cisplatin group, and 85% (95% CI, 79 to 92) and 93% (95% CI, 88 to 98) in the cisplatin-doxorubicin group (median follow-up, 46 months). Acute grade 3 or 4 adverse events were more frequent with combination therapy (74.4% vs. 20.6%). CONCLUSIONS: As compared with cisplatin plus doxorubicin, cisplatin monotherapy achieved similar rates of complete resection and survival among children with standard-risk hepatoblastoma. Doxorubicin can be safely omitted from the treatment of standard-risk hepatoblastoma. (ClinicalTrials.gov number, NCT00003912.)

Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study.

PURPOSE: Preoperative staging (pretreatment extent of disease [PRETEXT]) was developed for the first prospective liver tumor study by the International Society of Pediatric Oncology (SIOPEL-1 study; preoperative chemotherapy and delayed surgery). Study aims were to analyze the accuracy and interobserver agreement of PRETEXT and to compare the predictive impact of three currently used staging systems. PATIENTS AND METHODS: Hepatoblastoma (HB) patients younger than 16 years who underwent surgical resection (128 of 154 patients) were analyzed. The centrally reviewed preoperative staging was compared with postoperative pathology (accuracy) in 91 patients (81%), and the local center staging was compared with the central review (interobserver agreement) in 97 patients (86%), using the agreement beyond change method (weighted kappa). The predictive values of the three staging systems were compared in 110 patients (97%) using survival curves and Cox proportional hazard ratio estimates. RESULTS: Preoperative PRETEXT staging compared with pathology was correct in 51%, overstaged in 37%, and understaged in 12% of patients (weighted kappa = 0.44; 95% CI, 0.26 to 0.62). The weighted kappa value of the interobserver agreement was 0.76 (95% CI, 0.64 to 0.88). The Children's Cancer Study Group/Pediatric Oncology Group-based staging system showed no predictive value for survival (P = .516), but the tumor-node-metastasis-based system and PRETEXT system showed good predictive values (P = .0021 and P = .0006, respectively). PRETEXT seemed to be superior in the statistical fit. CONCLUSION: PRETEXT has moderate accuracy with a tendency to overstage patients, shows good interobserver agreement (reproducibility), shows superior predictive value for survival, offers the opportunity to monitor the effect of preoperative therapy, and can also be applied in patients who have not had operations. For comparability reasons, we recommend that all HB patients included in trials also be staged according to PRETEXT.

Treatment of unresectable and metastatic hepatoblastoma: a pediatric oncology group phase II study.

PURPOSE: To estimate the disease-response rate, proportion of patients whose tumors can be made resectable, event-free survival (EFS), and toxicity in children with unresectable or metastatic hepatoblastoma (HB) after sequential treatment with the following: (1) carboplatin (CARBO); (2) CARBO, vincristine, and fluorouracil (CARBO-VCR-5-FU); and (3) high-dose cisplatin and etoposide (HDDP-ETOP). PATIENTS AND METHODS: Thirty-three assessable patients with stage III (n = 22) and stage IV (n = 11) HB were treated sequentially with one course of CARBO (700 mg/m(2)), followed by three courses of CARBO (700 mg/m(2)), day 0; 5-FU (1,000 mg/m(2)/d), by continuous infusion days 0 to 2; and VCR (1.5 mg/m(2)), days 0, 7, and 14. After that therapy, patients whose tumors were resectable underwent surgery and then received two additional courses of CARBO-VCR-5-FU. Children whose tumors remained unresectable after CARBO-VCR-5-FU or who demonstrated no response or progressive disease during this therapy received two courses of HDDP (40 mg/m(2)/d), days 1 to 5; and ETOP (100 mg/m(2)/d), days 2 to 4. RESULTS: Five-year EFS estimates were 59% +/- 11% for stage III disease (n = 22) and 27% +/- 16% for stage IV disease (n = 11), respectively (P =.037). Twenty-seven (82%) of 33 patients had at least a partial response to chemotherapy; 18 (55%) of 33 responded to CARBO; 24 (80%) of 30 responded to CARBO and CARBO-VCR-5-FU; and nine (75%) of 12 responded to HDDP-ETOP. Surgical resection was achieved in 19 (58%) of 33 patients, including 15 (68%) of 22 stage III patients and four (36%) of 11 stage IV patients. Five-year EFS for patients whose tumors were completely resected was 79% +/- 10%. CONCLUSION: Patients treated sequentially with CARBO, CARBO-VCR-5-FU, and HDDP-ETOP had response rates and EFS comparable to other therapeutic regimens. This regimen is effective in treating localized, unresectable HB and potentially has less toxicity than other regimens. Novel approaches are needed for patients with metastatic disease.

Guidelines for surgical treatment of hepatoblastoma in the modern era--recommendations from the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL).

Cisplatin-containing chemotherapy and complete surgical resection are both crucial in the cure of hepatoblastoma. Radical resection can be obtained either conventionally by partial hepatectomy or with orthotopic liver transplant, but the surgical approach to hepatoblastoma differs considerably across the world. Our main aim in this paper is to present the surgical recommendations of the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL), as well as to stimulate international debate on this issue. We discuss biopsy, verification of resectability, resection principles, indications and potential contraindications for orthotopic liver transplant, as well as thoracic surgery for pulmonary metastases. We suggest that heroic liver resections with a high probability of leaving residual tumour should be avoided whenever possible. In such cases primary orthotopic liver transplant should be considered. Superior survival rates in hepatoblastoma patients who have received a primary transplant after a good response to chemotherapy support the strategy of avoiding partial hepatectomy in cases where radical resection appears difficult and doubtful. We recommend early referral to a transplant surgeon in cases of: (i) multifocal or large solitary PRETEXT IV (PRE Treatment EXTent of disease scoring system) hepatoblastoma involving all four sectors of the liver and (ii) unifocal, centrally located tumours involving main hilar structures or main hepatic veins. Because complete tumour resection is a prerequisite for cure, any strategy leading to an increased resection rate will result in improved survival. We advise the more frequent use of orthotopic liver transplant, as well as the standardisation of techniques for partial liver resection. These guidelines should not be seen as final, but rather as a starting point for further discussion between the various national and international liver tumour study groups.

