Treatment of Hepatoblastoma
Treatment Options for Stages I and II
Hepatoblastoma of pure fetal histology: For tumors of pure fetal histology, complete surgical resection followed by watchful waiting or single-agent doxorubicin.
In the Children's Oncology Group (COG) study COG-P9645, stage I pure fetal histology hepatoblastomas with two or fewer mitoses per 10 high power fields were not treated with chemotherapy. Completely excised tumor of purely fetal and favorable histology may be carefully followed without further therapy. A small focus of undifferentiated small cell histology within an otherwise pure fetal histology tumor must be treated with aggressive chemotherapy.
Hepatoblastoma with non–pure fetal histology: Gross surgical excision followed by four courses of combination chemotherapy with cisplatin, vincristine, and fluorouracil or cisplatin and doxorubicin or cisplatin alone.[3-6]
Combination chemotherapy has been demonstrated to have significant benefit in children with hepatoblastoma. Cisplatin-based chemotherapy has resulted in a survival rate of greater than 90% for children with postsurgical stage I and stage II disease.[3-5,7]
A randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin, to which it was compared.
Treatment Options for Stage III
- Chemotherapy followed by reassessment of surgical resectability followed by complete surgical resection.
In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% will survive disease-free.
A North American randomized clinical trial demonstrated comparable efficacy with cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of hepatoblastoma. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/fluorouracil was significantly less toxic than the doses of cisplatin/doxorubicin used.
A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease. A regimen of intensified platinum therapy with alternating cisplatin and carboplatin was associated with a decrease in EFS.
- Chemotherapy followed by reassessment of surgical resectability. If the primary tumor remains unresectable, an orthotopic liver transplantation may be performed.
Patients whose tumors remain unresectable should be considered for liver transplantation.[5,11-15] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is desirable.
- An alternative treatment approach of transarterial chemoembolization for surgically unresectable disease.[17,18]
Treatment Options for Stage IV
- Chemotherapy followed by reassessment of surgical resectability. If possible, this is followed by surgical resection of primary tumor and extrahepatic disease. Additional chemotherapy will follow if the primary tumor was completely resected.
The standard regimen is four courses of cisplatin/vincristine/fluorouracil  or doxorubicin/cisplatin combination chemotherapy [5,19] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy should be given.
In a study employing a well-tolerated regimen of doxorubicin/cisplatin chemotherapy, about 50% of patients with metastases at presentation survived 5 years from diagnosis. Half of these survivors had developed progressive disease that was successfully treated with surgery and other interventions. In another study, platinum- and doxorubicin-based multidrug chemotherapy induced complete regression in approximately 50% of patients, with subsequent 3-year EFS of 56%. A prospective feasibility trial of dose-dense, cisplatin-based chemotherapy and radical surgery in 62 patients with high-risk hepatoblastoma (SIOPEL-4 [NCT00077389]) resulted in a 3-year EFS of 76% and 3-year OS of 83%.[Level of evidence: 3iiDi] In this study, of 37 patients with distant metastases, 27 (78%) were surviving disease free at 3 years.
Several studies have tested different chemotherapy regimens. A randomized clinical trial compared cisplatin/vincristine/fluorouracil with cisplatin/doxorubicin. Although outcome was nominally higher for children receiving cisplatin/doxorubicin, this difference was not statistically significant, and the combination of cisplatin/vincristine/fluorouracil was less toxic than the regimen of cisplatin/doxorubicin. The cisplatin/doxorubicin used in the international studies appears to be less toxic than that in the North American study. Addition of carboplatin to intensify the cisplatin/doxorubicin may have reduced its efficacy. A regimen of intensified platinum therapy with alternating cisplatin and carboplatin was associated with a decrease in EFS. A combination of ifosfamide, cisplatin, and doxorubicin has also been successfully used in the treatment of advanced-stage disease.
If possible, stage IV patients with resected primary tumor should have remaining pulmonary metastases surgically removed. A review of patients treated on a U.S. Intergroup trial suggested that resection may be done at the time of resection of the primary tumor.[Level of evidence: 3iiA]
- Chemotherapy followed by reassessment of surgical resectability. If extrahepatic disease is in complete remission and the primary tumor remains unresectable, an orthotopic liver transplantation may be performed. There are discrepant results on the outcomes for patients with lung metastases at diagnosis who undergo orthotopic liver transplantation following complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for this group of patients, while others have noted high rates of hepatoblastoma recurrence.[11,12,15,17] All of these studies are limited by small patient numbers; further study is needed to better define outcomes for this subset of patients.
- Chemotherapy followed by reassessment of surgical resectability. If extrahepatic disease is not resectable (post neoadjuvant chemotherapy), alternative treatment approaches may include the following:
- Nonstandard chemotherapy agents.
- Transarterial chemoembolization.
- Radiation therapy.
Patients whose extrahepatic tumors remain unresectable or who are not transplant candidates should be considered for alternative chemotherapy such as irinotecan,[23-25]; [Level of evidence: 3iiA] high-dose cisplatin/etoposide, continuous-infusion doxorubicin, radiation therapy,[3,27] or chemoembolization by hepatic arterial infusion.[18,28]
- Chemotherapy followed by radiation therapy followed by surgical re-exploration for patients in whom extrahepatic disease is controlled, but the primary tumor remains unresectable following treatment with standard chemotherapy regimens.
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
COG-AHEP0731 (Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Liver Cancer): Attempted complete surgical resection for all PRETEXT 1 tumors and those PRETEXT 2 tumors with greater than 1 cm radiographic margin on the middle hepatic vein, the retrohepatic inferior vena cava, or the portal bifurcation. Biopsy only of PRETEXT 2 tumors with less than 1 cm radiographic margin on the middle hepatic vein, the retrohepatic inferior vena cava, and the portal bifurcation.
- Stage I pure fetal histology with an alpha-fetoprotein (AFP) level greater than 100 ng/ml, non-small cell undifferentiated (very low risk): Resection and observation with no chemotherapy.
- Malogolowkin MH, Katzenstein HM, Meyers RL, et al.: Complete surgical resection is curative for children with hepatoblastoma with pure fetal histology: a report from the Children's Oncology Group. J Clin Oncol 29 (24): 3301-6, 2011. [PUBMED Abstract]
- Haas JE, Feusner JH, Finegold MJ: Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Cancer 92 (12): 3130-4, 2001. [PUBMED Abstract]
- Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993. [PUBMED Abstract]
- Perilongo G, Shafford E, Maibach R, et al.: Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2. Eur J Cancer 40 (3): 411-21, 2004. [PUBMED Abstract]
- Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000. [PUBMED Abstract]
- Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children's Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000. [PUBMED Abstract]
- Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991. [PUBMED Abstract]
- Reynolds M, Douglass EC, Finegold M, et al.: Chemotherapy can convert unresectable hepatoblastoma. J Pediatr Surg 27 (8): 1080-3; discussion 1083-4, 1992. [PUBMED Abstract]
- von Schweinitz D, Hecker H, Harms D, et al.: Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89. J Pediatr Surg 30 (6): 845-52, 1995. [PUBMED Abstract]
- Malogolowkin MH, Katzenstein H, Krailo MD, et al.: Intensified platinum therapy is an ineffective strategy for improving outcome in pediatric patients with advanced hepatoblastoma. J Clin Oncol 24 (18): 2879-84, 2006. [PUBMED Abstract]
- Reyes JD, Carr B, Dvorchik I, et al.: Liver transplantation and chemotherapy for hepatoblastoma and hepatocellular cancer in childhood and adolescence. J Pediatr 136 (6): 795-804, 2000. [PUBMED Abstract]
- Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004. [PUBMED Abstract]
- Molmenti EP, Wilkinson K, Molmenti H, et al.: Treatment of unresectable hepatoblastoma with liver transplantation in the pediatric population. Am J Transplant 2 (6): 535-8, 2002. [PUBMED Abstract]
- Czauderna P, Otte JB, Aronson DC, et al.: 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). Eur J Cancer 41 (7): 1031-6, 2005. [PUBMED Abstract]
- Austin MT, Leys CM, Feurer ID, et al.: Liver transplantation for childhood hepatic malignancy: a review of the United Network for Organ Sharing (UNOS) database. J Pediatr Surg 41 (1): 182-6, 2006. [PUBMED Abstract]
- D'Antiga L, Vallortigara F, Cillo U, et al.: Features predicting unresectability in hepatoblastoma. Cancer 110 (5): 1050-8, 2007. [PUBMED Abstract]
- Xianliang H, Jianhong L, Xuewu J, et al.: Cure of hepatoblastoma with transcatheter arterial chemoembolization. J Pediatr Hematol Oncol 26 (1): 60-3, 2004. [PUBMED Abstract]
- Malogolowkin MH, Stanley P, Steele DA, et al.: Feasibility and toxicity of chemoembolization for children with liver tumors. J Clin Oncol 18 (6): 1279-84, 2000. [PUBMED Abstract]
- Perilongo G, Brown J, Shafford E, et al.: Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors. Cancer 89 (8): 1845-53, 2000. [PUBMED Abstract]
- Zsíros J, Maibach R, Shafford E, et al.: Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study. J Clin Oncol 28 (15): 2584-90, 2010. [PUBMED Abstract]
- Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007. [PUBMED Abstract]
- Zsiros J, Brugieres L, Brock P, et al.: Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): a prospective, single-arm, feasibility study. Lancet Oncol 14 (9): 834-42, 2013. [PUBMED Abstract]
- Katzenstein HM, Rigsby C, Shaw PH, et al.: Novel therapeutic approaches in the treatment of children with hepatoblastoma. J Pediatr Hematol Oncol 24 (9): 751-5, 2002. [PUBMED Abstract]
- Palmer RD, Williams DM: Dramatic response of multiply relapsed hepatoblastoma to irinotecan (CPT-11). Med Pediatr Oncol 41 (1): 78-80, 2003. [PUBMED Abstract]
- Qayed M, Powell C, Morgan ER, et al.: Irinotecan as maintenance therapy in high-risk hepatoblastoma. Pediatr Blood Cancer 54 (5): 761-3, 2010. [PUBMED Abstract]
- Zsíros J, Brugières L, Brock P, et al.: 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). Eur J Cancer 48 (18): 3456-64, 2012. [PUBMED Abstract]
- Habrand JL, Nehme D, Kalifa C, et al.: Is there a place for radiation therapy in the management of hepatoblastomas and hepatocellular carcinomas in children? Int J Radiat Oncol Biol Phys 23 (3): 525-31, 1992. [PUBMED Abstract]
- Sue K, Ikeda K, Nakagawara A, et al.: Intrahepatic arterial injections of cisplatin-phosphatidylcholine-Lipiodol suspension in two unresectable hepatoblastoma cases. Med Pediatr Oncol 17 (6): 496-500, 1989. [PUBMED Abstract]