Prognostic stratification for children with hepatoblastoma: the SIOPEL experience.

PURPOSE: To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. PATIENTS AND METHODS: Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). RESULTS: In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP ≥ 1.2 × 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 × 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%. CONCLUSION: Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Efficacy of irinotecan single drug treatment in children with refractory or recurrent hepatoblastoma--a phase II trial of the childhood liver tumour strategy group (SIOPEL).

PURPOSE: To assess the clinical activity of irinotecan as single drug in children with refractory or recurrent hepatoblastoma. PATIENTS AND METHODS: Four cycles of irinotecan were administered (20mg/m(2)/day intravenous (i.v.) infusion on days 1-5 and 8-12, every 21days) unless tumour progression occurred or resectability was achieved earlier. Tumour response was assessed according to modified SIOPEL and Response Evaluation Criteria In Solid Tumours (RECIST) criteria. Main end-points were best overall response rate (RR), early progression rate (EPR) and progression free survival (PFS). RESULTS: Twenty-four eligible patients (median age 58.0months; 19 boys) were enrolled in the study (11 relapses, 13 refractory diseases). Of the 23 evaluable patients six had an overall partial response, 11 stable disease and six progressive disease, of which four were early progression (RR: 26%, EPR: 17%). In eight patients the residual tumour could be completely resected; seven patients became tumour free. At last follow-up 12 patients were alive (six with no evidence of disease, six with disease). PFS at 1year was 24%. Patients with relapse had a higher RR than patients with refractory disease (46% versus 8%) and patients with isolated lung lesions showed a better response than patients with other tumour localisations (50% versus 13%). The main grade 3-4 toxicities, diarrhoea and neutropenia, occurred in half of the patients. CONCLUSION: Irinotecan has a significant anti-tumour activity and acceptable toxicity in patients with relapsed hepatoblastoma and therefore should be considered for the treatment of these patients. Exploration of the role of irinotecan in the initial treatment of hepatoblastoma is warranted.

Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study.

PURPOSE: The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. PATIENTS AND METHODS: High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. RESULTS: Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. CONCLUSION: The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.

2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group.

Over the last 15 years, various oncology groups throughout the world have used the PRETEXT system for staging malignant primary liver tumours of childhood. This paper, written by members of the radiology and surgery committees of the International Childhood Liver Tumor Strategy Group (SIOPEL), presents various clarifications and revisions to the original PRETEXT system.

Surgical treatment of hepatoblastoma in children.

Hepatoblastoma is the most common liver malignancy in children. With rare exceptions, complete tumour resection is required to cure the patient. Radical tumour resection can be obtained either with standard partial hepatectomy or orthotopic liver transplantation. At present, the surgical approach to hepatoblastoma differs significantly between treatment groups in different parts of the world. Our aim was to review current surgical policy in hepatoblastoma. All aspects of surgery in hepatoblastoma are discussed, including biopsy, tumour resection principles, modern achievements in the field of liver surgery, and the indications and potential contraindications for liver transplantation. Every effort should be made to resect hepatoblastoma completely either by standard partial hepatectomy or by the use of liver transplantation in difficult or clearly unresectable cases.

Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group.

BACKGROUND: Surgical resection is the cornerstone of treatment for patients with hepatoblastoma (HB). The Society of Pediatric Oncology Liver Tumor Study Group launched its first prospective trial (SIOPEL-1) with the intention to treat all patients with preoperative chemotherapy and delayed surgical resection. The objective of this article was to assess the assumed surgical advantages of primary chemotherapy. METHODS: Between 1990 and 1994, 154 patients age < 16 years with HB were registered on SIOPEL-1. The pretreatment extent of disease was assessed, and, after undergoing biopsy, patients were treated with cisplatin 80 mg/m(2) intravenously over 24 hours and doxorubicin 60 mg/m(2) intravenously over 48 hours by continuous infusion (PLADO). Generally, tumors were resected after four of a total of six courses of PLADO. RESULTS: One hundred twenty eight patients underwent surgical resection (13 patients underwent primary surgery, and 115 patients underwent delayed surgery after PLADO). A pretreatment surgical biopsy was performed in 96 of 128 patients (75%). Biopsy complications occurred in 7 of 96 patients (7%). Twenty-two patients showed pulmonary metastases at the time of diagnosis, and 7 patients underwent thoracotomy. Operative morbidity and mortality were 18% and 5%, respectively. Complete macroscopic surgical resection was achieved in 106 patients (92%), including 6 patients who underwent orthotopic liver transplantation. The actuarial 5-year event free survival (EFS) rate for all 154 patients in the study was 66%, and the overall survival (OS) rate was 75%. For the 115 patients who were included in the surgical analysis that followed the exact protocol, the EFS and OS rates were 75% and 85%, respectively. CONCLUSIONS: Biopsy is a safe procedure and should be performed routinely. Preoperative chemotherapy seems to make tumor resection easier. Reresection of a positive resection margin does not necessarily have to be performed, because postoperative chemotherapy showed good results. Resection of lung metastases can be curative if there is local control of the primary tumor; however, results showed that the patient's prognosis was worse. Surgical morbidity or mortality rates were not necessarily higher in large multicenter studies. More importantly, countries of lesser economic status also can contribute effectively to these trials.